So on behalf of Novartis, just want to welcome you all to our R&D Day here in London, and also to say a big thank you for making the time for all of you to come here and participate, and for everybody else who's on the web. So thank you. Before we start, the safe harbor statement. The information presented today contains forward-looking statements that involve known and unknown risks, uncertainties, and other factors. These may cause the actual results to be materially different from any future results, performance, or achievements expressed or implied by such statements. For a description of some of these factors, please refer to the company's Form 20-F and its most recent quarterly results on Form 6-K that respectively were filed with and furnished to the U.S. Securities and Exchange Commission. I think for the people who are here, they've got a printout of all the deck slides, and people on the web also can find it on the Novartis website. The agenda is a fairly packed agenda. We're going to begin with Novartis strategy and growth update from Vas, then have the Novartis Research and Development overview from Fiona and Shreeram. We'll then break for a Q&A panel, and then we go after a longer break for coffee and refreshments, we'll then go into the deep dive into the three main therapeutic areas, and we'll also touch upon neuroscience. So that's cardiovascular, renal, and metabolic immunology. We'll cover neuroscience, and then we'll finish off with oncology. We've allowed plenty of time for coffee and refreshments, so you'll have a chance to mingle and ask additional questions during the coffee break to the speakers. The speakers are listed on this slide four. Vas, obviously, CEO. Harry, CFO. Fiona and Shreeram, Head of Biomedical Research and Global Product Development and Chief Medical Officer. Angelika, who's Head of Development, Head of Immunology. Dave, Development Head of Cardiorenal Metabolic. Jeff, Development Head of Oncology, and Norman's here as well, with Development Head of Neuroscience and Gene Therapy. And with that, I'll hand across to Vas. Thank you. All right. Well, thank you all for joining today. We're really grateful for the time and look forward to giving you an update both on how the company's overall strategic outlook is looking, as well as to give you some insights into the R&D pipeline as Shreeram outlined. And you'll have time to ask each one of our development heads questions along the way. I'm going to focus my comments on the financial outlook overall big picture strategy before handing it over to Fiona and Shreeram to go into more detail on the R&D portfolio. Now, we believe Novartis today offers investors a differentiated profile for the short, medium, and long term, and presents an attractive shareholder value creation opportunity. We have a focused strategy that we've implemented over the recent years with four core therapeutic areas and two plus three technology platforms. We'll be coming back to that repeatedly over the course. Upgraded, and I'll go through some of the details behind that, a 5% CAGR with 40% margin. And we believe in the longer term, our ability to consistently deliver mid-single-digit sales growth. We've also seen over the recent years, very consistent, strong performance with respect to cash generation, sales, and core operating growth. And lastly, we've worked hard over the last five years to become a leader in material ESG factors, as reflected in various rankings now. We believe we're on solid footing with respect to ESG. Now, you've all tracked well over the recent decade, how Novartis has transformed from a relatively broadly diversified healthcare company in 2014, moving systematically over the course of years, course of the years today to a pureplay innovative medicines company. What that's been able to deliver, I think, is an attractive shift in our overall financial outlook and financial profile. Our margin expansion has been significant, moving from 26% to 36.9%. Our group free cash flow, these are nine-month numbers, CHF 6.8 billion-CHF 11 billion. As a percent of sales, 15.6%-32.4%. And as we've outlined, we expect these trends to continue as we continue our our march towards the 40% margin in 2027. We've also been able to, as we've made those changes, deliver strong operating performance. 7% sales growth, 2018-2022, 14 core operating income growth, 2018-2022, and then the 790 basis points of margin expansion. These are all continuing operations, innovative medicines numbers. So I think it nicely shows that as a pure play company, we know how to do this well. We can deliver consistently over time, and we have the right financial profile, we think, for investors in the long run. Now, we rolled out last time we met together a focus strategy, which we remain committed to. It's around focus and therapeutic areas, technology platforms, but also geography, where we've elevated the U.S., and that's allowed us to really focus on our U.S. launches, as well as ensuring we fully resource Japan, China, which has become an important growth driver, as well as Germany. And we have our priorities to accelerate growth and drive those returns, strengthen our foundations, including the cultural transformation at the company, and be relentless about driving operational excellence inside the organization. And we're also committed to our approach to capital allocation. You saw this slide from Harry at the quarter. We continue to invest in the core internal business, $45 billion of R&D over the 2018-2023 period. Value creating bolt-ons, and I'll say more about that in a moment. A consistent growing annual dividend that we did not rebase post either the Alcon or the Sandoz spin. I think supporting the powerful cash generation that we have at the company, and a steady approach to share buybacks, over $30 billion in share buybacks, and we announced a new $15 billion share buyback, which we commenced in July 2023. So finding ways to return capital to our shareholders. Along the way, we of course focused the group, and you know the actions we took well. Now, from a deal-making standpoint, our focus remains on bolt-on, M&A, and BD&L, typically below the $5 billion range. We, of course, evaluate all deal options, but you can see here we're very intent and intentional now at looking at each one of our core therapeutic areas and asking: Can we either deepen the pipeline like we did with Chinook, or can we build out new capabilities like we did with DTx, with the potential to target siRNAs into the central nervous system? That's the approach we're taking, taking a much tighter lens, trying not to do deals that take us too far afield away from the focus areas that we've outlined. Now, I mentioned earlier, and you saw in our press release, we are raising our guidance for the five-year period, both for in terms of the sales CAGR and maintaining the 40%+ margin guidance, which includes absorbing corporate costs. So along the way, as we shifted the profile of the company, we're fully absorbing the historical corporate costs with a single margin for the organization, and believing we can deliver 40%+ in 2027. And I'd like to walk you through, in the next few slides, the dynamics that led us to make this guidance increase. So one, we continue to see strong momentum in our growth drivers. When you net out the Xiidra divestment, which we closed in September, we have seen really strong performance this year as a focused organization on our key growth drivers. Kisqali showing very strong performance in the metastatic setting, but also now with the opportunity to move and expand into the adjuvant setting, and we'll, of course, be talking quite a bit about that later today. Pluvicto with a very strong uptake in its first full year on the market, with potential now to expand significantly in earlier lines. Cosentyx seeing a very solid launch trajectory in the US and now expanding ex-US, where we're seeing very solid uptake of the medicine. That's given us confidence that we can get to that 5% with these medicines in our hands. And it's also worth noting when you take a broader look at the portfolio, the majority of the assets that drive that 5% growth are de-risked. We do have GX impact in the period. We continue to model Entresto with a mid-2025 LOE for modeling purposes. Tasigna and Promacta also go LOE in the period. But then we have Kisqali, Pluvicto, Cosentyx, Leqvio, Cosentyx, Scemblix, all with the ability to give us that lift to overcome the generics and the generic entries and drive the dynamic growth that we expect. And we maintain in this view a probabilized pipeline view. Iptacopan, remibrutinib, atrasentan, pelacarsen all are probabilized when we give you these 5%—this 5% outlook, and it'll certainly be our ambition to fully realize both the approvals and ultimately the launches of these assets to drive even more dynamic growth in the period. Now, importantly, today will be as much about that 5-year period as it is that the period beyond 2027, where we believe we can drive mid-single-digit growth consistently over time. That belief is underpinned first and foremost by the de-risked in-market brands and the pipeline and the LCM extensions, which we'll talk about over the course of the day, but also a broad range of pipeline assets, which we expect to be able to file in the 2022-2027 period, and then with additional filings thereafter. We'll go through many of these assets over the course of the day. Our ability to deliver that consistent mid-stage pipeline delivery will be what enables us to deliver those 2027 and beyond growth numbers. Now, I did want to walk through some of our peak sales guidance. We did make some shifts on the peak sales guidance from what we've historically told you. I'll walk through this in a bit of detail, because this will be our opportunity to address some of the commercial topics during the day. Entresto, we continue to see very strong dynamics in the U.S., in Europe, but importantly now with hypertension and heart failure in China and Japan. That allows us to raise our peak sales guidance, even with our current LOE assumption, to $7 billion now for Entresto. With Cosentyx, we're maintaining our $7 billion dollar peak sales guidance, and the two real important drivers now we are seeing for Cosentyx growth are both the launch of the IV indication in the United States, where we see strong uptake, as well as the hidradenitis suppurativa launch around the world, where we've been able to maintain a clean label relative to our peers, and we think this is going to be also an important opportunity for the brand. We, of course, have other life cycle management beyond that, and we have a slide later in the document, to go over with you. Kesimpta, dynamic growth. Our big opportunity here is to grow with the B-cell class, as the B-cell class grows around the world, but also to continue to try to gain share. We have the ambition to get to 50% B-cell class share. That is something that will take us time, but if we can get there, that will enable Kesimpta to well exceed a $4 billion peak sales goal. Now, with Kisqali, we are performing extremely well coming out of the ASCO data last year in 2022 in the metastatic setting. We're now approaching 50% NBRX share in the U.S. in the metastatic, and then also in a market leadership in multiple markets in Europe. That allows us to give you now guidance on the metastatic setting of $4 billion, and of course, we'll separately talk about the adjuvant setting in a moment. Then lastly, Pluvicto and Leqvio, we maintain our multi-billion-dollar guidance. For Pluvicto, this is in the VISION population. We can guide now that we expect in VISION, we have multi-billion-dollar potential. And with Leqvio, while the launch has been slow, we are now starting to see traction in the U.S. and Europe, but also now importantly in China and soon to be launched in Japan, which gives us confidence we're on the mid- to long-term trajectory we want to be on for Leqvio. Now, what's exciting, I think, is the opportunity to expand further. I already mentioned Kesimpta and Cosentyx, but with Kisqali, the multi-billion-dollar potential of the adjuvant setting. With Pluvicto, multiple earlier line studies, importantly, PSMAfore, PSMA ddition, as well as an additional study in the oligometastatic setting, which Jeff will talk about later today. And then with Leqvio, we have the opportunity with the outcome studies that we will read out through 2026, 2027, and 2028 to give this brand a broader data opportunity, as well as to expand into primary prevention. Now, just saying a high level word, because you'll hear this multiple times throughout the day, but our thinking in each one of our therapeutic areas is to be very, very clear about the diseases we want to go after and making sure we have alignment in research, development, and commercial on those diseases. If we want to enter or exit a disease, that's a company decision, and that's really a shift from where Novartis was historically, where we had a lot more dispersion into the decision-making on which diseases to play in. We have anchor brands in each one of those therapeutic areas, which gives us the commercial and development and medical affairs capabilities to be confident we can launch future products in the space. And then lastly, we have assets which we've already shown you now with submissions in the 2027 time frame to enable us to continue to build that therapeutic area strength for the long run. Now, these assets, as well as you'll hear over the course of the day, over the course of the day, have significant sales potential. I won't go through it here, but I think the real point being that we believe in these assets, and we believe they have significant potential. Some of them are relatively new to the portfolio. Atrasentan, we added through the Chinook. Lutathera was not one we were expecting with a post, a top-line data readout, which we gave you with full data in Q1. We're excited about the potential of Lutathera, and then, of course, other brands that you know well, and we'll talk about today. I do wanna highlight three opportunities we believe that at least have the potential in the mid to long run, to give us the opportunity to have more breakout growth, if they ultimately deliver their scientific potential. Fiona will go through in detail the power of radioligand therapies, where we think the therapeutic index of managing the safety with a high-efficacy cancer medicine allows us to go after a range of solid tumors, and you'll see the breadth of the pipeline later today. CAR-T in immunology is an exciting space, very early, a lot to be proven, but if the potential of achieving a B-cell reset in these very severe immunological patients and allows us to go across the full range, this is a very exciting opportunity with potential to really deliver deep remissions for these patients. And then certainly with siRNAs, where we have a position with Leqvio, we've done a number of deals. We believe both in neuroscience and cardiovascular disease, we have the opportunity to expand over time to infrequently administered high-efficacy medicines. I did want to say a word about our manufacturing transformation. We've not talked a lot about it, but it's been, I think, a real success story in the company. We've moved from, especially with the spin of Sandoz, a network of 70 sites down to 30 sites. It's much more streamlined, and it has really unique capabilities. We're the largest producer, at least have the capacity to be the largest producer of cell and gene therapies. We are the largest producer of radioligand therapies, the largest producer of siRNAs. We have a scaled capability in each one of these advanced technology platforms, and we've delivered strong quality and compliance performance over these years. This also has allowed us to build a bespoke CMO business, which really targets, really, I think, some of these unique technologies and leverage our manufacturing capabilities to deliver, supply to other companies. In closing, I did want to say again, a word about our building trust with society efforts. I hope many of you got a chance to, participate in our ESG Investor Day or members of your firms. We continue to think hard about what are the material factors that matter for a company like Novartis. We work hard to think about how we're gonna mitigate those risks systematically, and then we always try to tie it back to the value creation in the company. And now, as I mentioned, you see us typically at the higher end of the rankings or at the top of the rankings as a firm. I think that shows that we're doing the right things. It's obviously a long battle that we need to fight in many of these areas, but that's one we're very, very committed to. So in closing, before handing the baton off, I did wanna come back to where I started. I hope I've given you the case that we have as a focus company with a focus strategy, clear and attractive growth prospects in the next five years and beyond, and that's the conviction we want to give you over the course of the day. The proof that we've delivered strong returns and have the ambition to continue that performance and the ESG leadership that we've delivered. So with that, I'll actually hand it over to Shreeram, and I look forward to taking your questions over the course of the day. Thank you very much! Thanks, Vas. Good afternoon. As Vas pointed out, the purpose of our company is to deliver transformative medicines in areas of major unmet need in the therapeutic areas that we choose to focus on. In this session, I, along with my colleague, Fiona Marshall, plan to share with you our overarching R&D strategy, the rationale behind why we have picked the therapeutic areas that we have chosen to work on, how we deploy our platforms in the service of the indications in those focused therapeutic areas, and how we work together to ensure that we're delivering on R&D productivity. Over the past 18 months, what has been very gratifying to see as we all work together, is that all of our development plans fundamentally pay attention to what evidence is going to be required for success in order to secure approval, access, and rapid adoption into clinical practice in the four geographic areas that we choose to focus on. At the heart of our ambition at Novartis are our people, who bring deep expertise in the areas that they specialize in, and a relentless attention to the purpose that we seek to work on. At this point in time, our clinical portfolio has 103 programs, starting from phase I, of which 83 are in areas of specific, high unmet medical need that we choose to prioritize and are in confirmatory development. We have more than 15 submissions coming up in the coming 3 years via these programs. While we've been industry leaders in having delivered the largest number of new molecular entities being approved by the FDA over the past years, we are now equally focused on the value that we provide from this pipeline to patients as well as shareholders. Looking at what it has done, what has it meant for us to focus on these 4 therapeutic areas that we chose to focus on? So cardiovascular, renal, and metabolic, immunology, neuroscience, and oncology. We picked therapeutic areas that we have had a long presence in and have had the full range of functional capabilities across the organization in research, development, and the commercial organization to allow us to be the ones that are able to work in those areas with focus. Having streamlined our portfolio over the past, since we last got together in 2021, by over 30%, while maintaining our R&D spend, it has allowed us to now invest all the resources necessary to ensure that those programs that we choose to focus on are executed with excellence, with no compromises on the actions needed to deliver value. It also allows us to keep building compounding capabilities on the areas that we choose to work in at all levels, and we believe that those compounding capabilities translate into better judgment and better decision-making that then has a greater likelihood of delivering success for our pipeline. Let me now take you at a high level through the rationale for our strategies in each of the therapeutic areas that we have chosen to work in. In cardiovascular, renal, and metabolic, the core diseases we choose to focus on include heart failure and hypertension. We've been in that space for a very long time. We've taken on the mandate of addressing atherosclerotic cardiovascular disease, which remains a significant area of unmet need, and we have chosen to then pursue our options into renal diseases, starting with glomerular diseases on the back of Iptacopan. A fundamental premise of our cardiovascular strategy to reduce CV risks is the premise that the main reason that we have not been successful in lowering cardiovascular risk as successfully as we could have been, is because patients do not take medicines that lower either their LDL or manage their blood pressure when they happen to be oral medications that are taken on a daily basis. On the back of inclisiran, we have successfully shown that an infrequently administered product, twice a year, with sustained reductions in LDL, has the potential to meaningfully transform cardiovascular outcomes, and those trials are now ongoing. You will see that theme play out in the details when we get to the therapeutic area later. In heart failure, we aim to further improve outcomes by targeting new mechanisms of action, like direct agonism of NPR1. On renal, Dave Soergel, my RDO head for cardiovascular, renal, and metabolic, will go through the details of how we have built upon iptacopan and then acquired additional assets to target complex glomerular diseases that lead to end-stage renal disease. And we opportunistically explore areas like atrial fibrillation that are at a very early stage in a preclinical setting with a focus on rhythm control. In immunology, building upon our success with Cosentyx, where the focus now, having just secured the approval for Cosentyx in hidradenitis suppurativa, we are focused on delivering the three remaining lifecycle management indications that are coming up. Having done that, we now believe that the remaining unmet needs in immunology are in difficult specialty diseases that have had no meaningful treatments, like Sjögren's syndrome, like lupus, like lupus nephritis, like chronic spontaneous urticaria. And we aim to deploy our understanding of immunology, built over many decades, in the service of meeting the needs of those patients, as you will hear in the presentations coming up. We are excited about taking our many years of experience now with our next generation CAR T therapies and applying them to deliver potential immune reset to patients with severe refractory autoimmune diseases. We'll talk more about that in the later presentation. In neuroscience, the diseases we aim to target are multiple sclerosis, selected neurodegenerative disorders, and neuromuscular diseases. Our fundamental goal there is to find interventions that allow us to modify those diseases so that we are able to ameliorate the risk of disease progression. We have a number of programs ongoing, 10 programs that are in clinic with approximately 50 trials planned. While we will not cover neuroscience in depth today, Norman Putzki, our neuroscience development head, is here, and he'll be happy to take questions... We also, of course, will build upon the learnings from our experience with Zolgensma and deploy all of those learnings in gene therapies deployed against these neurological disorders. In oncology, we have chosen three main solid tumors: breast, prostate, and lung, and then our long-standing heritage in hematology. The principle that we want to live is how can we take our products and move them into earlier lines of therapy, into earlier stages of disease, so that we have the possibility of delivering to patients a treatment-free remission or a cure? You'll see that theme play out along the various presentations that we will go into in-depth. For RLT, we'll spend a lot of time talking about the RLT platform, which offers this unique precision delivery of radiation in a see where you treat paradigm, as a way of addressing both earlier lines of solid tumors, as well as single products that