Good morning. I'm Tim Power. I'm Head of Investor Relations here at BMS. You know, just really wanna welcome you to our R&D Day this morning. We are really thrilled to have you with us today. We've got a lot to go through, and we're gonna show you a lot of the progress we've been making on our pipeline and our research. Our next slide is our legal slide, but if I go to the agenda, you can see we really do have a lot to cover this morning. And you're gonna hear today from three members of our leadership team, from Chris Boerner, our Chief Operating Officer and incoming CEO. You'll hear from Robert Plenge, our Head of Early Research, and from Samit Hirawat, who runs Global Drug Development. Now, beyond those, we have many members of our management team with us today, including Giovanni Caforio, our Board Chair and Chief Executive Officer. Also, from our leadership team, we have David Elkins, our CFO, Adam Lenkowsky, our Chief Commercialization Officer. I know you know both David and Adam well as well. We have many members of our leadership from science and research across the company, so many members of Robert's team and Samit's team as well, to take part in Q&A, to meet with you either over lunch or over coffee. Because we have a lot to cover, you'll see we've put a couple of breaks in so you can get an opportunity to go out and refill your coffee as well. We'll finish up with plenty of time for Q&A, and then we'll have time to catch up over lunch also. Before I hand over to Chris, we're gonna just show you a short video, and I think when you see this, you'll see just what a powerful impact our medicines can have on patients. Hi, I'm Stephanie, and I have obstructive HCM. I'm Ed. I'm Stephanie's husband. I was a big runner, and my husband and I were both runners, and we loved to travel to marathons in different cities. Gradually, I began to notice that I couldn't perform the way that I had. I started to have difficulty with shortness of breath. I started to have palpitations. Then the symptoms started to happen with regular, everyday activity. Eventually, the symptoms became more and more pronounced, just walking up my own stairs. So that's when I knew I had to... I had a bigger problem on my hands than I realized. One day, Ed and I were in church, and I asked him to take me out in the middle of the sermon because I thought I was gonna pass out, and they set up an appointment for the next day. So that day, I had an echocardiogram, and they told me I had obstructive HCM. He mentioned the medical options that were surgical, and he said, "Oh, there's this new medicine." And it seemed pretty obvious after the visit with him that we should try Camzyos. After I started taking Camzyos, I noticed that I was able to walk up hills without shortness of breath. I was able to keep a decent pace without having heart palpitations. I could participate in pottery and different activities, volunteering. I just feel better. I have more energy. I feel comfortable making plans for the future that involve active things again, and that makes me really happy. I'm back in the game. One, it is absolutely great to see all of you today. On behalf of the company, I really wanna say a very big thank you for you taking time to be with us today. I know this is a very busy time of the year, both professionally and I suspect for many of you, for personally as well, and so we are just very pleased that you could be with us today. I'm actually happy that we could start this morning with that video because I think embedded in that video are some of the themes that you're gonna hear today. Certainly, you'll hear about the impact that medicines like Camzyos are having for our patients today. But also, I think embedded in that video is the importance of having a very strong R&D engine that will continue to help us bring forward innovative medicines like Camzyos into the future. And so, my colleagues and I are very happy to be with you, to have a chance to talk to you and give you a glimpse of where R&D is today, but also importantly, where we hope to take R&D over the course of the decade. Before diving into the main thrust of the discussion today, though, I think it's helpful for us to step back and provide some context for where we are as a company. One of the advantages of being in a transition role as an incoming CEO is that it gives you the opportunity to step back out of an individual function and think about the business and look at the organization more holistically. And as I look at where the business is today, we start with a very strong foundation. The base business is strong and is gonna continue to drive future growth. We have across many elements of R&D, we've seen very strong execution, and I would highlight specifically the execution on the regulatory team. And you see that as evidenced not only by the 9 FDA approvals that we've executed over the last three years, but also the over 20 indications and over 45 regulatory approvals globally that we've seen and that that team has executed over the same period of time. What I would point out is these are high-quality approvals, as evidenced by the labels we've gotten with products like Sotyktu, and just a few weeks ago with the frontline Reblozyl label. Commercial execution is strong, and you see that in the growth that we've seen over the last few years. Now, to be very clear, we've got more work to do there, and that's a very important focus for the company today, but the starting point is strong. Importantly, we see momentum in the business that's gonna fuel performance this year, as well as through the middle of the decade. We start with a good foundation. At the same time, we recognize that we have entered a period with headwinds, and that many investors are focused on, appropriately, the impact of IRA on the industry and on us as a company, and more specific to us, the impact of the LOEs, not just Revlimid, but also Eliquis, and as we get towards the end of the decade, Opdivo as well. And I appreciate that that frames how many investors have the conversation about BMS. At the same time, I believe we have very tangible opportunities to help us navigate these headwinds, and importantly, drive sustained, reliable