could address multiple tumors. Fiona will be going over that in more detail in the next section. With that, Fiona, let me call you to the stage to go over our platforms. Thank you very much, Shreeram. So, very happy now to really take you through some of the platforms that we're excited about. Importantly for me, you know, the platforms must align very closely with the disease areas of interest. So rather than doing platforms for platforms sake, we do platforms because we really believe that these advanced platforms and technologies can target some of the underlying drivers of disease and give durable responses in quite often differentiated ways from low molecular weight. So traditionally, Novartis has had a heavy emphasis and leading chemistry expertise. We still do have, you know, that still strong chemistry expertise. There are many targets that still are best drug with low molecular weight compounds. And we do chemistry in all of its guises, so not just directly acting inhibitors and activators, but allosteric modulators, covalent modulators. There are many things now, targeted protein degradation, that you can get compounds to do. So that will always be part of our portfolio, but as you can see here, we're shifting resources significantly towards biologics. I'll talk to you a bit about our biologics capabilities, but also these other platforms that Vas has already told you about, and you can see already increased resources, both in research as well as in development, in preparation for this. So in the case of biologics, again, we believe that biologics can give very durable responses, targeting important drivers of disease. Of course, we've brought monoclonal antibodies to market in the case of Cosentyx, for example. But there are many other ways of using protein engineering now to deliver advanced biologic capabilities. So proteins themselves and, and engineering natural proteins to give long-lasting effects, different antibody formats, antibody drug conjugates, and multiple specific antibodies. So within discovery, of course, what we're doing is really trying to build the next wave of technologies with our own proprietary expertise. We are working on next generation ADCs. We're very much leveraging AI in this space to optimize the properties very rapidly to develop new biologics, but also incorporating early on in research, all of the important pharmaceutical components in terms of scale up, how we deliver those, how their duration is, optimized. Now, as I mentioned earlier, all of these platforms to me must align with our core therapeutic areas. We want them to be very reproducible and robust, so that when we bring a candidate forward from research, it can easily be picked up by our technical R&D to scale up. We know how to do the safety testing, we know how to do the dose response finding, and these may seem trivial when it comes to low molecular weight. These are not trivial exercises for some of these complex modalities. You still have to understand what the dose is, what the therapeutic index is, and we really have, you know, built incredible, robust expertise in all of these modalities now. So this, I believe, gives us really a sustained competitive advantage, and these are, these are scalable. And you can see, of course, these different modalities now. We have the pathfinder in different disease areas like Leqvio, it, and for RLT, but we're also bringing up these different modalities across the rest of our therapeutic areas. So Vas has already shown you this slide. Really, by way of introduction, I'm just gonna go into a few more detail on each of these important platforms. So starting off with radioligand therapy, and you'll be hearing more about Pluvicto, and what we're doing there. But for us in research, what we're trying to do is now really map surface proteins on different cancer cells, identify unique targets. For some of these, we know from you know previous experience of what are selectively expressed on cancer cells, but really now understanding what makes a good target for radioligand therapy. We then design the vector, which can be a low molecular weight molecule or a peptide, even a protein, that acts as the vector. And then the benefit of RLT is you then have a different payload that you can bind in, depending on the different radioisotopes. So first of all, we can add in an imaging agent, gallium, that allows you to do PET imaging. This can be used for diagnosis, patient stratification, as well as follow-up. Then using the same ligand, but now putting in different radioisotope, lutetium. Lutetium is really the radioisotope that we have the most depth of experience with. As an RLT, really shown to produce efficacy and safety. We know how to manufacture it. And so you have this theranostic pair, as it's called, this idea, if you can see it, you can treat it. So this is really what our strategy is, is really now to build a pipeline of different radioligand therapies, exploring novel cell surface targets for solid tumors. Really building on, not just tumor cells, but also cells within the tumor microenvironment. So for example, cancer-associated fibroblasts, we have the FAPI inhibitor. And we've built a really advanced radioligand therapy preclinical laboratory in Basel, that allows us now to develop new RLTs, test them out, really understand the mechanisms of action that are occurring, and also what makes some of the best combination therapies with RLT. And then, you know, continue to extend this, also through business development. So each of the components, we're really taking, you know, one at a time and iterating on each of these, finding new targets, finding new vectors. Some of this is done in collaboration, for example, with PeptiDream, with Bicycle Therapeutics, with Molecular Partners, and then looking at different isotopes. Now, again, these complex modalities are not trivial in terms of scaling up, and so, you know, really, I think this presents a barrier of entry to other people who would like to move into this area. And, you know, the way that I think about it is, because we do have, you know, clinical trials network, we do have this discovery lab to test out different combinations. We've now got, you know, R&D manufacturing that allows real sort of delivering to patients. This allows us to be really a preferred partner for biotech companies that are interested in moving into this area. Again, you heard from Vas and Shreeram about really the depth of human capabilities that we have across all of these components. So that allows us then to build a continued portfolio, building on Pluvicto, Lutathera. Of course, in each of those cases, we continue to take those into different settings, different tumor types, but also then a range of different RLT drugs coming forward, many of which have opportunities across multiple different tumor types. So moving on then to CAR-T and cell therapy, again, really building on the history that we had with CAR-T, really the first entry in Kymriah. But by studying that from a research point of view, understanding what were the drivers of efficacy, led us to this understanding that the stemness of the T-cells within early CAR-T was what was the real driver of efficacy. So this produces really the benefit of having research, working with development, getting clinical data back, and also then incorporating manufacturing together. And I think this is the sort of thing that really only a big pharma has all these components that can come together. This led us to really design the T-Charge second generation platform, where we very much optimize the stemness of the T-cell by reducing the manufacturing time, going into patients much earlier with a lower dose, and that expansion actually occurs in vivo. And already we've seen the durable efficacy that the T-Charge platform can produce. So we're expanding really our footprint of CAR-T, as you heard, into other indications, particularly severe autoimmune disease, potentially neuroscience, but we continue to progress CAR-T in oncology settings. So these are two that are using the T-Charge platform, PHE, which is our BCMA T-Charge in myeloma. YTB323, which is our CD19 T-Charge. And again, we've shown that the concept of T-Charge to produce durable responses is playing out, and you'll hear a bit more about this from Jeff later. And then more recently, the opportunity for CAR-T in solid tumors led us to the acquisition of this DLL3 CAR-T from Legend. And then, again, Angelika is gonna talk to you about how, you know, we are very excited about the concept of the B-cell reset in autoimmune disease. Again, CAR-T, like RLT, really not a trivial modality to be scaling up and manufacturing, and really, again, leveraging the foundational capabilities, the experience that we've had of working in this area for, you know, being really the CAR-T pioneer, has allowed us to build up CAR-T networks, to build up the manufacturing platform, and really having global operational capabilities. And again, something that is very difficult for smaller companies to achieve. And so here is our pipeline. I've mentioned all of these already, and you're gonna be hearing more about them, and look forward to having some discussion around these. So moving on then to xRNA, and again, building on Leqvio, I think most of you here probably understand how RNA works, but we've been doing a number of different... Concentrating on a number of different aspects within the research group of really how to optimize xRNA. So again, using chemistry around the sequence, how do we optimize the durability, the stability, and then what delivery vehicles do we use? Of course, we're very good at this now for hepatic delivery, and we have the ability to look at different combinations. The interesting thing from the xRNAs is that you can combine multiple ones together in a single formulation with no detriment to each of the components. So it's very amenable to combination therapy, and we think this gives real opportunity in managing multiple risk factors in cardiovascular disease. But of course, where we want to do, because how many different targets would be, you know, the potential to knock down with xRNA, we wanna be able to get extrahepatic delivery into multiple different cell types of interest. So really build, we, this is our strategy here. First of all, building on outcomes in cardiorenal and metabolic disease, adding into Leqvio, not just PCSK9, but Lp(a), then multiple other ones coming forward. Again, continued focus on durability. We know we can get once every six months. We've got the promise of a longer duration than that, potentially once a year, combinations, and then the extra tissue targeting. And this has led us to acquire a company called DTx. So they have a FALCON platform. This is a fatty acid conjugated to the RNA, and it allows uptake and delivery to, several other different tissues, depending on the particular fatty acid that you have, and the most advanced program there is in Charcot-Marie-Tooth disease. So really interested in opening up other tissues that fall within our disease areas, myocardium, kidney, as well as CNS. Again, building this platform portfolio, primarily, first of all, in cardiovascular disease, but also real opportunity in neuroscience. You know, patients who have severe neurodegenerative diseases like Alzheimer's disease, to be able to give those patients, you know, once a year or twice a year injection is a huge benefit over multiple, injections, which is, very difficult for the carers, for example, or particularly people who are in residential care. And we think some of these platforms that we're delivering now offer that opportunity, both in rare diseases like CMT-1, but also in these broader disease areas. Okay, so that's a bit of a lightning. You'll be hearing a lot more about this going forward, and I'd like to invite Shahram back up to the stage just to close out this section. Thanks, Fiona. I think you have a very good sense now for what it is that we have chosen to work on, but success comes from also being focused on how we do it. We truly have transformed our ways of working together and our focus on relentless productivity. It comes through paying attention to the details and being committed to operational excellence. You've already heard about how we went about acquiring the two assets from Chinook, what came on the back of a streamlined organization, building upon internal knowledge that was gained from the eptacopan rare glomerular disease programs, and then being able to successfully assess the value of the two assets that Chinook had to enter target IgA nephropathy. If I wanted to, in... On the second column there, if I had to tell you, and give you a little flavor for what it takes to make sure that we can succeed in taking on a program in a difficult disease area to work in, like Sjögren's syndrome, the fact that a seamless organization in translational medicine has been working in this space in partnership with the development team, and literally paying attention to all levels of details. For which centers should we work in? How do we build centers? How we train them to be able to give us the data in a reliable manner? It's the attention to all of those details that then, in an organization that gets focused, translates into these trials actually recruiting nearly six months ahead of the original plans in terms of the Sjögren's phase III. We already heard a lot about the YTB autoimmunity plan, which really is one team within Novartis now across research and development and the U.S. organization, as well as our major geographies, to bring the right centers together so that we can connect the hematologist with the rheumatologist to be able to launch our phase II plans. We'll hear some more about it. And finally, I want to say at the heart of it all, for productivity, we are focused on making sure that the programs that we progress bring value. And the value conversation happens right at the start, from having clarity on what drives value, what's gonna be necessary for success, and how that informs the plans. We, of course, so this is really a new way of working, where we are truly working together as an integrated organization, and the same applies to our deployment of the AI interventions that we deploy to enhance our performance in R&D. Fiona and I actually jointly govern the entire R&D efforts and how we're deploying AI. We pay as much attention to what tools we are deploying, as much attention to the data that we're deploying them on, and whether they are in the early-stage applications in the discovery stage, or interventions that I'm overseeing on how we might use AI to enhance our performance in trials. It's a seamless way of working that pays relentless attention to what is immediately an intervention that has impact, and then how do we scale what works? So with that, I think, I hope that we have provided you with a good sense for on this R&D day as a pure play medicines company of the focused therapeutic areas we're working in, enabled by our differentiated technology platform, and we're on our path to deliver high-value medicines addressing major unmet needs. With that, let me invite Vas and Harry back for the Q&A session. All right. All right. Very good. So we have about 40 minutes for Q&A. I'd suggest, please limit yourselves to one question, and we'll make multiple rounds as we go. So I'll start with Andrew, and we'll work the way around the room. Andrew? Thank you. It's Andrew Baum from Citi. As we've discussed before, Novartis has a history of being the first adopter across novel technologies, and often it hasn't worked in the case of Pluvicto and Radionuclide, it has. Thinking about your autoimmune efforts with the CAR-T, you won't find anyone who's more excited than I am in terms of the potential for CAR-T in autoimmune. But one thing that troubles me is, allo CAR-T, and to the extent this represents an existential risk, not just for you, but the other autologous that are in development. And I know in oncology it's an experiment that was tried, but this is a very different concept. So given you're opening very large programs, large trials, it's gonna take a lot of bandwidth, how do you handicap the risk of competition from the allo? You want to take that, Fiona? Yeah. I mean, Andrew and I were talking about this topic outside, and I think the fact that Allo hasn't really delivered on the promise in oncology. I think we can learn a lot from the oncology setting across to the immunology area, 'cause you essentially are trying to do the same thing, which is to take out the B cell population. And so for us, we're concentrating on CAR T. We believe that that's the right strategy. It's already got some very, you know, encouraging data so far, which we believe that we can build on, and that's our area of focus. Yeah, I mean, I think the two points I'd add, so I think it's we have to be very sensitive to the fact that both Allo and also bispecifics, there's many ways that this can go, and we're trying to build the capacity to... We lead with CART because we think that's where, as you know, the Schett Lab data really, really builds on. Go broad, try to be a leader and get to those indications as fast as we can. But behind that, be realistic that, and I think Angelika can talk about this a little bit later, that we might have to use other therapies, because as you want to move earlier lines in severe immunological disease, having bispecifics, maybe Allo, if they can get past some of the safety issues, are gonna have to be part of the portfolio. So it's on our minds. I have to say that right now, the race, we think at the, as the first step, is to win the CAR-T therapy race and some of the key immunology indications. Richard? Thanks. Richard Foster here from JP Morgan. So just thinking about that mid-single-digit sales growth in the longer term, is that a CAGR from 2027, or is it an annual ambition? And what would you say is the biggest driver in the pipeline of confidence in that mid-term or longer term growth? Thanks. Certainly our thinking is a CAGR, because obviously with individual years in that period, of course, we will have a Cosentyx LOE, which we'll have to overcome. But I think it's not one asset. I think it's the constellation of things I tried to outline at the outset. I mean, you have medicines like Kisqali, like Kesimpta, Scemblix that have a long runway, and they can take us well into the early 2030s. You have the new assets, new indications that we talked about, including for Pluvicto and Kisqali, and then you have the pipeline assets, which we'll go over the course of the day. Certainly, I think the thing we'll have to navigate is the IRA. I mean, certainly for us, IRA is not a material impact through this next five-year period, but it starts to become an impact depending on how the policy evolves. So we're gonna have to, of course, deliver not only with internal innovation, but also to look at external innovation as well to bring in. We think overall, when we look at the constellation of assets, we have enough here to get to that mid-single digit growth rate consistently over time. I think we just have to build more conviction that whether some of the assets that you see here today, like VAY, like our RLT platform, can really drive that growth longer term. Graham? Thanks. I'm just gonna follow up from Richard's question actually there. So on, on that growth rate post 2027, is that taking you out into the early 2030s? So what's the kind of time frame on that you're thinking? So you've obviously got big LOEs, Kesimpta, and Kisqali in 2030, 2031, which are actually a big part of the, the current growth rate. And are there any assumptions built into that, that you could extend patent life, on either of those assets? So Novartis in the past has been, I'd say, quite innovative in its, patent strategies, both the small molecules and, biologic therapy. So should we be thinking this is a, you know, mid-single digit through those LOEs, or is this really a guide up to 2030 that you're really, or an aspiration up to 2030 you're giving us? Thank you. Yeah. You know, the way we model, we model in five-year increments, so we look at 2027-2032, and in that time period, we assume the LOEs that we currently have, so that as models, so you have 2029 for Cosentyx, we have Kesimpta longer. Of course, we will try to protect these assets as long as possible. Kisqali goes at different time points as well, and it's important to note U.S., Europe, China, Japan, all go at different time points. Entresto goes in Japan until 2033, I believe. So there, there's of course a lot of dynamics, but my guess is the biggest difference between our view and the external view is on the pipeline assets, and it's really gonna come down to the conviction we can build on the mid-stage pipeline over the discussion today. Harry, anything you want to add? Yeah, maybe, just a little reminder, right? Most of the, the consensus or the analyst says that analyst community one to two years ago thought that the current midterm, five years, we would grow 1%. Right? Now, everybody is asking for four, five, so today you've got a 5%, right? It's just a year, 1.5 years. So I think it comes down to a fundamental conviction. Are we able to have these pipeline assets have good BD&L and M&A to support our fourth therapeutic areas to bolster that growth? Within 1.5 years, moved up from one to five or four, the consensus is now, right? So I think that's important because everybody knows the LOEs. LOEs are not as cliff as actually most people think, right? Different geographies happen. We have a lot of tail end. Diovan, still, one and a half billion. Just think about that, right? So with all of that, so it's our fundamental belief that we, with this pipeline, with the normal modeled, you know, intake from Bolt on M&A, will be in that clearly a mid-single digit. But it's, it's big. These are assumptions, right? That's why most people don't model longer than five years. We do that. I think four or five sales analysts do that, and we are convinced we have the pipeline innovation power to grow. I think one of the things we have to deliver on is, as Fiona mentioned, and Shreeram mentioned, the RLT pipeline will start to mature at the end of the decade. So if we are successful in moving this beyond Lutathera and Pluvicto, you will have, at that point in time, FAPI, let's see about some of the other targets, Bombesin, Folate, et cetera, start to mature. Alongside that, we would hope that if we see transformative efficacy in CAR-T therapy and immunology, you'll start to get those approvals as well. We've seen with Pluvicto, first year ramp, I mean, it's approaching $1 billion in its first full year. So if we can hit those RLTs, you know, with the right, right efficacy and safety, obviously, the ramp is very fast, and I would expect similarly, CART with immunology would be very fast, if we're able to really deliver durable remissions in these patients. So let's go maybe to the back here. I think I can see who that is. Light in my face. Thank you. It's Kerry Holford from Berenberg. Hey, Carrie. Hi. Thank you for taking my question. It's on margins. A number of your global peers suggest margins, operating margins in the 40%+ range are not desirable and perhaps are indicative of not investing enough in the pipeline, to drive future sustainable growth. So in addition to that target, you also have an LOE period to transition through to 2027. So I wonder if you could talk us through the thinking behind wanting to grow margins from here over that more tricky period, and why you are not perhaps looking to grow at least out of sales, your R&D, internal R&D budget, or indeed, perhaps, that you're looking to supplement more of it from external sources. So your thinking behind that, please. Yeah. Thanks, Carrie. Yeah, thank you very much, Carrie, for that way of question, because usually the question comes, "Why is it not much more than 40%?" Right? And, I'm basically, answering along the lines what you just outlined, which is we always want to make sure that we are investing into the pipeline and into the launches in the top line, you know, to optimally support pipeline and top line, of course. And so we don't want to be cornered by any short, mid, or long-term margin