growth over time. And delivering on that growth is the primary focus that I have, as well as the management team, because we know driving growth is the way we're gonna deliver value for the company and ultimately deliver value back to shareholders. So what are some of those levers that we have? Specifically, I'd highlight that, as I mentioned, we have a strong base business, and we have tangible opportunities to extend that business, particularly on the IO side, and we'll talk more about that today. We talked at J.P. Morgan about the long-term opportunity associated with our newly launched portfolio. As expected, we've seen that portfolio become more de-risked over the course of this year, and we have additional opportunities to de-risk that program further in the coming quarters. We're moving our pipeline forward. We now have 12 registrational programs that will be visible to us over the next 18 months, and that compares to 6 that we talked about at the beginning of the year. We have an exciting early set of assets that will form the next wave of innovation. Beyond the focus on the product portfolio, you will hear today about efforts that Samit and Robert have to increase R&D productivity and efficiency. Having a top-tier R&D engine is absolutely critical because it not only enables us to execute on the programs that are in the portfolio today, but also is critical to maximizing new opportunities that enter that portfolio, either organically or through business development. Of course, business development will be important, an important area of focus for us as it enhances the things that we're doing internally, and it helps us, again, drive long-term growth. As I think about the enablers of delivering that growth, clearly R&D is gonna be absolutely important. That's gonna be the focus for us today. Strong commercial execution is gonna be critical, and specifically ensuring that we have the right talent, we have the right resourcing, we have the right focus, and that's a big focus area for not only the company, but for Adam Lenkowsky's team as well. It's gonna be important we continue to use our balance sheet wisely and specifically to use that balance sheet to strengthen the growth profile of the company. Of course, absolutely nothing gets done in any organization if you don't have the right people and the right culture. Continuing to drive a high-performance culture that retains and attracts the best talent is gonna be important, and you're gonna hear from Robert and Samit about their efforts in R&D on that dimension today. Let's dive in. The essence of what you'll be discussing with you today is the focus that we have for enhancing and building a world-class R&D organization. The components of the way we think about that are highlighted on this slide. First, we have five clearly defined therapeutic areas as a company, and our goal is to drive increased depth in each of those areas. Second, embedded in these therapeutic areas are a number of platforms, and in particular, two exciting, high-potential growth platforms that we see with protein degradation and cellular therapy. Third, we must continue to evolve the operating model in R&D to increase the volume of potential medicines that enter the clinic, increase the probability of success that those drugs actually become medicines for patients, and then deliver those medicines to patients faster. Finally, as Tim mentioned earlier, you'll have the opportunity to meet some of Robert and Samit's teams, but clearly, having the best talent in the industry is gonna be important for how we deliver on our objectives in R&D. So I'm not gonna dive into this slide in detail, as Robert and Samit will cover it. What I will highlight at the beginning, though, is that in each of the therapeutic areas that we operate in, we have identified areas where we have strengths, but we want to enhance those strengths. So think, for example, how we can extend our leadership in the cardiovascular space. We've identified where we have a narrow leadership position, and we want to do more to diversify beyond that position today. Think, for example, our position in solid tumor oncology. We've also identified very specific areas where we have a nascent position or where we want to build additional capabilities and adjacencies, for example, in the neuroscience space. My point is that when we talk about building depth in our therapeutic areas, we've thought about how we do so in a very specific and targeted way. Two of the areas that we have been building depth in over the last number of years are, as I think you all know, protein degradation and cellular therapy... For protein degradation, we believe this is a platform that is ready for prime time. It is on the brink of enabling strong IND generation, and we are seeing exciting proof of concept data to expand beyond malignant hematology into other areas, notably solid tumor and non-malignant, non-malignant hematology, among others. We'll talk more about that today. For cellular therapy, Abecma and Breyanzi are just the beginning. We are planning to bring forward an innovative pipeline of assets, including assets that can take this modality into exciting new areas like immunology and neuroscience. And again, both Robert and Samit will talk about that as well. I mentioned earlier the importance of improving and continuing to push on R&D productivity and efficiency. What I'll preview with you now is that we have very tangible objectives that we will be holding ourselves accountable to, and that now you'll be able to hold us accountable to as well. Notably, our goal is to deliver approximately 10 INDs per year, to increase the probability of success for candidates that enter the clinic, ultimately becoming medicines, to approximately 20% from the industry average, which is about 10% today, and to achieve top quartile cycle times, which is today about 6.5 years at the median from IND to approval. You'll see how we go about improving on productivity and efficiency during the course of the discussion today. If we layer all of these pieces together and we successfully execute, we will be on the verge of delivering what we think is a catalyst-rich period for the