guidance. But on the other hand, you know, we are 37, basically, right? In the 9 months this year. We have made a lot of progress over the last years. And actually, you know, if you just would straight line that, we would be quite beyond 40%. But, you know, I, what we say is, and my conviction is also, the moment we get to the 40%, you know, I think that is with good productivity. We are leaning out the organization, which we have done, and all of that, but we always invest in top line and pipeline. Beyond 40%, I believe it has to do a lot with the product mix. And we are-- we don't want to forgo areas which may have a little bit lower growth margins, if you will, right? Because these are good businesses and so on. So that's why 40% we see, without any problem, if you will, without a compromise in terms of R&D investments or launch investments. Beyond that, we are careful. And, the R&D budget is growing. You saw one slide here. And if we have even more phase IIIs and fantastic in-licensing or M&A, bolt-on M&A, we will not hold back R&D investments because of margin. But we have also areas where we can drive further productivity, as we have shown you over the last few years. So that's why we hold on to this 40%+, and the plus depends on the product mix. So then, maybe here in the front. Emily? Hi. Thanks. Emily Field from Barclays. I just have a question on sort of prioritization between small molecule and large molecule in the R&D pipeline. You mentioned by 2030 that you see a big shift moving to biologics, but sort of when we think about some of the pipeline programs that may be launching then, by then, whether it be iptacopan or remibrutinib, we think, at least personally think of Novartis as being more in the small molecule space. So is this sort of an earlier portfolio shift that because of IRA, you're shifting more of the focus to large molecule? Fiona, you want to- Yeah, I can start from the research point of view. I mean, it isn't just that the IRA, it's actually the types of treatments that we want to bring to patients that have really durable efficacy and are really targeting the underlying drivers of disease. So often these modalities give you that real benefit in those types of settings, compared to small molecules, which may be more symptomatic treatment. So that's really what we're trying to achieve in patients that is as much driving this change and the leadership expertise that we have in these areas. So it certainly is changing the way we're doing research, but also business development as well. So, you know, we look at what's the right balance from business development across our whole portfolio. I mean, I think, you know, certainly your question on the IRA, it's on our minds, but I think we follow the science first, and I think the science is what's driving the shift. I would say that we are systematically evaluating pipeline assets to ensure we factor in the IRA impact. Certainly, you know, assets that are small molecules, predominantly for the elderly, that are not single indication rare diseases, are just simply harder to make sense when you evaluate them versus alternative opportunities. I think that's not unique to Novartis. That's an industry-wide shift we're going to see, I think, over the coming years. It may be worth adding, it's not just the IRA. I mean, in research now, we actually have commercial input on all projects that we start to make sure that we're aligned, that these are gonna be the right size for, for Novartis. That the development team, you know, are enthusiastic about taking those forward as well. Laura? Thank you. Good afternoon, Florence Esteves from Société Générale. Vas, could you elaborate a bit on potential inorganic growth, which areas, which kind of products could look for to strengthen the pipeline existing portfolio? Inorganic, you said? Yeah, inorganic. Inorganic. Yeah. You know, so I think there's a few important, you know, shifts we've made. One, I mean, historically, we've had a pretty broad purview of deals that... And when we've sometimes brought in assets that were outside of our core areas. I think, looking hard at those, sometimes those have not worked well. I don't think Xiidra in the end, with the test of time, was a good deal. We didn't have the expertise to really, I think, make the most of that asset. So going forward, we really try to focus on therapeutic areas that we listed here, the diseases. I mean, the hunting list you can think about is the diseases you see on these charts. To do a deal outside of those diseases has to be something that we, as a leadership team, find so compelling that we're willing to move away from that. So we're saying focus on those core therapeutic areas. We're looking for new technology capabilities that we can bring in. Certainly, I think as Fiona mentioned with DTx and lipid technology to target siRNAs, we didn't have an RLT for FAPI, so we went and got one from Clovis. And so we're trying to augment our core technology platforms, and then we're trying to stay very disciplined around that. And that means saying no to a lot of deals, but we think there's enough there within that space to find enough attractive opportunities. I mean, Chinook was a nice one. If eptacopan is in renal, we have a pipeline in renal. We bring in Chinook, we get two phase III renal assets, one of which is readout positive already, as well as I think three or four preclinical candidates that Fiona is now working on. So that's the kind of profile of opportunity we're looking at now. I think just right behind you, so Richard. Yeah. Thanks for taking my questions. Richard Parkes from BNP Paribas Exane. If I think back to your R&D Day in 2019, Which was in this hotel, by the way. Oh, yeah, it was. I think you outlined a wave of mid-stage pipeline assets that we're about to move into phase III, including eptacopan, remibrutinib, pelacarsen. And all of those assets are at the same sort of linchpin that we're gonna be talking about today. But in today's presentation, I get less of a sense of kind of high conviction, mid-stage assets that you're expecting to move to late-stage development. So I'm just wondering, is that just a reflection of where you are in your cycle and you're more comfortable about near-term growth? Or is it gonna take a bit more time for the new, more focused Novartis kind of structure to embed in terms of R&D? So just talk about your conviction about that next wave. Yeah, I mean, I can start and maybe, Shreeram, you can, you can add. I, I think, one, we wanted to gear this, this day to assets that are very close to, to licensure, and so to help really provide the markets with a, a deeper understanding of assets we're gonna launch in the next three years, and that's how we've geared things today. We are seeing... I think we will touch on, and Shreeram will try to touch on each of the therapeutic areas, some assets that are advancing, and we think that can also generate attractive value. I would say, though, it is indicative of a, of another shift. I mean, in 2019, we still had a lot of things in our pipeline, and we've really tried to focus down and say, rather than have lots of, lots of assets, really maximize the assets that we have. So Pluvicto now goes into 4 indications. If eptacopan goes now across six or seven indications, you'll see later VAY736 across three oncology, three immunology indications. So I think it's much more about going deeper on assets where we see a lot of opportunity than continuing just to feed more, you know, phase II assets into the pipeline, rather be patient enough to see assets that we can build into very significant medicines. The only thing I'll add, Vas, is that there is now complete alignment and clarity between Fiona and myself on the board that we chair, as to what is going to be the data that is gonna be the basis for actually moving a product forward into phase III. So there is a series of assets that we govern together that we have complete clarity on what we expect to see. Jeff? Anyone got back here to the front. Hi, it's Peter Welford with Jefferies. Up here. Um- Jefferies. I'm thinking of Jefferies, sorry. Just, a question really on, siRNA. I guess there's, there's two aspects to this. One is, does the belief that you're now gonna go over every 6 or every 12 months therapies reflect management's, I guess, sole belief now that there is going to be success of Leqvio commercially, and this idea can work in both the U.S. and rest of world, so you do want R&D now to continue driving that? And related to that, is the focus in R&D now taking existing known mechanisms and turning it into those therapies, or are you going against bigger picture? And particularly, I'm thinking metabolic, where I don't think you've really got anything yet in metabolic using this perhaps paradigm. Yeah, shall I pick it up? Yeah, please. Yeah, I mean, yes, we do believe in the future of Leqvio and really in the future concept of being able to give these very long-lasting- ... you know, high compliance, adherence, managing as many different risk factors as possible, in combination. I mean, we think this has a remarkable opportunity in, managing cardiovascular risk reduction. So in doing that, in research, yes, we're taking a combination of known risk factors, as well as novel ones that may come from human genetics, for example. I think, you know, to the question on Leqvio, it's certainly slower than we hoped for. But we are seeing all of the signals that we're building a large prescriber base. We're seeing greater depth, and I also think we're seeing the beginnings of interest in other large markets, I mean, Japan, China, as I mentioned, very early days, but we start to see traction. And so I think that gives us confidence that eventually we'll get to the point with the outcomes trials, with moving into primary prevention, with maybe in some geographies, even being frontline ahead of statins, that having a every six months or eventually every year alternative is gonna be the way to go, in cardiovascular disease. And we believe a better path than pursuing orals in this particular therapeutic area. So hence the pivot. And we're trying to build the pipeline, and hopefully we can demonstrate that to you in the coming months and years, that there'll be more and more assets entering the clinic, in siRNAs. Right here in the front. Holger? Yeah. Holger Blum from Adamant. A question on the portfolio focus that you've shown pretty impressive shrinkage from 155 to 103. Guess you won't reduce it by 50 over the next year. What is the right target size you have in mind? And maybe you can explain a bit how the year has evolved, how many of these projects did fail? How many you just decided not to fund anymore, and how many could you rescue, maybe by partnering out and maybe having optionality via milestones later on? And last one to that is the business development side probably added to the portfolio. So what... In that 103, how many were added by business development? Raj? I mean, I mean, I would say that the size of the portfolio seems to be at the place where we think it's the right place to be for an organization that focuses in the areas that we choose to focus in, and around 103 clinical stage programs, of which 80 are in confirmatory development. I would say that the reductions happened both as a result of specific data readouts, where we had very clearly applied our thresholds for what we think needs to be seen for the program to progress forward. And there were others, like Vas said, where we were perhaps working in areas that we were not currently planning to focus on. So some of those went onto the list for potential to divest. There have been those. And then in terms of, I think, entries from the external world, other than Chinook, a large number of them currently have been mostly early stage. But I think for the most part, this 103 now reflect, reflect a rationalized version of portfolio that pretty much has come from within. Yeah, and I mean, I think an important component is how we actually did the portfolio review, and it did involve, you know, myself, Shreeram, Ronny from the strategy team, as well as commercial input. You know, looking literally through the entire portfolio and discussing where we thought the high value was for Novartis, where we were well set to take it forward and have a lead. And so taking all factors together was how we made the reduction. I mean, some of the consequences, and Shreeram talked about it, is, you know, one is the clinical portfolio, but Fiona and her team have done a great job also rationalizing down the research portfolio. I mean, when we benchmarked ourselves with the new R&D leadership team, we were at the top of the chart in number of assets, number of preclinical programs, number of trials. But that also meant we had some of the lowest resourcing per project, lowest number of chemists- Mm. -drugging, trying to drug a candidate. And so by making this shift, keeping resources growing in R&D, but now dramatically reducing the pipeline size, we actually put more resources against our clinical stage assets, against our early product portfolio, which we hope will then accelerate and help us find, you know, the assets that we really want to go after. I mean, right now, we're about peer median, we think. And that's reasonable. We don't necessarily want to go lower, but we don't want to—no longer want to be the company that's highlighted with the most of everything, because that's not the battle we wanna win any longer. Please? Uh, Seamus, Ross, sorry. Thanks. Seamus Fernandez at Guggenheim. So just trying to get a sense of just the dynamics of the overall P&L as we move forward and sort of the spending as we see it going forward. To me, it kind of looks like the incremental sales is almost flowing exclusively straight through as you increase the sales margin. So just trying to get a better sense of you know how to think about gross margin progression, R&D you know to some degree, SG&A, but also we got some surprises on the tax line from some of your peers. Yep. Wondering how we should be thinking about below-the-line dynamics as well, given Novartis' very compelling tax year? You have the right man for this question. All right. Terry. Thank you, Seamus. Finally. No, but you know, I think, you know, when we think about our current situation, margin close to 37%-40%, I do expect the margin improvement almost exclusively to come from SG&A. And basically, as you described, that the majority of the sales growth basically falls through, given that we will have some incremental SG&A investments, but it basically growing significantly below the top line. Right? So that's the majority. On the growth margin, I expect that to be roughly stable. Now, we will work continuously on, of course, manufacturing, supply chain efficiencies, but we have some growth drivers that have a bit higher royalty burden, which is also part of the cost of goods. So kind of flattish, plus, minus growth margin. And then on R&D, also, in average, right? It's never a formula, as I mentioned. We will always invest in great programs in R&D, but that R&D roughly grows with sales. So there will be R&D increasing, and we will be in the range roughly of 19%-20% of sales. Again, not a formula. We will maximize value always and invest, but a long story to say, SG&A will be it. And I think that's also the power, of course, in research development and business development, to have four therapeutic areas with clearly defined diseases. But the same is true in a commercial execution, so we can leverage much better our commercial infrastructure as we resource allocate from maturing products into new launches and pre-launches. So much more efficient commercial execution, if you will. Inflation is not such a big deal, and we have product productivity programs to offset it, so all of that is well under control. From the taxes, you know, we have been in the range of 15.5%-16%. I think there will be a little bit of increases, maybe if the OECD Pillar Two gets increased, but nothing significant. We have a few products that have US IP, but again, you know, in the long term, I see ourselves in a core, core tax rate of 16%-17%. But, you know, short term, the range of 15.5%-16%, so not a big deal from the bottom line, in terms of below-core EBIT and quite manageable. Very good. Let's go to Eric, and then we'll come over to the web. On your slide, talking about the new modalities, there are two magic words with ADCs and multispecifics. We're not necessarily aware of how advanced Novartis is into those two fields, where some of your peers are already into the market with- Mm-hmm. some products. So, could you maybe say where you are? What's the most advanced product for each of those two modalities? If you have anything you need internal or if you need to make some BD acquisitions, should we expect Novartis to be active in those two fields in terms of NBD? Yeah, thanks, Eric. I'll give this to Fiona this time. Yeah. No, I mean, we do have everything we need to deliver both of these modalities. We have got a number of ADCs in our portfolio, and we have taken ADCs into the clinic, but we haven't disclosed those yet. And of course, we're learning, you know, where would be the best use of ADCs relative to RLTs. And so, yeah, what was the other mode? Bispecific. Oh, bispecifics. Yeah. I mean, we are doing a number of different bispecifics across multiple different therapeutic areas, particularly in immunology, for example, where we see the value of combining known validated targets with then novel additional targets that bring synergy. And certainly in the oncology area, you know, we've talked about different immune cell engagers, whether that's T-cells or other immune cells within the tumor microenvironment. That's something that we have really quite a robust portfolio coming through. One of the things that we'd want to highlight, though, and hopefully you get a sense throughout the day, is we believe RLTs have a unique therapeutic index. And so when you look at the safety profiles, at least to our eyes, and you see some of the topics that come up with ADCs, specifically with respect to lung, but as you know, other AEs with ADCs. In general, thus far, with dotatate-based RLTs, we see some salivary gland, and we see maybe a little bit of bone marrow, very manageable. And one of the reasons we think Pluvicto is taking off as well as it has in the United States, is the safety profile. And so what you have is a high-efficacy medicine that actually has a safety profile. When you look at the data that we presented at ESMO, the overall AE profile was not far off or actually looked, you know, across trial comparisons. But better than the ARPI that we had in that trial in terms of the, in, in terms of the AE profile. So you're having a medicine then that not only is looking good in late line settings, post-chemo, looks good pre-chemo, but what that allows you to do is maybe move RLTs into much earlier lines of therapy, because nobody is going to take the risk of a category A death in an early, early cancer patient who can be treated by alternatives. But we can take RLT all the way, as Jeff was talking about, to the oligometastatic setting. You'll see with the top line data we presented on Lutathera, that we'll present in January, we can move that up to the frontline setting, and it's all underpinned by the safety. So I think our core belief is we can get high efficacy with an attractive safety profile, given the therapeutic index we see with RLT. I think we want to go to the web. Is that right? Yep. There are two questions from the web. First one from Rajesh at HSBC. His question is: Can you please elaborate on the criteria for moving assets to phase III? What are the main parameters you're looking at, and how does it differ from the past? And then the second one is from Steve, from Cowen. ... Management has stated that one of the virtues of RLT and CAR T is that they have manufacturing and logistics moats that hedge against competition. Should we think about these products as effectively having no meaningful patent expirations, such that when we come to Novartis 2040 R&D Day, we will be learning about new products in the pipeline being added to a portfolio of legacy RLT and CAR T products that are still growing? All right, so while I ponder Steve's question, let's start with Vasant and hopefully we get an easier one. I think, yeah, I mean, I think that the decision making for what we look at to move a program into phase III is quite simply evaluating the data that has been delivered from our phase II B studies, evaluating the competition and how the world has evolved, and then assessing our probabilities of success towards delivering the target product profile that we believe is going to be essential for us to be able to get approved, gain access, and move into rapid clinical practice. With the thresholds, though, on the sales that we use now. Yeah. Well, yeah, and our expectations are that we only will develop products that have peak sales of $2 billion in order to move them into full development. The thresholds we use are for an asset. We want the total asset potential to be over $2 billion- Yes. and an indication level over $500 million. Five hundred. I mean, that's what we now do we adjust if there's an opportunity to build on, on Cosentyx or will we adjust? Yes, we will. But in general, our expectation is if we don't have a case for the asset to be over $2 billion peak sales, then that's probably not an asset that will make sense to help Novartis grow, given our, the size and scale of the company. So I think, Steve, to your, to your question on, on moats, we certainly believe that in, in RLT and, and to some extent as well in cell therapy, we've built unique capabilities. If you take RLT right now, we have two manufacturing facilities in the U.S., we have facilities in Europe. We've already announced just I announced two weeks ago that we'll be building a facility in Japan. And so we're building up a global network of RLTs, which we think will make us completely unconstrained. Even today, we are unconstrained from a supply standpoint. We can supply all the markets for whatever demand is needed, and more importantly, our ability to deliver now within five days for Pluvicto, three days of Lutathera, and get those doses even the day before. So that means you have two days and four days to the clinic, is getting up to very high levels. The trailing, I think six weeks, were 100% on time delivery in the United States. That took us two years of figuring it out, lots of learning, lots of mistakes. So I think that that capability is, is real and that know-how is real and not easy, to replicate, and there's a lot of know-how tied up on that. I would be, though... I have to be clear, though, there can be other players who develop RLTs and develop CAR therapies, so we will face competition. So it's on us to keep lifecycle management, coming up with better products, continuing to develop. But our expectation is that as we build out the capability that hopefully an RLT center knows Novartis will provide the full range of hopefully not only lutetium, but actinium-based therapies across the range of potential targets. They don't need to go to another place and work out the complex logistics with another company. And we hope as well, with CAR therapy and immunology, you know, we can build that up as well and keep a steady flow of assets coming through. I'm willing to sign up for, let's call it the mid-2030s. I don't know about 2040 yet, but we'll see. We'll see how things go. So I think, do we stop here, Samir? One more question, and then we'll start. One more question. So who has not asked a question yet? Maybe in the back, I think. Thank you, guys. It's Mark Purcell from Morgan Stanley. The RLT leadership presents a really exciting opportunity. But as you mentioned, to get some stable long-term remissions, you sometimes need combination therapy, and in the past quarter, you've pivoted away from immune oncology, for example. So can you help us understand? I mean, you can't invest in every oncology technology, but how are you looking to sort of build combination assets with RLT? And then a specific sort of follow on, in terms of PSMA ADC versus PSMA RLT, is that something that is an exciting complementary approach for you, or do you see it as competitive? Thank you. Yes. I think, Mark, I'll answer just at a high level and I'll leave it with Jeff. Jeff will be the right person, I think, to give you a more detailed answer on this. We do acknowledge we're going to need to be able to do combination therapies. We are already running combination trials, for example, with Lutathera and a PD-1 inhibitor, in small cell lung cancer. We're looking at other combination studies as well in the prostate cancer space. Now, we are doing those through third-party assets because we don't have, obviously, a PD-1. We gave back the rights to BeiGene. But I think combinations will be important for given certain diseases to really get to deep responses, and that's a capability. Maybe, Jeff, you could pick that up in more detail in a moment. We'll take a break here for how long, Samir? Quarter past the hour. All right, till quarter past, and then we'll continue from there. So thank you all very much. All right. CRM. All right. Well, welcome back, everyone. Now we start going deeper into each of our three chosen therapeutic areas for the day. The plan. I have with me, Dave Soergel, our Development Head for Cardiorenal Metabolic Development Unit, who many of you know. Himself, a card-carrying cardiologist of many years and a drug developer, both in the biotech and large industry setting for a long time. So my plan is to go over three assets at a high level with you quickly. Mainly Leqvio, pelacarsen, and XXB750. And then Dave plans to do some deep dives on eptacopan as well as Atacicept. As we discussed earlier, our core premise in reducing cardiovascular risk comes from our ability to address challenges with adherence, with the premise, again, that the use of antisense oligos or siRNA to reduce cardiovascular risk factors over an extended period of time, with infrequently administered agents, gives us the best potential for meaningful reductions in cardiovascular risk. On Leqvio, we've had a lot of discussions. The relationship of LDL lowering and its benefits on cardiovascular outcome are well established. We have multiple large cardiovascular outcome trials now running on Leqvio. On the left side of that slide, you see the data that were used in order to design those trials. The premise being that the longer you maintain a lowered LDL level, the better the cardiovascular risk reduction, which is, the magnitude of which can be defined by Mendelian randomization approaches, where you can evaluate what this might look like over an extended period of many decades. On the upper line there, with meta-analysis of shorter randomized trials, which still on average, about five years of median, showing the other magnitude. Our trials are actually explicitly designed to evaluate potential benefits on cardiovascular risk reduction in that range. Our two secondary prevention trials, so ORION-4 and VICTORION-2-PREVENT, are enrolled and running with data expected, as we said, in 2026 and 2027, and V1P, our primary prevention study, is expected to read out in 2029. Dave and I often have this discussion about how running large outcomes trials takes discipline and paying attention to the details in terms of the population enrolled, as well as the event rates and how they are accumulating. But above all, also the responsibility to resist the urge to want to close those trials out early, because I think we have one shot at being able to establish the magnitude of the benefit that we can accomplish with an intervention like Leqvio. At least at the present time, we aim to complete these trials as planned and to be able to provide the practicing physicians the necessary information that guides their practice in the use on a daily basis. We're proud to say that Lp(a), which of course is an independent genetically determined risk factor for cardiovascular disease, one in five people worldwide with an elevated Lp(a). Traditionally, not paid much attention to because people did not have any real means of addressing this risk, but of late, perhaps driven by the increasing interest in agents that can lower Lp(a), where we are at the leading edge with pelacarsen, our GalNAc-conjugated ASO, lowering Lp(a) levels successfully, as shown on the right side of that slide, in our phase II studies, and now being evaluated in HORIZON, our ongoing phase III study, which has the potential to be the first trial to demonstrate the benefits of lowering Lp(a). The recruitment is complete. The trial is running. We expect the primary readout in 2025. And then finally, keeping with the theme of long-acting agents that allow us to treat cardiovascular risk factor and coming to hypertension, XXB is an early-stage program. It's just delivered phase I data that we presented at the AHA, and we are in the early stages of recruiting a study in resistant hypertension in phase II, and plan to evaluate in heart failure in a phase II study that we'll start next year. But XXB is a monoclonal antibody that is a direct agonist at the natriuretic peptide receptor 1. We've learned a lot about this biology through our work on Entresto, and we believe that the agonism of NPR 1 in a non-competitive manner with the endogenous ligands by XXB has the potential to have the benefits that are outlined on the right side of that slide. Just one small slide to show you the early data that we presented at the AHA, where in this phase I healthy volunteer study, where ambulatory blood pressure was monitored, after a 240 milligrams single dose, you see a highly efficacious reduction in blood pressure of about 18 millimeters of mercury systolic. Nice lowering over a 24-hour period, and a restoration of a nighttime dip, which is part of the physiologic response that is important. Again, early times, we will look forward to generating more data in patients with both hypertension and heart failure before defining the next steps on this program. So with that, let me hand over to Dave for eptacopan and atrasentan. Dave? Excellent. I'll go and sit there since you're going to say a lot of things. Well, it's great to be here with everybody this afternoon, and it's especially a pleasure to provide an update on eptacopan, which will be our first order of business. Then our second order of business will be to talk a little bit about the evolving IgAN landscape, and specifically about how eptacopan, atrasentan, and zigakibart all fit into that evolving landscape. First we'll touch on eptacopan. Eptacopan, as you'll recall, is our oral factor B inhibitor targeting dysregulated activation of the alternative complement pathway. We believe it has the potential to become the preferred treatment in several rare complement-driven disorders in both hematology and nephrology. Today I'll focus on three of these opportunities: paroxysmal nocturnal hemoglobinuria or PNH, where we anticipate a U.S. FDA decision soon, and where eptacopan, we believe, could be practice-changing in the management of these patients. Second, IgA nephropathy, where we anticipate a filing for accelerated approval early next year, where we recently released top-line results. And then, C3 glomerulopathy, where we expect phase III data imminently from that trial. So first, let's start with a reminder about eptacopan's mechanism of action, because it really is sort of fundamental to understanding why we're in all of these diverse indications with eptacopan. So the complement system is a component of the immune system that clears foreign matter from the body, and there are three ways that the complement system can be activated. First, by antibody antigen complexes, which is depicted on the figure on the left, through the classical pathway. Second, by microbial surfaces, via the lectin pathway, and then third, by the alternative pathway, which is constitutively active surveillance mechanism, always looking for foreign materials to clear from the body. The alternative pathway amplifies the alert that there's foreign material present and mobilizes the system to clear it, and factor B plays a critical role in this amplification sequence. An inhibiting factor B with eptacopan dampens this alert signal, but leaves the classical and lectin pathways active. In contrast, C5 inhibitors, which work on the distal end of this sequence, inhibit the formation of the terminal membrane attack complex or MAC, which more completely inhibits the function of all three pathways. Dysregulation of the alternative pathway is an important factor in several rare complement-driven diseases, and we're pursuing several of these depicted on this slide in the eptacopan development program. In each case, complement, and specifically the alternative pathway, has been implicated in the disease pathophysiology. And in each case, the current standard of care is either subpar or in some cases, non-existent beyond supportive care. So we think there's a real opportunity in these indications for a better medicine like eptacopan. So now let's turn our attention to paroxysmal nocturnal hemoglobinuria, which I will from now on refer to as PNH. PNH is a complement-driven disease characterized by hemolytic anemia, thrombophilia, and bone marrow failure. And in PNH, abnormal hematopoietic stem cells produce blood cells that are unable to prevent complement from activating on their surfaces. And so when complement adheres to these abnormal red cells, they're lysed, and this produces the hemolytic anemia that that's part of the disease state. Anti-C5 antibodies were an important advance for these patients, but there remains significant unmet medical need, as depicted on this slide. Over 80% of patients, surprisingly, over 80% of patients treated with this anti-C5 compounds did not achieve normal hemoglobin levels and half of these patients, so 39% of individuals, remain transfusion dependent. Many patients, because of this anemia, continue to experience debilitating fatigue from their anemia. So why do we believe that eptacopan is gonna be a meaningful advance for these patients? And basically, it's because of its mechanism of action. So in untreated PNH, red cell hemolysis results from the activation of the membrane attack complex that I referred to in the previous slide and shown in the bottom of the figure again. This results in anemia, free hemoglobin in the blood, and elevated LDH, and this is what characterizes so-called intravascular hemolysis, this, these sort of three features. In PNH, C5 inhibitors effectively prevent the terminal step that leads to intravascular hemolysis. However, the problem is that inhibiting C5 doesn't prevent the amplification via the alternative pathway. This results in coating or opsonization of abnormal red cells with C3 fragments, which marks them for clearance by the reticuloendothelial system in the liver and the spleen. This is called extravascular hemolysis. 80% of C5 inhibitor patients continue to have anemia, as I mentioned before, and therefore could benefit from more effective inhibition of extravascular hemolysis. Based on our phase II data, we expected that eptacopan could be an oral monotherapy for PNH, as it effectively appeared to control both intravascular and extravascular hemolysis. The phase III data reinforced this expectation. In treatment-naive patients and in C5 inhibitor-treated patients with anemia, oral eptacopan highly... was highly effective at addressing anemia, preventing the need for trans- blood transfusion, and improving fatigue. ALPHA PNH, which is summarized on the right-hand part of this slide, enrolled patients with residual anemia, anemia, despite treatment with C5 inhibitors, and randomized them to continued use of the C5 inhibitor or to eptacopan monotherapy. At six months of treatment, 82% of patients treated with eptacopan experienced a clinically important increase of at least 2 grams per deciliter in their hemoglobin, and 68% of individuals experienced a hemoglobin level of at least 12 grams per deciliter, which is a near normal level. This compared to only about 2% of those treated with C5 inhibitor infusions. Similarly, in treatment-naive patients in the APPEAR trial, which is on the left-hand part of the graphic, over 90% of individuals experienced at least a 2 gram per deciliter increase in their hemoglobin, and almost 63% experienced a hemoglobin level of at least 12 grams per deciliter, while almost all patients avoided the need for red blood cell transfusions. In both populations, we saw clinically important increases in improvements in fatigue in both of these populations. So these are the results that have led experts in the PNH field to extol eptacopan as a potentially groundbreaking new therapy for PNH patients and a practice-changing option, because it showed that oral eptacopan was as or more effective at treating PNH than infused C5 inhibitors. So with eptacopan, we have the opportunity to redefine the treatment paradigm in PNH. Today, of the 6,000 patients living with PNH, about 30% are treated with complement inhibitors, and eptacopan has the potential to be a more effective treatment for the many C5 inhibitor-treated patients with residual anemia. The remaining 70% are not treated for a variety of reasons, including milder symptoms and preference to not have infusions. For these patients, based on our data to date, eptacopan should be a safe, effective, and more convenient option, and therefore, there's a possibility that we could increase the treatment rate in this 70% untreated group. And of course, new patients could start eptacopan from the beginning when they're diagnosed. So we're excited about eptacopan's potential to change the lives of people living with PNH for the better. So now we will shift gears and talk about another rare complement driven disorder, but this time in the kidney, C3 glomerulopathy. C3G is a severe primary glomerulopathy that's primarily diagnosed in people in their teens and twenties. So these are young individuals with their whole lives in front of them. And as you can see in this figure, on the left-hand panel of the slide, kidney survival in these patients is dismal. About half of patients, 50% of patients, require dialysis or a transplant within 10 years. So the time when they're requiring a transplant is when they're in their 20s and 30s. So absolutely devastating. And even worse, if a patient does get a transplant, there's a high risk of having the disease recur in the transplanted kidney. C3G is driven by genetic or acquired factors that lead to complement activation and deposition of activated C3 in the glomeruli, and this causes inflammation, scarring, and loss of kidney function, on the trajectory that you see there. So despite this high unmet medical need, there are no specific treatments available for C3G. Care is geared to attempt to preserve kidney function for as long as possible, and avoid transplant and dialysis. It really consists solely of ACE inhibitors and angiotensin receptor blockers, and it may—they may extend to immunosuppressants if symptoms persist. But, you know, despite the fact that this looks like a very well-organized and rational treatment paradigm, there's actually very little data to support any of these treatments in C3G. So this, this offers us an opportunity with eptacopan, we think, to offer an alternative for patients that can really improve their lives and extend the lives of their kidneys substantially. And the data from the phase II study increased our confidence in the, in eptacopan's potential in C3G. In C3G patients who had not yet been transplanted, who we call individuals with native kidneys, we saw a large improvement in proteinuria on the top part of the, the right-hand part of the slide. Stabilization of renal function and normalization of serum C3 levels, both at three months and at one-year follow-up. Importantly, in patients with transplanted kidneys, we saw a similar stabilization of renal function and normalization of serum C3 levels. As you can see on the bottom part of the right-hand part of the slide, we also saw a dramatic reduction in pathologic C3 deposition in the glomeruli of individuals with the diagnosis. So now we're eagerly awaiting the results from the Appear C3G phase III study, which we expect very soon. This trial includes patients with native kidneys, biopsy-confirmed C3G and proteinuria, despite optimized ACE and ARB therapy. Patients were randomized one-to-one to eptacopan or placebo, and the primary endpoint is proteinuria at 6 months comparing eptacopan to placebo. The patients then may enter an open label treatment extension period for another six months, and as I said, we expect the data in December, so anytime now. So our plans for eptacopan C3G are summarized here. As I mentioned, APPEAR C3G, we expect the data soon, and we would anticipate with positive results to conduct a U.S. filing in 2024 on the basis of that study. We've also studied another phase III study in immune complex membranoproliferative glomerulopathy or IC-MPGN. If IC-MPGN is a close relative of C3G, but it's a distinct histopathological entity and similarly doesn't have a specific treatment option. So gives us an opportunity again to expand the treatable population with eptacopan, with a therapeutic that we think could be targeted for these individuals. So to wrap up eptacopan then, this is a broad and dynamic development program, as you can see, and it's designed to bring innovation to patients who currently don't have good options to manage their complement driven diseases. I'll call your attention on this slide just to the key milestones expected for each of the indications on the bottom part of the slide there. As mentioned, for PNH, IgAN, and C3G, we have the near term milestones that I mentioned. For aHUS, we have an ongoing phase III study and expect submission enabling readout in 2025. And IC-MPGN, we just started and expect to read out in 2026. So a lot going on with this program. Okay, so changing tack a bit now and discussing IgA nephropathy in some depth, and we'll include eptacopan here, as well as the recently acquired medicines from the Chinook acquisition, atrasentan and zigakibart. IgA nephropathy or IgAN is a rare progressive kidney disease that strikes people again in their first few decades of life, so people with a lot of life in front of them. There are approximately 180,000 people in the U.S. living with IgAN, with an annual incidence rate of about 7-20 per million. The classical presentation of IgAN is gross hematuria associated with an upper respiratory illness. Though many patients actually just have microscopic hematuria or proteinuria when they're first seen. So it can take many years to make a definitive diagnosis in these patients, which is ultimately made by a renal biopsy. In IgAN, the key risk marker for disease progression is proteinuria. Reducing proteinuria is an important clinical goal for practitioners, and the U.S. FDA has recognized proteinuria as a potential basis for accelerated approval, provided that the benefit on kidney function is confirmed through longer follow-up of a phase III study. So IgAN is a great example of how a deeper mechanistic and clinical understanding of a disease can drive innovation. And over the past few years, there's been a wave of innovation in this disease that will provide treatment options for many patients. And we think the three medicines that we have in our portfolio now will be great options for individuals living with IgAN. So the pathophysiology of IgAN has been described as a four-hit model. At the root of IgAN, on the far left of this slide, is the formation of abnormal galactose-deficient IgA by plasma cells and mucosa, and this is typically described as hit one. The inciting factor or factors that causes this abnormal production of IgA is not known, but in many cases are present concurrently with a URI, upper respiratory illness, as I mentioned earlier. This is why the mucosal immune response has been implicated in the pathophysiology of the disease. The second hit then is an autoimmune response to the abnormal IgA, so formation of IgG antibodies to the abnormal IgA that's been produced by the plasma cells, and then formation of immune complexes, which often contain complement fragments, is hit three. Hit four is then immune complex deposition in the glomerulus and activation of the complement producing inflammation, scarring, and renal dysfunction. So if eptacopan acts at this final hit, preventing activation and amplification of complement and potentially reducing renal damage. So looking at the similar schematic with the four-hit model and showing this time where atrasentan and zigakibart work, I think you can see from this figure that these two molecules work in very distinct places compared to eptacopan. Atrasentan is an endothelin receptor type A inhibitor, and zigakibart is an APRIL antagonist, and they act at distinct steps in the disease pathophysiology and have the potential to work in a complementary manner, along with eptacopan, to preserve renal function. So atrasentan, which is on the far right of the slide, intercedes at hit four, but it does it in a very different way than eptacopan does. It reduces intraglomerular pressure, so it has a hemodynamic effect at the glomerulus, which reduces the load on the remaining glomeruli and allows them to function normally for longer. It also reduces inflammation within the kidney. Eptacopan, by contrast, doesn't have a hemodynamic effect, but it does reduce inflammation by inhibiting complement activation, as I mentioned in the previous slide. Zigakibart, by contrast, acts at hit one. It APRIL is a key survival factor for plasma cells that produce the abnormal IgA. And so by antagonizing APRIL, you fundamentally intercede at the root of the disease by inhibiting the production of abnormal IgA. Ultimately, when you think about it, these patients live for 40 or 50 years after they're diagnosed, and IgAN is a progressive disease. So it's very likely that many of these patients are going to require multiple modalities of therapy, as they go through that journey over the next several decades of their lives. And we're excited to be able to offer many different options for patients, depending on where they are in their disease state and whether or not they need additional therapies. So we've reviewed in the past, the very compelling proteinuria reduction data from our phase II study, with eptacopan. So now we've had the readout from the phase III ALIGN study and have shown that treatment with atrasentan, compared to placebo, results in clinically meaningful and highly statistically significant reduction in proteinuria, which, as I mentioned, is a key marker for disease progression, in patients with IgAN. So with these data in hand now, we're planning for a regulatory submission for accelerated approval in the U.S. in the first half of next year. The trial will continue in order to confirm atrasentan's benefit, on eGFR at two years, as required by the U.S. FDA. So just to be clear, why, you know, why haven't we shown any phase III data? We've issued press releases about highly statistically significant results and a big treatment effect, but we haven't actually shown you any data, and that's because we have an ongoing confirmatory trial that remains blinded. We have an agreement with the U.S. FDA that we have to be very careful about what data we put in the public domain for an ongoing clinical trial. So any data that we release will be done in after consultation with the FDA in order to maintain study integrity. So atrasentan has also shown significant reductions in proteinuria in the phase II ALIGN trial. Here, you see that treatment with atrasentan reduced UPCR by over 54%, suggesting that it, too, could be an effective agent to preserve kidney function in IgAN. Now, note, these are phase II data. This is single-arm study with relatively small numbers, so the effect size looks large, and that gave us a lot of confidence when we were looking at the medicine, you know, before we made the acquisition. The other important thing beyond the proteinuria reduction that we saw in IgAN patients was the safety profile of atrasentan. So there's been extensive experience with atrasentan in different indications, and the most relevant other indication that atrasentan has been explored in is diabetic kidney disease. And this gave us a lot of confidence, both with respect to the overall safety of atrasentan, as well as very specifically, the liver safety of atrasentan, because other endothelin receptor antagonists have had issues with liver safety in the past.... So last month, we read out the nine-month interim analysis also for the phase III ALIGN trial. So in patients with biopsy-proven IgAN on optimized supportive care with ACEs and ARBs, atrasentan reduced proteinuria, again, to a clinically meaningful degree that was highly statistically significant. And as with other IgAN trials, it'll continue to completion to 2025 to confirm the benefit on renal function. And again, we submit, we would anticipate submitting, in the U.S. for accelerated approval in the first half of next year. So in addition to the phase III readouts that just occurred, we've also started our phase III trial with zigakibart, called Beyond. So there's really a lot to be excited about in the IgAN space right now, and we have an opportunity, I think, to really change the lives of IgAN patients and prevent the progressive decline in renal function that these individuals experience, and ultimately prevent the need for dialysis or transplantation. Thank you very much. Let's go to Q&A. Maybe we, yeah, we can do Q&A. Yeah. So I think, so I think we have somewhere 15 minutes or so for Q&A. So this is now a dedicated Q&A on our, on this portfolio. Happy to take questions. Yeah. Richard Parkes from BNP Paribas Exane. On IgAN, can you help us understand a 180,000 patients, quite, quite a lot of patients for a rare diseases drug. So can you help us understand how we segment that as more, more likely eligible patient population? Mm-hmm. And then, adding to that, you talked about it being a heterogeneous disease, and we've obviously got multiple mechanisms that look like they're likely to work. But, how, where are we with biomarker development that might help us understand which drugs might work better in which patient populations? Yeah, I mean, I think the second, the second part of your question first. I think the, you know, that's an active area of research. I think as new therapeutic modalities have come forward, there's been a lot more interest in biomarker development. We were both at ASN, actually, American Society of Nephrology, last month, where there were a lot of interest. There's a lot of interesting work trying to subsegment this population. It's still early, though, so, but we're obviously keeping our eye on that space very carefully. With respect to the first part of your question, so of the 185,000 patients who are diagnosed with IgAN. So as I mentioned, there's a bit of a diagnosis conundrum here, right? Because patients, you know, with very minimal proteinuria tend not to be diagnosed until very late in the disease, right? So the symptoms are very nonspecific, because essentially, you have proteinuria, and you have abnormal renal function at some point on the lab test. However, of the 185,000 patients who are diagnosed, we estimate about 30% have substantial proteinuria, so greater than one gram per day, which puts them at the highest risk of progression to renal failure. So if you look at the numbers that we were describing, the individuals who have one gram per day proteinuria or above, those are the individuals who tend to progress to end-stage renal disease and require transplant. Maybe I'll just build on that a little as the nephrologist here. So if you think about IgA nephropathy and the injury that happens that results in protein leaking from the kidney, the single biomarker that actually was the predictor of greatest risk was the amount of protein, so the patients with more than 1 gram a day. The traditional management of these patients has been based on the use of renin-angiotensin system blockers, so ACE inhibitors or ARBs, as the basic way of reducing the hyperfiltration happening in the remnant parts of the kidney and thereby protecting those nephrons from declining function over time. Added to that is recent data on SGLT2s playing a role in chronic kidney disease progression. So what we see is that atrasentan, with its mechanism of action, is likely to be more liable to be used more in the foundational space, whereas zigakibart and eptacopan, both as being drivers of potentially interfering with actual pathogenic mechanisms of injury, may play a role in a, in a, in a different part of the treatment paradigm, pending the availability, of course, of the full data sets. When we were at ASN, the question you asked, which is: how will we manage patients with which kind of treatment, was top of mind, given that this is one space where with the FDA having introduced the use of a surrogate endpoint, there's a lot more innovation happening, and so a lot of people are now working on figuring out where is the best treatment, say, for which patients. Next question. Thank you. Emmanuel Papadakis, Deutsche Bank. Maybe follow on eptacopan, just in terms of clinical differentiation. The UPCR data in phase II was not particularly differentiated versus several competitors, some of which have already reached market. So, your optimism that the UPCR data we'll see in these phase III will look materially improved. We've also seen some mixed conversion of preliminary UPCR into subsequent eGFR results. Is it that you're more confident, perhaps, on converting an initially moderate UPCR benefit into subsequently a good eGFR? So just help us with the- Yeah ... concept there. Then maybe a quick follow-on on sparsentan, if I may. You, you highlighted the safety database. Are you hoping to avoid a black box in REMS for that, unlike its, sorry, atrasentan relative to sparsentan? Thank you. David, why don't you do it? Yeah, sure. So, starting with the second question first, on sparsentan, I think you're referring specifically to the black box warning and REMS on liver safety monitoring? Yeah, 'cause there are other warnings, you know, on endothelin receptor antagonist. So yeah, based on what we saw in the SONAR data, and subsequent publications of the experience in that, you know, very extensive patient population. There did not appear to be any liver safety issues, it identified in that study. The second thing that's important is the chemical structure of atrasentan is different than other endothelin receptor antagonists that have liver safety issues. So we believe that on the basis of those two things, both the clinical data and the structural makeup of the medicine, that we'll have a good chance at avoiding. Of course, it'll bear discussions with the FDA when we go to the registration. Your first question was around the phase II data with atacicept. So the first thing to consider is that if atacicept is a fundamentally different mechanism of action than any other therapeutic intervention in IgA nephropathy. So it would work on top of ACEs and ARBs, it would work on top of SGLT2, work on top of atrasentan, zigakibart, take your pick, because it works at reducing the inflammation in the kidney that's produced by the immune complexes. So the degree of proteinuria reduction we saw was actually excellent in the phase II study. The initial release that we talked about was at 3 months. So remember, if you look at three months' data, you would expect that improvement to grow over time. And indeed, when we looked at the six-month data and the one-year data, it did. The reduction in proteinuria continued to get better. So I think we were very you know positively. You know, we view the proteinuria data very positively from the phase II study. And then, of course, we just issued a press release from the phase III study that said that the results were clinically significant and clinically meaningful and highly statistically significant. So we're very confident. No, and I think, Emmanuel, this is where the idea that different mechanisms of action may show a different relationship between proteinuria and eGFR behavior over time. I think we don't actually have a large number of data sets. Two trials that you might be referring to have kind of behaved in a certain way. Mm-hmm. But I think given that our trials remain blinded and we are expected to maintain that blind, at this point in time, we're confident in the UPCR reduction and the eGFR information will evolve in a couple of years. But I recognize your premise that that is gonna be the important driver of distinction of different therapies. Matthew? I guess I can't see the people. I think we should just stand. Stand. We should just stand. I can see. It's hard to see people. So it's Graham Parry from Bank of America... Yeah, Graham Parry from Bank of America. Just a question on XXB750. Just what, what's your target product profile for that? So is this, you know, sort of supercharged Entresto with subcut, less frequently dosed? When you're running, thinking about the sort of forward to a phase III program, is this gonna be head-to-head versus existing hypertension, heart failure agents? Just helps understand sort of how you see that fitting in into the treatment paradigm. Thanks. Yeah. So the ongoing phase II study is in so-called resistant hypertension patients. So individuals who've had other, you know, treatment modalities optimized in a run-in period, and then they're randomized to XXB750. So we see XXB750 as an add-on therapy to individuals who have difficulty controlling their blood pressure with available therapies. I mean, I think that speaks to the TPP, right? So you have to be able to show that a medicine that does that, both that's highly effective, as we saw from the phase I data and from the preclinical data, and is long-acting, is both highly effective and well-tolerated. So those are key outcomes from the phase II study, and so far, things look excellent, and we're looking forward to revealing those data next year when they come out. Matt, I think a little too early to comment on the exact plans for heart failure, because it'll really depend upon what data we gather from the ongoing phase II study after we have data from the resistant hypertension trial. So it's early times. Okay. Thank you. Simon Baker from Redburn Atlantic. Two if I may please. Firstly, on atrasentan and PNH, you talked about expansion to that 70% who are not currently treated. How far into that group do you think you can get? What... In other words, what percentage of that group could get inhibitors therapy but currently don't? Mm-hmm. To give us some idea of the potential there. And then secondly, on zigakibart, beyond IgAN, as an anti-APRIL antibody, what do you see as the scope for other therapeutic indications? Mm. I'm particularly thinking about SLE. Thanks so much. Mm-hmm. Yeah. I mean, I think the... So with respect to the second question, we are actively looking for other opportunities for anti-APRIL. It is a very interesting mechanism of action, a very specific mechanism of action for plasma cell. And if you saw the preclinical data with the zigakibart, it's very, very good at reducing IgA and IgM, but it doesn't affect IgG particularly much, or, you know... So as in terms of a safety profile, it looks like it's very interesting to pursue potentially other indications. I forgot the first question. Well, the proportion of patients in PNH that are not previously- Oh, right. Yeah, yeah. The naive one. So PNH is a highly variable disease, and it really depends on the size of the abnormal hematopoietic stem cell clone, right? How much of the red blood cell mass is derived from those clones into abnormal PNH red cells. So in classical PNH, those clone sizes are large, and those people have profound anemia, you know, profound fatigue, and so forth. So those are the obvious patients, probably the 30% who are currently treated. The 70% have variable-sized clones and variable contribution of other bone marrow-depressing features in their disease. So the extent to which we can penetrate in that population really depends on how much of their anemia is dependent on PNH, the clone size, versus bone marrow failure. And so it's gonna be variable, but it's something that we're, you know, we're actively looking at. Yeah, and I think the only build I have is that the insight we have is that patients sort of, and their physicians, get used to accepting patients having fatigue and- Yeah and being anemic and not being able to lead the normal quality of life. And we think that this will be a journey where, having had the experience of treating patients who are anti-C5 unresponsive, and then gain that experience with the drug, we'll start moving patients into the much easier to start oral eptacopan for a disease like PNH, because patients should have the opportunity to live as close to normal a life as they can. Brad, do you want to go to the web for the last question? No, we have one more minute. Okay. All right. Another question from Steve from Cowen: AstraZeneca has oral PCSK9 data in-house. What profile does Novartis anticipate? What profile would be a risk to Leqvio, and what profile would be uncompetitive? Does Novartis have any data supporting the thesis that more convenient dosing can translate into improved population level, CV outcomes due to better adherence? Yeah, I mean, I think the most compelling piece of information that I can share is that even after a heart attack, half the patients stop taking their statin, right? So there are effective ways of preventing a second heart attack now, and it's really by optimizing LDL lowering and, you know, people adhering to high-intensity statins, and yet people do not do that. And so as Shreeram mentioned earlier, and Fiona mentioned also with respect to RNA, xRNA technology, long-acting agents take that adherence out of the equation. So you know, I don't wanna... I don't think that Leqvio is solely, though, about the convenience of use in the six-month dosing. It also profoundly lowers LDL. And so if you get rid of the sawtooth nature of whether or not you take your statin, or whether or not you happen to dose your PCSK9 monoclonal, and you have a smooth reduction, profound reduction in your LDL, you're likely to have better outcomes overall at a population level and at an individual level. So I think, you know, that's the strongest information I could share. All right. Thanks, Dave. I think we're at the end of our cardio, renal, and metabolic section, so we can... Andrew? Andrew, one more? Yeah. Thank you. Just a question on pelacarsen, following up from the conversation we had. Could you just confirm that Horizon, there's unlikely to be any data from Horizon in 2024? Because I think you list 2025. And then second, there clearly is a lot of competition chasing the same target with agents which have better scheduling in terms of frequency. Mm-hmm. You do have a less frequently dosed oligo, in early research, but to get it to market a timely way requires the FDA to approve using a surrogate. And so my question is, whether Lp will be viable as a surrogate, assuming Horizon works. Do you have any understanding? Have you had discussions with the agency? Mm-hmm. Because obviously, that depends on your ability to compete. Yeah. I mean, with respect to surrogacy, I mean, it, you know, Horizon will be the first study to show that lowering LDL, Lp(a) actually improves cardiovascular outcomes, so it's early to talk about surrogacy at this point. With LDL lowering, it took quite a bit longer for LDL to become a surrogate for approval. But I think that, I think with a positive Horizon study, and then with additional outcome studies showing a similar benefit, for example, the pelacarsen study that's ongoing as well, there's a basis for a discussion about approval on the basis of surrogate LDL, Lp(a) lowering, but that's gonna bear discussion with actual data in hand. So it's hard to know right now whether that will be the future or not. Yep. Dave, our expectation on data is 2025. Yes, 2025. We're... Yeah, we don't, we don't anticipate sharing anything earlier. Good. Thanks, Dave. Steve? All right. Frame shift to immunology. So, so I think on immunology, we've had a lot of conversations about, about what our core, core principles are. I plan to quickly share with you, an update on Cosentyx and where we stand with our lifecycle management, covering ianalumab, our, our B-cell depleting antibody, and then, talk some more about YTB. Again, delighted that with Cosentyx this year, we were able to secure approval for Cosentyx and hidradenitis suppurativa, a terrible disease. Again, a major unmet need, only 5% of patients treated with a biologic. Those that are treated experiencing loss of efficacy over the course of a year. With the Cosentyx data demonstrating durable effects, seen over a year, and us having gotten it approved with the FDA with a great label that also supports the use of every two weeks dosing for those that don't respond, and whether there's the absence of certain safety considerations that some of our competition has, we are quite enthusiastic about the Cosentyx HS approval that was recently secured. We also secured approval for the IV formulation earlier this year, and that offers us... Again, is being received with early times, but I think that physicians, rheumatologists, see that as an important option for them to have. The team is now focused on, of course, delivering all the three major lifecycle management actions that are ongoing, both with giant cell arteritis, polymyalgia rheumatica, and rotator cuff tendinopathy, and getting those done and delivered, prior to loss of exclusivity for Cosentyx. I want to spend a little time on the ianalumab, VAY736, which is our dual mechanism of action, anti-BAFF receptor antibody that delivers deep, long-term B-cell depletion. And we believe through this mechanism, has the potential to be effective in a number of B-cell mediated diseases, where prior, targeting of B-cells with, say, anti-CD20s may not have been necessarily as efficacious. As a result, the ianalumab is being actively evaluated in phase III programs, in Sjögren's syndrome, in SLE, in lupus nephritis, on the immunology side, and as you will hear, also on the hematology side, for the treatment of both first and second line immune thrombocytopenic purpura and warm antibody autoimmune hemolytic anemia. Our confidence in ianalumab comes from two sources of phase II data. First, our positive study in Sjögren's syndrome, a disease that has been traditionally difficult to demonstrate positive results in, in terms of efficacy. But we were pleased to report that, in our phase II studies, that we saw both, an SI response as well as movement of patients from mild to moderate, moderate to severe disease activities into the milder ranges in a 24-week period. But even more importantly, beyond the Sjögren's data, we were also excited about our data from the SLE study, where unlike the traditional prior data with other agents that have shown about a 20% improvement in responses in terms of SRI 4 proportion of responders over a year. We were, in this 28-week study, able to see nearly a 40% improvement in those patients responding with a 4-point improvement in the SRI 4. So super excited to have seen these phase II data. And when I'm often asked, what is the asset that I believe is perhaps less understood or less valued by those outside, I certainly see ianalumab as an agent that we are closely focused on and see great potential in. I think that in the spirit of B-cell depletion and targeting autoimmunity, much excitement, as we've been discussing in the community, about the possibility of an immune reset, mainly, B-cell depletion, resulting in the removal of an autoreactive B-cell clone, autoreactive clone, with reconstitution, with essentially a naive immune system that then results in disease remission. With the exciting data from the folks at Erlangen and Dr. Schett's department, having seen that across a number of different refractory autoimmune diseases, we've certainly now rapidly started our plans for evaluating our well-established second generation T-Charge CAR-T CD19 YTB, and taking it into this space. Our translational teams are running the early assessment, which was presented—the 3 patients were presented at ACR. It's early data, but as this data have evolved, they have stayed as expected, in keeping with the course for the patients seen in the Erlangen data set. What we are focused on, of course, is making sure that we bring all of our capabilities together in order to both engage regulators, as well as make the plans for the phase II studies across multiple indications both in lupus and beyond and moving those forward. And so please stay tuned for progress on that front. But again, we recognize that it's early times, but we believe that this is the kind of early disruption that, should it work out, has the potential for transformation. Fully recognizing the fact that moving from the more refractory patients into earlier lines of autoimmune disease patients will require a better understanding of benefit, risk, and also modification, potentially of the necessary lymphodepletion regimens that go along with it. So with that, I'm pleased to introduce Angelika Jahreis, our Immunology Development Unit head, herself, a rheumatologist and a more than two-decade drug developer with long-standing experience in immunology. Angelika, I'll hand it to you for Remy. Thank you, Shreeram. Remibrutinib is indeed a very exciting molecule. It is an oral BTK inhibitor, a Bruton's tyrosine kinase inhibitor. It's highly selective, potent, with best-in-class potential. We have just shared our data at the EADV Congress for this molecule, and I would like to highlight three attributes of the two phase III studies that really stood out. One was that we have seen consistent as well as transformative efficacy in patients with inadequate response on antihistamines. Secondly, and that is really important to patients, was the fast onset of action, because patients suffer from quite intense pruritus. So for us, onset of action is something that is critically and crucially important to patients. Lastly, and that is something that is, has been raised for the class, is that this molecule has shown favorable safety, and in particular, we have seen favorable liver safety. So with that, there is great excitement in the community about this asset. Now, based on the oral convenience, the efficacy I will share with you, as well as the safety that you will see in the following, we believe there is a significant opportunity for remibrutinib as a first option after antihistamine therapy. Now, let me start with, sharing with you the selectivity data from the kinome assay that we have done across more than 450 kinases. And as you will see on this slide, the red dots represent kinase inhibition, above a certain threshold. For remibrutinib, you see a large red dot that represents the inhibition of Bruton tyrosine kinase, as well as a small dot, which is a 175-fold lower inhibition of TEC kinase, but no other kinases are above the threshold.... Why do I highlight selectivity? I highlight selectivity as off-target binding can lead to off-target toxicity, so selectivity for kinases is crucially important. Now, let me shift gear, and let me talk about the disease that we are talking about. And I would like to start out with the quote on top, and really ask you to take a look at it, because it's from a patient, and it summarizes very well how patients feel about CSU. CSU does not kill you, but it also does not let you live." I'm sharing with you two pictures here, one of the hives of a patient with severe disease, and as you can imagine, having 50 hives, hives or more, which is the definition of severe disease, really leads to intense itch that impacts your quality of life, your sleep, your fatigue, your ability to be productive, to work. Huge impact. Just remember and recall when you were stung by a few mosquitoes, how that impacted your sleep. Having this daily occurrence of hives to that amount, as well as unpredictable onset of action, is highly debilitating. On the other picture, I share a patient with angioedema, and about 50% of patients have angioedema, which is a swelling of the subcutis or mucous membranes, and this is a very disfiguring picture just of the mouth, but imagine having that on your tongue or on your throat, and then having to experience an inability to breathe. So this is a life-threatening complication leading to asphyxia. And one question that comes to mind when you think about this disease is: how can we treat it best? And currently, there is a true paucity of treatment options available for these patients. There is a single mode of oral therapies available, which are antihistamines, and based on the paucity of these treatment options, physicians currently uptitrate antihistamines to up to four times the level of antihistamines that are typically given, leading to side effects like somnolence and fatigue. Of those patients with CSU, only 60% respond to even uptitrated doses of antihistamines. So 40% of patients do not respond and cannot be controlled with antihistamines, and these patients have a huge unmet medical need, because these patients are refractory or unresponsive to standard of care, and there is very limited biologic penetration. Remibrutinib inhibits a central node in the pathogenesis of chronic spontaneous urticaria. Chronic Spontaneous Urticaria, we've learned in recent years, is an autoallergic or autoimmune disease, and as you can see on this graph, on this slide, that either autoallergic disease or autoimmune disease both go through a central node of Bruton's tyrosine kinase to lead to the release of histamine. Remibrutinib blocks that central node, inhibits selectively that central node, and thereby resolving the key molecules that propagate the disease. I will share with you now the data from the studies that we have done. These were two adequate and well-controlled studies. The primary endpoint for efficacy was week 12, and I'll share with you the week 12 efficacy data. The readout for safety is over the entire placebo-controlled 24-week period. Endpoints on the left, see, you see on the left, on the left-hand side of the slide, and before I go into the results, I want to just highlight two different, three different attributes of the patient characteristics. First, remember that patients, in fact, 60% of the patients involved in this study had severe disease. In general, we only involved patients with moderate to severe urticaria, chronic spontaneous urticaria, in this trial. Also, 50% of patients here had angioedema, and that's very different from other trials that have been reported in CSU. 30% of these patients had prior biologic exposure to anti-IgE. So with that, I'm very excited to share the data that Dr. Saini shared at the EAACI Congress two weeks ago. As you can see here, this is the primary endpoint for the European submissions. That is the mean change in urticaria activity and severity scores over seven days. We had a statistically significant and clinically meaningful reduction by 65% in the mean UAS7 across, consistently across both studies. What is very exciting about these data is truly the early onset that remibrutinib has. As you can see on these slides here, across both studies, we already saw a separation of the curves at week one, which is incredibly meaningful to patients that suffer from a debilitating disease. In addition, we saw across both signs and symptoms, itch as well as hives, we saw a consistent effect.... Itch is being described by patients like ants crawling under their skin, their skin being on fire. That is what patients experience, and we have seen a 65% reduction in itch, as well as hives, at twelve weeks already. I would like to talk a little bit about well-controlled disease that is shown on this slide. Well-controlled disease is measured by a UAS7 of less than 6. That means a mild itch, as well as a few urticaria over time. This is important to patients. Why is that important to patients? Because if you think about severe disease, as shown on the slide that I've presented before, compared to patients who have well-controlled disease, the impact on their health-related quality of life is about a tenth of that. So these patients can already live normal lives, and therefore it's important. A third of the patients at week 2 already achieved well-controlled disease, and 50% at 3 months. Now, the treatment goal for all of us, treating physicians, is to achieve complete disease response with complete absence of hives and itch. I'd like to again bring back that picture of that patient, because going from that level of disease to absolutely no hives and no itch over a continuous seven days is quite a dramatic improvement in disease severity. And that is what we have shown with remibrutinib at three months. Now, this slide summarizes the efficacy data, and Marcus Maurer, one of the key eminent people and physicians in the treatment of CSU, and also the head of our steering committee, commented on how consistent the data were across all endpoints and how meaningful that is to patients. I would also like to call out how important fast onset of disease, as well as achieving well-controlled disease, and that a third of the patients were free of hives and itch, how important that is to patients as well as treating physicians. I think we cannot underestimate these data. But as we all know, in a disease like urticaria, efficacy is one part of the equation. We also want to look at safety, and that has been a key interest of the community, to understand how safe are BTK inhibitors. We have seen, this is now the week 24 data, comparing remibrutinib versus a pooled safety from both phase III studies, comparing it to placebo in this pooled comparison. The overall adverse events were comparable to placebo. Infections comparable to placebo. As you can see, serious adverse events, there was no significant difference. Treatment discontinuation were balanced as well. With respect to petechiae, we saw a slightly higher, higher rate of petechiae in these patients who were daily, twice daily, assessing themselves for urticaria on their body. What, what has been a keen interest is the liver toxicity, and we have seen no signs of liver toxicity. When we looked at elevations of ALT and AST across three times upper limit of normal, these were balanced across both studies. In addition, I would like to highlight that the liver transaminase elevations observed were transient, reversible, and most of them were reversible by continuing on therapy. We have also published data at the archive meeting of the 52-week phase II extensions, where patients were treated for 52 weeks on 100 milligrams twice a day on remibrutinib. So four times the dose that we have studied here in the phase III studies, and the data are very consistent. We have seen no safety signal there, and importantly, liver safety findings were fully in line with the data that I'm sharing with you here. I'd like to conclude the presentation of the CSU data with what Dr. Saini said at the archive meeting, and he talked about how clinically meaningful these data are of a convenient oral therapy for patients who are not controlled currently on antihistamines, with consistent, profound safe, efficacy and a favorable safety profile. So next steps for us are to bring the, to bring this molecule to patients as quickly as possible, and we plan for global submissions with the entire 52-week data readout, by in the second half of next year. Now, let's look forward. Remibrutinib, we also have programs ongoing, not only in CSU, as I've shared with you right now, but we've also initiated phase III studies in a sister disease to chronic spontaneous urticaria, which is Chronic Inducible Urticaria with a similar mechanism of actions. We also have a phase II study ongoing in food allergy, which is a very prevalent disease, where we have similarly an activation of mast cells and basophils, with mast cell and basophil degranulation leading to the symptoms of food allergy. And we will be sharing with you soon data from a study in hidradenitis suppurativa, and next year, we will share this data at a major conference. In addition to the programs that are currently in immunology, in the immunology development unit, we also have a very exciting program ongoing in neuroscience. And Shreeram, I wanted to invite you to speak a little bit about the program. Thank you, Angelika. I know that Norman is here as well. I know that everyone is interested in the MS program. The two studies are ongoing. We continue to monitor patients, use the appropriate liver monitoring that has been expected by the FDA, and to date, haven't seen any signs that concern us, but we of course continue to monitor. This is a higher dose than was studied, but we're very reassured, and I think as Norman has often told me, among the investigator community in MS, the data from CSU have actually been a very encouraging development. These data, of course, are expected to be reading out in 2026. I just want to end quickly on just a quick snapshot of our key MS port pipeline. We will not be going deep on it, but I just comment to say that the key focus now is on the remibrutinib MS studies that are running, as well as the Zolgensma IT program, which is on track and expected to read out in 2025. 2025. Norman is here to take any questions, but with that, I think we'll break for now the Q&A on immunology and neuroscience. Andrew? We'll start with Andrew, then. Many thanks. Just going back to your autoimmune targets in immunology. The FDA just put out a warning of malignant transformations, T-cell malignancies in patients treated with Kymriah, and pretty much every other BCMA and CAR-T in lymphoma. Given the equation in autoimmune versus oncology is somewhat different, and therefore one would be more nervous, and given YTB has greater in vivo expansion than Kymriah or many of their competitors, how do you think about assessing this risk, and do you see it as a regulatory concern? It is certainly an important risk, and patient safety is always of utmost importance. I think, in autoimmune diseases, we have to consider which patients we treat, and we will follow them very carefully. We are treating patients who have serious refractory autoimmune diseases with organ-threatening or life-threatening disease. So I think the equation, too, in these patients and the promise for this therapy to lead to long-term remission makes this, for me, a very positive benefit-risk assessment. Now, talking specifically about YTB, I think as you may be aware, that for YTB the dose of the cellular dose is much lower than we give. We give 12.5 million cells, whereas for other cell therapies, a much higher larger dose of cells need to be given. If this wouldn't reduce the risk, right, of any malignant transformation is unclear because the transformed cell numbers that we provide is much lower compared to other therapies. So I think the data will have to play out. I would also like to, and maybe, Jeff, you can comment on that, but that the risk to date, as I understand it, is extraordinarily low, right? It is certainly something that we have to watch, but the risk, as I understand it, is extraordinarily low. Yeah, and I think... I mean, I think, Richard, the, you drew a link to in vivo, greater in vivo expansion and the risk of transformation, and I'm not sure that those two are- Yeah necessarily linked. I also think it's early times from having received the FDA pharmacovigilance message about having seen what they called a signal and its incidence and how real it is that I think it's early times. But, but I think your point about us matching the benefit risk for in the autoimmune space is, of course, an important consideration, but I don't believe this particular one is yet ready for that discussion. Thanks. Richard Foster from JP Morgan. Just on the liver safety of remibrutinib, maybe you could just give us a little bit more detail on when the ALT rises occurred in the CSU trials. Were the rises sort of three times upper limit normal, or were there some at ten times upper limit normal? Some of the severity of those would be very good. And just also on the monitoring frequency that you're using in the RMS trials, if you could give us an idea of whether that's now weekly or whether that is bi-weekly or what it is that you're doing, that would be very helpful. Thanks very much. Maybe I'll start, and then I'll ask Norman to comment on the MS trials. I mean, I think, Richard, I think I'll just say to you that from the data that we have gathered, we are not seeing a risk of liver toxicity that is attributable to remibrutinib in the CSU program. I think, I think that's where I will pause. I think in terms of the MS program, we are monitoring as required by the FDA across all MS studies. You have a mic on, yeah. Yeah. Yeah, thank you. We get the question a lot on liver tox in the MS program. So essentially, we had to revise our protocol to just follow FDA guidance for liver tox monitoring across all BTKI trials in multiple sclerosis. So that was not triggered by any data that were generated in our program. So just the FDA taking a blanket approach to the monitoring. And We test every two weeks initially, if I recall correctly, the first three months. Still every two weeks or only once a week? I think I would need to look this up and get back to you in detail, but I think we monitor every two weeks for three months, and then monthly. ... Okay. Thank you. Mark Purcell from Morgan Stanley. Just staying on the same topic and remibrutinib and ALT elevations. I'm not aware of BTK receptors in the liver, and so just in terms of hypotheses which might help when it comes to, you know, class mar- sort of class labeling, et cetera. Have any studies been done mechanistically to look at some of these off-target kinases and their potential involvement with liver changes? You listed a whole alphabet, BMX, CDK3, RS2, et cetera, et cetera. So it'd be interesting to understand that, or is it potentially a disease phenomenon that you're not seeing it in CSU and less systemic autoimmune diseases, you're seeing it more in disease where there's more skin inflammation? So just, I guess, a disease difference or a tyrosine kinase selectivity difference. It would be great to get your hypotheses. Sure. I think, with respect to, BTK, it's very clear that in XLA, which is a, is a, a loss of function mutation in, in humans, right? That is not associated with any, any liver toxicity, nor have we seen, nor if you look at knockout mice, do you see any liver toxicity. You are correct, right, that, BTK is not expressed in, hepatocytes, and we have not seen any signs of, hepatotoxicity in preclinical or clinical studies to date. I can't comment on, other molecules and, the potential why they lead to... why they may lead to, to hepatotoxicity. It could be a idiosyncratic effect, I do not know. But, certainly from the data that we have seen, we have no indication that, this is an on-target effect. Actually, all the data suggests that this is not a PTK-driven disease effect. Um, Seamus? Seamus Fernandez from Guggenheim. So can you talk a little bit about ianalumab and sort of the comparison between your CD40 data with the secukinumab in Sjögren's in particular? It seems like Sjögren's could be a potential breakthrough treatment, and you know, we haven't had any successful options there. And then just separately, on ianalumab, more specifically, SLE, and other B-cell targeted therapies, why would targeting BAFF specifically in this setting be more successful than potentially targeting CD20, where we've seen some issues? And maybe this comes down to patient selection, and your patient selection is improving. Thanks. You thought a lot about it. Yes. So with respect to Sjögren's, I think for the first time with the ianalumab, we have certainly seen a dose-dependent effect. And we have seen, as Shreeram has shown, in our phase II data, we have seen that about 30% of patients have a clinically meaningful response, response, with respect to the SI index, which is the index that we measure by the response. So this has been the first time we've seen a dose-dependent effect, also the first time we've detected such a large difference, and this is the largest trial. So I think these are quite positive data for Sjögren's. As you rightfully noted, we have a pipeline of molecules in Sjögren's, as we think that this is a very important disease that currently does not have adequate treatment options. Actually, it has no approved treatment options for Sjögren's, and it is one of the larger rheumatic diseases. So huge unmet need in Sjögren's, and we are quite excited that three molecules have actually met the primary endpoint, the ianalumab, Iscalimab, that you highlighted, as well as a study with remibrutinib that has just been published. So good pipeline in Sjögren's. To talk a little bit more about about lupus. In lupus, what is... Certainly, if you think about the BAFF receptor and the fact that ianalumab is a afucosylated molecule and thereby depletes these cells, we deplete a much larger and broader B-cell lineage, the CD20 molecules. So yes, trial designs have evolved since the early days of CD20 molecules in lupus, but in addition, we are not only depleting a broader B-cell population that is important in lupus, we are also depressing BAFF levels that tend to increase under B-cell depletion. We are depleting and depressing the BAFF levels that are a key factor that leads to the growth of these B-cells. The dual hit is kind of what we think has led to the very exciting data that we have seen, with an early response already at week 24 in an SRI 4 response of 44%, which is quite unprecedented for other molecules. But it's a small study, so we will have to see that we can replicate that in phase III. We are cautiously optimistic, but very excited about the prospect of this molecule across B-cell mediated autoimmune diseases. Thank you. It's Keri Halford from Berenberg. Couple of questions on remibrutinib, please. ... firstly, on the dosing and dose frequency, could you just confirm what you're using in the different indications? You mentioned it was higher in MS. So can you clarify what that is? And indeed, whether you have plans to go from twice daily to once daily dosing, if that's an option. And then also, you've raised your peak potential since the previous update to now more than $3 billion from more than $2 billion. So can you just talk us through what's driven that upgrade, and what indications are assumed within that? Yes. So happy to confirm the dose for chronic spontaneous urticaria. Our phase III studies, we treated patients with 25 milligrams twice a day. And for the MS studies that are currently ongoing, we are treating patients with 100 milligrams twice a day of remibrutinib. We are for all of the dermatology indications that we are conducting currently, we use the 25 milligrams twice a day dose. We expect to keep it twice a day, right? Yep, we expect. That's the kinetics of the- Yes. We have. Yep. Angelika, I think in terms of the raised guidance, I think it was... I mean, do you want to comment? But I think it's raised on the basis of the fact of the data that we've seen for CSU, the fact that we believe we have an opportunity to intervene in a population that currently has limited options between antihistamines and biologics. I can. Yeah. So I think a couple of things lead us to have the optimism on remibrutinib. One, as both Angelika and Shreeram have shared, very compelling data in CSU with a sizable market population that is in this pre-biologic setting. It's an undertreated disease. Most patients ultimately don't get to biologics, so to have an oral option, importantly, with rapid action. So I think, Yes ... some of the commentary is focused on cross-trial comparisons of the overall efficacy. But generally speaking, for these patients, they want to see an impact quickly because they're unable to sleep and have a debilitating hives and itch. So to have that response within two weeks was something that was our upside case, certainly on the target product profile for this medicine. So that caused us to have a lot more optimism on this front. And then I think that, combined with the level of efficacy we saw with the strong safety profile at this dose, and given the data we currently have in other conditions, as Angelika mentioned, you know, both MS, food allergy and hidradenitis, potentially in other conditions, we'll see about Sjögren's. There's an opportunity, we think, with this lower dose now, to make the medicine a significant medicine in immunology alone, irrespective of what we ultimately learn in the much more competitive multiple sclerosis space. And so that means as a standalone asset within immunology, we think this could be a lot more commercially compelling. I think it's me, Emmanuel- Hi, Emmanuel. Deutsche Bank. Thanks. Quick follow-on question on the REMIX-1/2 data. You commented that approximately 30% of patients had already received a biologic. We've seen some other products struggle recently in terms of showing a benefit in omalizumab-experienced patients. Could you just comment on the consistency of benefit you saw from remibrutinib in that subgroup of patients, and what we might expect to therefore see in terms of the labeling? i.e., could it potentially be both naive and biologic-experienced patients? And then very quick question, what does the FDA actually want to see in the 52-week data? Thank you. Let me start with the latter one. I think in general, for a new molecular entity, 52-week data is across immunology, what FDA would expect from any molecule in order to be assured of its safety. So 1-year data is not anything atypical. That is typically what we share with the agency for immune-mediated diseases. If it is a new molecular entity for life cycle opportunities that may be shorter, but for initial indications, that is just what we typically expect. Now, with respect to your other question around the consistency of data, we will share this data next year at the AAAAI meeting, and you can take a look at this data. But I, the data has been quite consistent. The data will be shown in more detail there in the omalizumab pretreated patients, whereas those patients who were not omalizumab pretreated. Okay. Peter? Final question. Hi. Just wondering, has there been any discussion internally to potentially deprioritize multiple sclerosis entirely for remibrutinib? I mean, I guess it just seems as though, you know, you're studying a higher dose. There's a potential for a safety finding in that study. You are clearly excited by the dermatology potential and advancing that. Why jeopardize, I guess, that peak potential versus going for a more competitive market? Or equally, why not go, if you are going MS, why not go for the perhaps bigger unmet medical needs, such as primary progressive, where an oral could potentially be advantageous, rather than pursuing the more competitive, relapsing market? Well, I'll start. I think that the opportunity in MS remains, so I think deprioritizing it at a time when we see no reason to do so, we have the trials running, and we plan to deliver them. We believe we have the potential to deliver potentially Kesimpta-like efficacy while impacting disease progression. That's number one. And I think on the dermatology side, the fact that we plan to take those indications always at the lower dose allows us to expand that dosing into a broader group of immune-mediated disorders. Norman, do you want to talk about primary progressive? Yeah, I think we should, yeah. Yeah. Well, I actually think the more data we see for this asset, I think that the potential of multiple sclerosis has rather increased, and we have not seen any data that would indicate a risk that we didn't think about when we incepted the program at the end of the day. So the more data we are seeing, phase I, phase II, now phase III, this seems to be a very powerful medicine. So and for multiple sclerosis, we aspire close to Kesimpta efficacy and a clean safety profile, and thus far, the efficacy we need to generate, but from a safety perspective, I think we are just reassured by the data that we have seen. Primary progressive MS is about 10% of the population. I think generally progressive MS is a high unmet need, and we are working in that space to address particularly progression independent of relapse activity, because we are getting really good at controlling relapses. In terms of priority, I mean, generally, the BTKI approach, we don't favor it. We have different plans that we can, yeah, talk about. We think that targeting mechanisms within the CNS more effectively than peripheral BTKI modulation should show more promise, but that's an ongoing conversation, and I hope we can talk about this soon in the near future. Okay. Thank you, Norman. With that, I think, Samir, we go to our next mingling break. We have a break till 5:00 P.M. Yeah. So break until five, and then we start with oncology. Thank you, Angelika. Thank you, Norman. Welcome back, everybody. And now for the review of our oncology portfolio. Again, like we said before, our primary principle here is the opportunity to move our assets into earlier lines of therapy, for patients where we have demonstrated benefit in a later line. Continuing to build our portfolio in the three solid tumors that we have chosen to focus on. We've heard a lot of discussions about RLT. So what I'm gonna do is to quickly give you an update on ianalumab in the hematology indications, quick brief on Lutathera, and then JDQ. Then Jeff, our development unit head for oncology, will go take deep dives on Kisqali, Pluvicto, and Scemblix, which I know are of great interest to everyone in the room and on the web. When it comes to ianalumab, we spoke about the unique opportunity for ianalumab to offer sustained B-cell depletion. And we expect to deploy that modality with the ianalumab administered IV to explore if we can deliver on one key promise, which is: Can a short course therapy with ianalumab delivered IV with four doses allow us to achieve disease treatment-free remission in ITP, over time, as well... In the presence of reduced steroid doses and in autoimmune hemolytic anemia, the ability to maintain durable hemoglobin responses? This hypothesis is now being tested in three phase III studies that are ongoing. One first line in ITP, a second-line ITP study, and then a warm antibody autoimmune hemolytic anemia trial that are all well on their way and recruiting, and we are excited about this possibility. When it comes to Lutathera, we are all aware of the excellent data that we had with Lutathera in gastric and pancreatic neuroendocrine tumors in the second-line therapy, which was NETTER-1. I must say that when you look at those progression-free survival curves with a hazard ratio of 0.18, the dramatic benefits that a radioligand therapeutic can offer in a safe, effective therapy is certainly, that is probably one of the best illustrations. We then decided to evaluate NET Lutathera in first-line therapy, again, in this principle of moving into earlier lines, and NETTER-2 delivered positive results that we expect to present at an upcoming congress in the first quarter. And then, again, keeping the principle of taking a radioligand therapeutic and deploying it against tumors where the target antigen is expressed, evaluating the role for Lutathera in both small cell lung cancer and glioblastoma multiforme are early-stage evaluations that we are undertaking. And then finally, when it comes to our interest in lung cancer, an area that we have been present in, we have chosen to take JDQ, our KRAS inhibitor for KRAS G12C mutants. Recognizing that there's competition in this space, but we believe that our molecule, with its unique attributes and specific features, allows us to dose it in a manner that allow... It is well tolerated, especially in combination with a PD-1, based on the early data that we have released. The plan now is to launch two phase III studies with JDQ in combination with Pembro. We are, we are gonna go with a PD-1 that is regularly used, and we believe that that gives us the opportunity to evaluate a role for JDQ in first-line non-small cell lung cancer. Those trials are expected to start in the coming months, and we look forward to pursuing that further. Happy to take questions later, but for now, I'm gonna hand it over to Jeff to take us through deep dives on Pluvicto, Kisqali, and Scemblix. Jeff, actually, all of you, I think, know Jeff. Jeff has interacted with everyone. Jeff, of course, has been involved in drug development and oncology now for more than two decades and is a key member of our team. Jeff, welcome. Thank you, Shreeram. Lots to be excited about in oncology, but as Shreeram alluded to, I'm gonna focus on 3 medicines today. Although they're in distinct disease entities, they share some common attributes. I think first and foremost, these are approved medicines, largely de-risked, with a proven benefit risk already in certain patient segments. I think secondly, there's a clear opportunity for indication expansion, in particular, to move these approved medicines into earlier lines of therapy, earlier stages of disease, representing a potential of expanding the benefit by anywhere from 2-4 times beyond the existing approved indications. And then lastly, they share commonality around either unique modalities or unique pharmacology, very strong scientific rationale, already proven established benefit risk, thus gives us reason to believe that these are high probability of success opportunities that we are prosecuting. So I'll start first with Pluvicto. So Pluvicto remains the first and only approved radioligand therapy that targets PSMA for patients with metastatic prostate cancer. I think secondly, the data that's already been presented for both the VISION patient population as well as PSMAfore, gives us further confidence around the opportunity of extending this into either earlier lines of therapy or earlier stages of disease. And then lastly, also provides us an opportunity to think about how we can actually diagnose patients differently using radioligand imaging, as well as the potential of treating what we see. So just a reminder of the epidemiology and how patients are treated today. Prostate cancer remains the second most common cancer, as well as the second leading cause of cancer-related mortality in men, you know, with nearly 1.5 million new diagnoses each year and almost 400,000 deaths.... Although there is a large advancements in the number of new treatments, I think the mainstay principles of how these patients are treated remain fairly consistent. When a patient's initially diagnosed, they undergo local treatment, either with definitive prostatectomy or localized radiation, such as EBRT. Then depending on a patient's prognosis, they are either watchful waiting or active surveillance. Unfortunately, a reasonable proportion of these patients see their disease recur, as evidenced by a rise in PSA. At that point in time, patients are then subject to androgen deprivation, you know, and or hormonal therapy, which unfortunately is not curative, and these patients are then subject to either chronic or episodic hormonal blockade, up to the point when all of a sudden they lose their sensitivity or become castrate resistant. About 35% of patients go on to develop metastases within two years of diagnosis. Once a disease metastasized, we see that their five-year survival rate actually drops off quite precipitously, and the median survival for these patients is only around 30, 30%. If we look at our overall development plan, our overall ambition is to actually continue to advance the practice-changing benefit that was observed in the VISION trial and the PSMAfore into earlier lines of therapy. If you look at the opportunity in these four distinct patient segments, you see that we could potentially expand this benefit anywhere from 2-4 times the number of patients that are currently treated today. Just as a reminder, for the original VISION trial, which was tested in patients who are second and third line, previously exposed to at least one or two prior lines of therapy. As you see here, this trial met both primary endpoints with a clinically meaningful and statistically significant improvement in radiographic progression-free survival, as well as overall survival. I want to just draw your attention to the Kaplan-Meier curve on the right, which is the overall survival data. As you can see here, these Kaplan-Meier curves separate quite early and remain separated throughout the entire duration of follow-up, representing a nearly 40% reduction in the risk of death. The reason why this is quite notable is, in this particular trial, crossover was not allowed, so I think these represent the true clinical benefit that Pluvicto could deliver when the trial is not confounded by subjecting patients to crossover. A similar level of benefit was observed for radiographic progression-free survival in the PSMAfore trial. These results were recently presented at the ESMO Clinical Congress back in October. As you can see here, the hazard ratio of 0.41 is quite consistent with the hazard ratio observed in VISION, representing almost a 60% reduction in the risk of radiographic progression-free survival. Notably, you see the median radiographic progression-free survival time north of 12 months, which is approximately twofold greater than just a switch to an androgen receptor pathway inhibitor. The PSMAfore data also demonstrated robust efficacy against a range of other clinically meaningful endpoints, showed favorable safety and tolerability, as well as improvements in quality of life, as shown on the slide. I want to draw your attention to the consistency and the meaningfulness of this clinical data, but also spend a minute on the overall survival data here, which, as previously mentioned, you know, is confounded by the fact that 84% of patients who saw their disease progress radiographically were then crossed over to receive Pluvicto. Just a reminder as to the why and the how. First was around the why. When we had designed this trial, we had very robust phase II data, as well as the emergence of the VISION clinical trial data, that suggested that there was a clear loss of equipoise, you know, for patients who were not receiving Pluvicto. So between our steering committee, patient advocates, and patients, there was a high demand and high expectation that they would be eligible to receive Pluvicto should their disease recur. The second part was, this crossover was an option. It was not protocol mandated that they require Pluvicto, and two conditions had to be met. Condition number one was that there was independent radiographic confirmation of disease progression in order to maintain the integrity of the primary endpoint. Condition number two, the treating physician had to use his or her best clinical judgment to decide whether or not Pluvicto or any other available standard of care was the best and most appropriate next therapy for these patients. On the basis of those two conditions, 84% of patients went on to receive Pluvicto after their disease was confirmed to progress. If we look at the potential impact that crossover may have had on the interpretability of the overall survival results, I draw your attention to these two particular swimmer plots. Note the difference in shape, as well as the area under the curve for the yellow highlighted bars here. As you can see for the curve on top, this significantly changes the overall trajectory, as well as the shape of the curve for patients who received Pluvicto after the disease progressed, compared to the bottom curves, where ultimately patients did not cross over to receive Pluvicto. If you look at the estimated landmark survival at 12 months, 92% of patients were estimated to be alive at 12 months, compared to 69% of the patients who did not go on to receive Pluvicto. I think at the same time, we also recognize that the data still remain quite immature. There was only about 134 deaths at the time of this analysis, which represents only about 45% information fraction. So on the basis of that, the trial continues as planned and will continue, you know, into 2024 to the next interim analysis, which would actually have about 100 additional deaths and represent about 75% information fraction. And it's on the basis of that, that we would then intend to file regulatory submissions worldwide. Shifting gears to our second trial, that was also started before the final VISION trials read out, is an opportunity to look at Pluvicto plus standard of care hormonal therapy in patients who are metastatic—who had metastatic disease and were still sensitive to hormonal therapy. So this is an opportunity to look at Pluvicto on the backbone of standard of care, androgen deprivation therapy, as well as androgen receptor pathway inhibition. For this particular trial, there was some actually very unique reasons behind the why of the study design. I think first and foremost, hormonal therapy is non-curative. It basically just suppresses testosterone levels to reduce cell proliferation, but ultimately, these patients are subject to the disease continuing to grow or recur years after or within months of treating therapy. Secondly, although radiation can sometimes be used in this particular patient population, it's not without limitations. Radiation is reserved for very localized therapy. It can have debilitating effects on local surrounding tissue and/or healthy cells, and it's unable to sort of reach a broader, more metastatic set of lesions. And then lastly, there's some unique biology that's really emerged over the years, that as you continue to suppress the hormonal axis, uniquely, you get upregulation of the PSMA antigen, which is a key criteria which drives efficacy for Pluvicto. So it's for those three reasons that we set forward to design this trial. We have fully completed enrollment, where we've randomized 1,144 patients, and this trial is ongoing with a primary endpoint of radiographic progression-free survival. The most recent addition to our Pluvicto development plan is this new trial that is now released on ClinicalTrials.gov. This is an opportunity to move Pluvicto into an even earlier line or potentially earlier stage of disease, where we talk about it being local regional disease in patients who have biochemically recurrent disease and already have oligometastatic disease up to 5 lesions. Interestingly enough, when we talk about oligometastatic disease and/or metastatic disease, we often refer to that using conventional imaging, MRI, CT scan, bone scan. But here, we're talking about a new way of diagnosing patients using a PSMA-labeled PET tracer. So here, these patients are diagnosed and enrolled on the basis of being PSMA positive, so, quote, unquote, "metastatic disease" using non-convention, conventional or novel imaging. This trial looks at, you know, the addition of Pluvicto following standard course of SBRT in these patients, with the primary endpoint being metastases free survival. And another very, very important and clinically meaningful endpoint would be the time to delay or the time to hormonal treatment. Because we know very well that taking androgen deprivation therapy and/or androgen pathway blockade is not without a significant number of side effects and compromising the daily quality of life for these, these men. So as we look forward to some of the upcoming next steps, it would be to file the PSMAfore data in 2024, continue to track events for the, PSMA ddition trial. You'll note here that we have revised the date for our primary analysis to be in 2025. That's based on a combination of where we are with the radiographic progression-free survival events as of today. In addition to those projections over the next year to year and a half, combined with having an adequate number of survival events at the point in time when we read this data out in 2025. As an event-driven trial, we'll continue to keep this group updated if anything changes from these initial projections. And then we are on track for our study start up with the delayed castration study in 2024. So now maybe shifting gears to Scemblix in hematology. I think this represents a very nice opportunity to build in not only our leadership but our legacy in chronic myeloid leukemia. For Scemblix, in particular, this is our first-in-class oral STAMP inhibitor that was uniquely designed to minimize the resistance that occurs from the first or second generation TKIs, and at the same time, because of the allosteric mechanism of action, improve the tolerability of upon the existing therapies. This drug was approved on the basis of data that emerged from a phase III study called ASC4FIRST, and we now have almost four years of follow-up that have reconfirmed a sustained and deep major molecular response, as well as very favorable safety and tolerability compared to the second-generation TKI, such as dasatinib. It's on the basis of that 96-week data that this drug is now approved in more than 60 markets worldwide. If we think about the approved setting as of today, which is in patients with third line plus, currently in the U.S., we've seen our NBRX up to 35% and our total market share right around 20%. We're starting to see some use in the second-line setting, specifically in patients that have developed a T315I ATP gatekeeper mutation, as per indicated, you know, within the existing label of Scemblix product. And if we look at the real opportunity for Scemblix, it's to move it into the frontline, newly diagnosed CML, and this represents the potential to have up to 4 times more patients benefit, you know, from these deep, sustained, major molecular responses. Here's just a reminder of the ASC4FIRST phase III data and the 96-week data that served as the basis to convert our initial accelerated approval in the U.S. to full confirmatory approval. As you can see from the slide here, we have more than a doubling of the major molecular response rate compared to Bosutinib, and we have about a four times lower discontinuation rate due to adverse events compared to Bosutinib. I think some of the reasons why we are seeing these deep, sustained, major molecular responses, as well as the improved tolerability, is because of the very innovative and unique chemistry. This is quite opposite in terms of how it binds, you know, to the BCR-ABL protein. It binds specifically to the myristoyl pocket compared to the first and second generation competitive ATP binders. When this drug binds to the myristoyl pocket, it actually causes a confirmational shift, you know, rendering the BCR-ABL protein inactive and thereby precluding it from developing the traditional mechanisms of resistance, like the first and second generation TKIs. If we look a little deeper around the overall selectivity, you know, for, for Scemblix, as you can see from these kinome trees highlighted in yellow, is very specific where Scemblix actually binds, with a high degree of specificity and very limited to no off-target kinase activity, in contrast to the range of first and second generation inhibitors, where you could see that they are quite ubiquitous in terms of off, off-target kinase activation, you know, as highlighted by the red circles on these kinome trees. If we think about why we believe this could be an interesting opportunity for patients in, in the frontline, there are a few limitations or shortcomings around the first and second generation TKIs. If we start by thinking about the overall treatment goal for patients with CML, it's to get them to be treatment-free remission. Unfortunately, despite the best of all available therapies today, only about 20% of patients actually achieve a treatment-free remission, and unfortunately, it takes about, on average, 8 years for patients to get there. If you look at the totality of the data, this is actually not surprising, because even as early as one year, there's about 60% of patients that fail to achieve the major molecular response or a deep molecular response, which has a high degree of correlation to long-term outcomes and long-term benefit. That, coupled with the challenge that patients can become refractory or intolerant to first or second generation TKIs, represents a clear opportunity, you know, for Scemblix. Which is exactly why we had designed this trial of Scemblix, you know, with two co-primary endpoints comparing the efficacy at 48 weeks of Scemblix to investigator choice TKI, and also a second primary endpoint comparing Scemblix directly to Imatinib. Some of the basis for this is because we recognize that geographic prescriptions and patterns of use between the first and second generation TKIs do vary quite dramatically, but roughly it represents about 50%-50%, you know, of investigator choice. So this trial is uniquely designed to attest both hypotheses. The alpha has been split accordingly in terms of the primary endpoint, which is a 48-week major molecular response. We also have other important measures of efficacy, safety, patient-reported outcomes, and quality-of-life measures built into this trial. Trial is fully enrolled. We are currently in the process of gathering our data, and we expect the data to be available in the first half of 2024. Last but not least, shifting gears to Kisqali. So Kisqali continues to have very strong performance in the metastatic setting, seeing our NBRX now approaching 50%, which is actually a doubling from just one year ago, based on the very strong efficacy we've observed across 3 clinical trials. We've also made considerable progress in the early breast cancer setting, where we've actually already filed the NATALEE data in Europe and in Switzerland. We now have updated data on the basis of 500 IDFS events, which will be presented later this year at the San Antonio Breast Cancer Conference. We have already sort of shared this data with health authorities worldwide, including the updated overall survival data, and we have completed our pre-submission meeting, you know, with the FDA, and we have aligned with them that this data would serve as the basis of our regulatory submission in the U.S., and we are currently on track to file that data by year's end with the FDA. It's not surprising that Kisqali is doing so well, and I think it's on the basis of very robust phase III data in the metastatic setting, where we've shown a consistent overall survival benefit and maintained quality of life across three independent trials, regardless of menopausal status, regardless of hormonal partner, regardless of baseline clinical characteristics. I think this degree of consistency and reproducibility also lends to a very strong foundation in support of our ambition in early breast cancer. We've actually seen patients, even in the metastatic setting, stay on trial as long as 8 years and continue to derive benefit, you know, from Kisqali. If we look at the opportunity in early breast cancer, it does remain an opportunity of high unmet medical need. And with respect to the overall risk of recurrence, it's actually quite notable for patients with either stage 2 or stage 3 early breast cancer, where the rates could be as high as 50% recurrence over the course of 20 years. So NATALEE was uniquely designed to capture this broad patient population, you know, of patients who were at risk for recurrence early as well as late, you know, following definitive surgery and/or chemotherapy, plus or minus radiation, depending on the stage of disease. I'm gonna just spend the next few slides to talk about a few key important insights that were instrumental, not only in the design, but the conduct, as well as the interpretation of the final results of the NATALEE trial. So first and foremost is around the unique pharmacology and the rationale behind three years of continuous dosing. So first, around the pharmacology, it's quite evident that the specificity and selectivity for CDK4 is very important for patients with breast cancer, and much higher for CDK4 relative to CDK6 for Kisqali. That, coupled with a higher degree of free drug concentration as well as a long half-life, we believe, are important attributes that allow more time on target with chronic dosing out through 3 years, to push more cells into irreversible cell cycle arrest and then ultimately lend itself to long-term benefit. If we look at the rationale for designing a study with a broad patient population, I talked about the risk across stage 2 and stage 3. But if we use the graph on the left, which focuses exclusively on patients with stage 2 disease, with or without nodal involvement, you could see this risk over a period of 2 decades is as high as 30%. If you plot out exactly where we are looking at the control arms on NATALEE, patients with stage 2 disease, with or without nodal involvement, have already observed to have a 10% recurrence rate in as early as 3 years. So providing further data and further affirmation that these patients are at risk for recurrence. Then lastly, was around our dose selection. So we had chosen to take 400 milligrams into the adjuvant setting, on the basis that we wanted to sort of improve adherence and tolerability while maintaining efficacy. If you look at the data that we presented at the most recent ESMO conference, which went a little deeper, you know, into some of the pre-specified subgroups, you see this high degree of consistency in terms of the IDFS benefit as it related to the primary endpoint, regardless of stage, regardless of menopausal status, regardless of nodal status, you know, age, and other important characteristics like Ki-67. If we look at the overall safety of 400 milligrams in the adjuvant or early breast cancer setting, there was no new safety signals that were identified. The 400 milligram dose was very well tolerated, with a limited need for dose reductions and/or dose discontinuations due to AEs. When we talk about the dose discontinuations due to AEs being around 19%, just as a reminder, more than half of these were protocol-mandated by laboratory findings in the liver abnormalities that did not return to baseline over a period of four weeks. This is not a limitation or a restriction in our current U.S. product label in the metastatic setting, but nonetheless, it was important, you know, in the adjuvant setting, since this was our first time taking Kisqali into a stage 2 and stage 3 patient population. If we look at the overall quality of life in the adjuvant setting, you one would not expect that you would see an improvement of quality of life because these patients aren't suffering from overt bulk metastatic disease. So the feeling or the expectation that they should feel better was not one that we set out to do. The goal was to be able to demonstrate that adding Kisqali on top, on top of standard of care endocrine therapy would not alter the quality of life. Here we show that quality of life was maintained throughout the entire dosing duration for the early breast cancer setting. In closing, the next steps for Kisqali hopefully are quite obvious. We continue to sort of advance, you know, this new data towards San Antonio Breast Cancer. I'm sure everybody is well aware that the abstracts will be released later on this evening, just shortly after my talk, within a few hours. The data is still embargoed, at least for the next four or five hours, but it will be presented on the Friday of San Antonio Breast Cancer Conference. We are on track for filing in the U.S. in December of 2023. We've announced here that we intend to use our priority review voucher, and based on the overall patient population enrolled, as well as the consistency of benefit across all pre-specified subgroups, as well as all pre-specified clinically relevant endpoints, we are also seeking a broad label consistent with the patient population enrolled. So with that, let's turn it over, invite Shreeram back up and open it up for a Q&A. Final stretch. You want to stand, sit? What do you want? Let's stand. Thank you. Thanks. It's Graham Parry from Bank of America. I've got two on Plerixa, one on NATALEE, actually. So on Plerixa, which I know this is addressed a little bit on the Q3 call, but just gonna have another go at it. In terms of the OS cut that the FDA wants to see, if you were to see essentially the same hazard ratios in both the ITT and the crossover adjusted analysis, but just with more events, is that essentially- ...What the FDA is looking for, are they looking for improvement on those measures? So some sort of statistical significance or not, or the 1.16 coming down. So that's the first question. The second was just on VISION, a bit more of a commercial one, actually. But, you're now saying $2 billion in the VISION population and $2 billion in the earlier lines, or $2 billion plus in the earlier lines, but that seems to have shifted a little bit more to earlier. So is something else going on here that you think you can penetrate more patients in post-taxane, or is there less confidence in the pre-taxane? And then the third question, just on the NATALEE, the 500 IDFS events. I think you said this is consistent with the prior data. Is that consistent just on quantum of hazard ratio, or also consistent on p-value as well? I know OS benefit shown with statistical significance yet. Thanks. So Graham, maybe I'll, I'll take a stab at the first one, and then, Vas, I'll pass it to you in terms of the, the commercial question. So in terms of FDA expectations around overall survival, there is no absolute or definitive guidelines around exactly what they, they need to see. I think when we designed the trial, we obviously expected that crossover would occur, but couldn't have predict exactly how much. That is, in particular, why we had put in the pre-specified, adjusted overall survival analysis to account for the fact of crossover. And just as a reminder, that hazard ratio was 0.8. I think one of the biggest challenges we had around the interpretability of the data at the last analysis, was the relative immaturity of the data. So I think what's really important at the next analysis is the fact that we'll have up to 100 additional deaths and a 75% information fraction, and I think that beyond the hazard ratio for overall survival, whatever it may be, it's important to continue to look at the overall totality of the data, which is actually quite, you know, quite robust across all of the pre-specified clinical endpoints, quality of life, as well as favorable safety. Maybe with that, Vas, I'll turn the second question to you. Okay, thanks, Graham. So, yep. So when you look at the commercial potential, I mean, what our intention is to clarify that we believe in the vision population alone, we have multi-billion dollar potential based on the outlook that we're currently seeing. In the US, ex-US, our unconstrained supply, the overall demand signals that we're seeing. We would expect each of the additional indications to have significant potential. So we're not saying $2 billion per se for the additional indications, but multi-billions, which can be more, $2 billion, $4 billion, whatever, based on, you know, how the data evolves. Certainly, as you saw from Jeff's slides, the patient populations, if you combine the hormone-sensitive and the castrate-resistant populations together, you know, they're 2.5 times the population of the post-vision population alone. There's a lot larger population that we would then be able to compete in. And that's certainly the intention. And maybe to your last question, Graham, obviously, you'll see the data in just a few hours. So because it's still under embargo, I can't give the specifics, but what I can say relative to survival and the consistency is we continue to show no detriment as per the definition related to the OS point estimate. I think you'll see a little bit more later, but we did not reach statistical significance at this point in time, you know, nor is that required, you know, in an adjuvant setting, at this point. I think my only point is that I do want to leave everyone with this principle that Jeff and I often discuss, that as you move into earlier lines of therapy, it is the expectation that you don't show any detriment on overall survival. The interpretation of that conclusion depends both on the point estimates, the overall confidence intervals, as well as actually the totality of the clinical data along the lines of what Jeff showed in the very interesting swimmer plot. So we expect this to be, you know, a sort of a holistic discussion on the back of a drug that's clearly shown an amazing benefit that's consistent across progression-free survival. Peter? Thank you. Sorry, Peter Welford, Jefferies. Two questions again. Just going back to Pluvicto, first of all, on the PSMAfore population and the overall survival. I guess, what happens if the not adjusted, but the normal PSMAfore OS, actually does reach stat sig on OS? Because, I mean, it's actually—the confidence interval is actually closer to reaching stat sig for a detrimental effect, if you like, than it is for the old, it's a crossover adjusted. I appreciate, you know, I don't think any of us doubt that this, this therapy is effective, but I guess, what does, what does that mean? I mean, that sort of suggests essentially that you're better off waiting using this therapy from an OS perspective, despite how so contradictory that may seem. And then just secondly, what's the rationale for using the four cycles of therapy in the oligometastatic setting rather than the six? And I guess any thoughts on Pluvicto in the real world, what you're seeing in terms of four versus six versus perhaps more therapy? Yeah. So Peter, I'm happy to start with the, I think the first question and, you know, obviously don't wanna speculate as to what the future results would hold, but regardless of the hazard ratio, I think the same conversation, right, still has to happen. It's the overall totality of the data and the understanding as to what confounding factors may have led to, you know, an outcome, you know, with respect to overall, overall survival. I think first and foremost, maybe to reiterate some of the other principles that the FDA highlighted in their FDA ACR industry workshop this past summer. So I think when they're looking at the totality of the data beyond a given clinical trial, I think one of the things they look for is, has this product previously demonstrated an overall survival benefit in another setting? The answer is yes, based on the VISION trial. I think the second thing that they would look for is, are there any confounding factors, albeit crossover and or subsequent lines of therapy that would explain, you know, the potential overall survival data. I think what's very clear is you see the confounding factor of crossover. What I didn't present today is the potential other factors that may have actually contributed to this. Beyond those crossover patients, there's another handful or so of patients that receive PSMA-targeted therapy in the commercial and or academic setting. The proportion of patients that went on to receive subsequent therapy, such as chemotherapy, right, was balanced across two treatment arms, so it didn't preclude the ability for patients to go on to receive other existing standards of care. When you look at the number of on-treatment deaths, they were quite low across both treatment arms, so we don't believe that they were introducing any harm or detriment from a safety standpoint. As Vas mentioned earlier, the safety profile is actually quite impressive and highly tolerable in this setting, so we don't believe we're introducing any untoward risk. I'll draw upon one last point from our experience with Lutathera, where we have much longer follow-up data. The reason why I'm drawing on Lutathera is because it uses the same dose in terms of gigabecquerels and the same number of cycles. And there, we've looked at five-year outcome data in Lutathera, and we didn't have any increased risk for secondary malignancies or new primaries. So I think all of those factors would also play into account to no detriment. Peter, you have to remind me again of the second question. Four versus- Oh, yeah. I think in, you know, in the early oligometastatic setting, here, you're talking about combining, you know, traditional radiation on top of, you know, the radioligand therapy. So based on the advice of our steering committee, that's where they've initially focused us. But I don't think we know exactly the optimal number of cycles in early-stage disease, but I can confirm in, in PSMAfore, right, the median number of cycles were 6. About 75% of patients received at least 5 cycles. All right, so we do see a very high proportion of patients completing the intended therapy. Yep. Oh. There's one from the web. Hello. Yep. So Tim, Tim Anderson from Wolfe. On Pluvicto, slide 119 indicates there is no compound patent yet in Europe, which seems kind of surprising. Is there a risk it's deemed to be not patentable in this particular geography? Maybe it doesn't really matter given its RLT. On Kisqali, your peak sales guidance is $4 billion, but as you note, that is only for approved indications, which is metastatic in this case. When NATALEE does get formally approved, can we expect you to update that guidance in 2024, in a sense, quantifying the early-stage commercial opportunity? Yeah. So, you know, I think, in Europe, it's probably not as relevant in the end, the compound patent, given the complexity of the manufacturing. It's much more with respect to know-how and the capacity and capability. There are various PSMA available through academic centers. What really is the difference is having industrial scale and the capability to produce this and be able to deliver it, within five days, to the patient. So I think we don't believe particularly relevant for our E.U. outlook for Pluvicto. In terms of the Kisqali adjuvant settings, you're right, Tim, that we guided to $4 billion on the metastatic indication. I think once we have the adjuvant approved, and we start to see the initial sales trends, we'd be in a better position, I think, to provide updated guidance. Wouldn't want to commit to a specific timeline as to when we'd do that. Yeah, Richard Parkes from BNP Paribas Exane. Got one on Pluvicto and one on Scemblix. On Pluvicto, at ESMO, it felt like some physicians were talking about focusing capacity for Pluvicto to patients with very high PSMA expression levels. So can you talk about what you saw in PSMAfore in that subpopulation, and what's the likelihood that ultimately Pluvicto gets more limited use in that population? And then secondly, on Scemblix, both Tasigna and Sprycel have had first-line labels but haven't been able to fully unlock that opportunity, given 50% of use is first line still in CML. How much of a challenge will it be for you to unlock that, given that we'll also see generics to both those agents? I'm just wondering how much you might need overall survival or treatment-free interval data, which is obviously going to take a very long time to generate? Yeah, two, two very important questions, Richard. So maybe starting with Pluvicto. So from the VISION trial, we do see that some of the best responders, the super responders, are patients, as expected, with the highest degree of SUV uptake, either max or, or mean. That being said, we also see very good responses in patients with low uptake or lower expression of PSMA. We haven't reported out that data for PSMAfore. That'll be part of an update at a medical congress in 2024. But I do not believe it to be a limitation or a reason for physicians to segment the patient population based on the overall benefit observed across two trials, as well as the safe and favorable profile that Pluvicto does provide. With respect to Scemblix, I think it's a great question, and that's why we designed the study as we did, to be able to provide a robust body of evidence across the investigator choice of TKIs, not just with respect to a major molecular response, but also to the relevance of quality of life and the safety of the product. If you think about these first and second-gen TKIs, they do bring a high degree of cytopenia to patients, so they're often fatigued, susceptible to infection. You know, there's some significant GI side effects, as well as a risk for cardiac toxicity. So I wouldn't underestimate the possibility of patients switching or using Scemblix just purely on the basis of the safety and tolerability. That being said, efficacy is really important for these patients and really important for the community of physicians that would intend to use this product. There, we've designed the studies to demonstrate clear superiority in a clinically meaningful way, you know, over the existing TKIs, as well as in the subset of patients with just imatinib. I think there, looking at our historical experience, we have a high degree, you know, of knowledge and insight correlating major molecular response at week 48 to long-term outcomes. So I think through our existing data sets as well as real-world observation, reinforcing the correlation and the importance of control at one year, will hopefully guide uses of Scemblix, should the data become positive. Seamus? Thanks. Seamus Fernandez from Guggenheim. So just hoping you could maybe give us a little bit of an update on the DLL3 deal that you signed with Legend, and, you know, how you're approaching that, and maybe a little bit of your enthusiasm for, that particular target, especially in the wake of the old Stemcentrx, situation. Yeah, no. Thanks, Seamus. And I know Fiona mentioned it a little bit earlier, but, I'll talk about kind of the reasons why we are excited. I think first and foremost, the target itself, you know, is highly and homogeneously expressed, you know, in patients with small cell lung cancer. I think secondly, in terms of the, the Legend product itself, it is a biparatopic inhibitor that affords a high degree of potency, with respect to, to this target, as well as the armoring nature, which hopefully will help it overcome a traditional and highly immunosuppressive tumor microenvironment. Then lastly, by bringing it into Novartis and applying the T-Charge platform, we believe that we could further enhance the T-cell stemness or the T-cell fitness or stemness around the product to hopefully introduce potential greater efficacy, you know, for patients with small cell lung cancer. I did wanna take a moment, Shreeram, just to address Mark's question- Yeah. -from the plenary, which you talked about combinations for, for Plerixafor. Yep. Maybe to start, we are already combining or experiencing combination-based therapies with Plerixafor, with respect to combining on top of ADT, ARPI, and now with-- it'll be with SBRT. I think for Lutathera, as Vas articulated, we're already combining with systemic chemotherapy. We're combining it with anti-PD-L1 therapy. So when I think about some of the important principles around combination therapy, first and foremost is the safety and tolerability of Plerixafor. And we believe it has the ability to combine with multiple modalities, which could afford us greater efficacy and may potentiate double-strand DNA breaks. I think the second part that I want to reiterate is if we look at the early data with Lutathera and/or Plerixafor in late line or last line, we probably underestimated the true possibility as a single agent because the response rates were rather low. They were in the low to mid-teens. But as we move this product into earlier lines of therapy, and in particular PSMAfore, the data that was shared at ESMO showed an overall confirmed response rate of 44%, and we actually had a CR rate of 21%. So the ability for these products to truly eradicate cancer cells may be even greater as we move it into earlier lines of therapy. That being said, because of the combinability, it's opportunities to combine orthogonally, opportunities to combine with systemic immunotherapy and/or T-cell engagers, opportunity to combine with systemic chemotherapy or antibody drug conjugates, and we are exploring a range of permutations in both prostate cancer as well as other disease areas. I think what our new organizational ways of working allows us to do is to approach that complexity in a very structured manner that accounts for all the necessary skills that come from parts of the research translation within our organization. Eric? Thank you. Eric Le Berrigaud, Stifel. One quick question about maybe one threat to the CDK4/6 on the horizon, with other CDK. Where is Novartis on this? Could you share your thoughts, and when could we expect to hear more about this from you? Thank you. I think important question, Eric, and maybe I would broaden it to what is the overall kind of life cycle strategy in, in breast cancer? So when we think about kind of the, the nearer term opportunities and leveraging our platform, I think Fiona touched a little bit around the gastrin releasing peptide program, which shows a very high degree of expression in patients with HR-positive breast cancer, and we've already reaffirmed our phase II dose, and we are moving that into studies post-Kisqali in combination with chemotherapy, as well as in combination with Kisqali, especially in patients who are believed to be some of the poor responders based on certain phenotypic criteria that would be available at, at baseline. I think beyond that, I think Vas previously mentioned our intent and our ongoing research programs that are looking at these CDK specific inhibitors. I'm actually very pleased to see that the field has moved in this direction because it was Novartis that really led, you know, led in this space, focusing on the importance of CDK4 over CDK6 as the basis to start to generate CDK-specific inhibitors. So more to come on our research programs as they advance towards the clinic. Yeah. Simon Baker from Redburn Atlantic. Just going back to PSMAfore. Jeff, you said there were no hard and fast rules from the agency on the effects and impact of crossover. But what about the adjustment method used? Does the agency have any guidelines on that? I know the EMA have discussed this. I don't know about the FDA, so any thoughts on that would be useful. And then on Scemblix, do you see or have we observed any mutations around the myristoyl pocket or is it well conserved? Thanks so much. Yeah. No, Simon, two, two very important questions. So we have discussed with, with the FDA specifically around the risk-adjusted crossover methodology, and there is a range of about five different choices. In this particular rank-preserving structural failure time is believed to be one of the most robust and a very important dataset that the FDA would look at as part of the overall assessment. We have offered up the opportunity as additional sensitivity analyses to run every and any other statistical method, but the FDA felt comfortable with the one that we already provided. With respect to the mechanisms of, of resistance, obviously, we continue to look at that as part of the assemble phase III data, and at least up through four years of follow-up, we haven't observed, you know, any particular pattern, mechanism of resistance, new mutations. But nonetheless, we are serially collecting plasma from these patients to look at the emergence of new mutations over time, and we'll continue to follow patients. All right. Thank you, Jeff. Thanks, Jeff. All right. Okay, so I think it's now for the final close. So thank you all for your attention this afternoon here in London. I think we... As you've seen from us, we are looking forward to a number of key events occurring across our pipeline now through 2027. I think we've gone deep on essentially most of the medicines that we have on this slide here, and we look forward to continuing our work on making sure that we can deliver them to plans. I'll leave you with the final image of our confidence in our company and how we expect to deliver the expected and upgraded guidance for growth through 2027 and beyond. With well-established brands on the top there that are part of that journey, and perhaps more insights for you to this afternoon on the programs and development that we expect to contribute to that growth. Thank you again for your attention, and Vas, do you want to say a final close? I just wanna... I also just wanna thank you. Thanks again to everybody who joined us here in London, everyone who's followed us as well online. I hope you sense our enthusiasm about our ability to deliver 5%+ growth in the coming years to 40% margin, but also, most importantly, the conviction we have that we have an R&D engine that can keep generating assets to replace our sales, enable us to grow consistently in the mid-single digits. Really leading platforms in important areas of medicine that we think can transform the care of patients in the longer run, and a great set of R&D leaders who can lead these programs consistently over time. So we'll look forward to keeping you up to speed, and, of course, at the earnings in late January. In the meantime, wish everyone happy holidays, and thank you again.