company. Rich in terms of new products and registrational assets that could be medicines over the course of the decade, rich in optionality for exciting early stage programs that could achieve proof of concept over time, and beyond new drugs, we have dozens of line extensions associated with our existing medicines. Of course, I and the entire management team are 100% focused on enhancing this picture, both organically as well as through business development. What you're gonna hear from us today is that we're on a journey to transform our approach to R&D. You're gonna hear from us how we intend to evolve the productivity and efficiency of R&D and the R&D engine at the company. We're gonna dive into some, though definitely not all, of the catalysts that we see coming, including some key catalysts that have the potential to exceed expectations based on evolving science. What we hope to leave you with is that we are focused on executing against an R&D strategy, and that in doing so, this R&D engine will become a core component of how we drive sustained long-term growth as a company. Driving that growth is not only my focus, but it's the focus of the entire management team. So with that, let's get started, and I'll turn it over to Robert. Robert? All right. Well, thank you very much, Chris. So I wanna continue with two key themes. How will we continue to build on our very strong foundation, and while at the same time continuing to evolve our organization to ensure we're delivering industry-leading R&D productivity? I wanna start by just first telling you quickly about how we are organized within research and development. So the research organization, which I lead, works very closely with the development organization, led by Sam, and you'll hear from him next. Both of our groups are generally organized by the five core therapeutic areas that you see across the top of the slide. Within research, we have the biology, modality, platform, and research functions that you'd actually expect from a large biopharmaceutical company. But we believe we have several things that are actually differentiating. So first is our unwavering commitment to our research framework, and I'm gonna tell you a bit about that, today. Second is we believe that we have capabilities and platforms that are truly differentiating. Two of those we'll discuss in detail today. They include targeted protein degradation and cell therapy. Our most important differentiating factor, however, is our people. We have amazing talent, many of whom are here in the front row, and you'll get a chance to meet them and ask them questions throughout the course of the day. So our job within research is shown at the bottom left-hand side of the slide, which is to deliver new medicines with transformational potential, with an increased probability of success throughout all stages of clinical development. So I know a lot of companies talk about this, so how are we going to do it? So we believe that there are three key research principles that are required to improve R&D productivity. First, at the very start of the drug discovery journey, is selecting targets with strong causal human biology. So we know, for example, that targets with human genetic support are about twofold more likely to be successful throughout all stages of clinical development compared to targets without human genetic support. Second, we select the right therapeutic modality matched to a molecular mechanism of action. And third, we think very carefully about how to bridge from research into development, with particular focus on early evidence of clinical proof of concept. And this includes focusing on targeted patient selection, as well as translational endpoints to ensure that our new medicines are working as predicted, based upon our preclinical models. So this is our research framework, and this is how we anticipate achieving our ambition of delivering an increased number of INDs with transformational potential and an increased probability of success throughout all stages of development. And we are investing very heavily in each of these three areas. So, for example, for causal human biology, we invest very heavily in human genetics, both germline genetics as well as somatic cell genetics. We also invest very heavily in translational data, including patients from our own BMS clinical trials, as well as patients from the real world. And we have a number of partnerships, as shown in the lower left, that allows us to build out this causal human biology engine. Matching modality to mechanism, we're really fortunate to have diverse therapeutic modalities at BMS. More than half of our clinical and preclinical pipeline is made up of small molecules and biotherapeutics. We have very focused efforts in nucleic acids, and as you'll hear about more today, we believe that we have two differentiated platforms in targeted protein degradation and cell therapy. All of our programs, all of them are assisted by artificial intelligence, and we have deep expertise inside of the company, as well as through our partner network, some of whom are shown at the bottom of the slide. Path to clinical proof of concept, we're investing very heavily in technologies and diagnostics, again, to ensure that we create the right mechanistic models to bridge from research into early development. So again, this is our research framework. We're investing very heavily in it. So now what I want to do is I want to give you an example of the power of this research framework. I'm gonna use an example that I think that you all know about quite well, which is Sotyktu. The target of Sotyktu is, as the name implies, the protein TYK2. The causal human biology for this particular program is incredibly strong. There's a lot of human genetic evidence to support this target across multiple immunologic indications, but there's one variant in particular that's particularly special. It's called P1104A. This is a loss-of-function variant that protects, protects from multiple immunologic diseases. This includes psoriasis, lupus, and multiple sclerosis. And as you can see in the figure on the bottom left, this loss-of-function variant leads to a decrease in certain signaling pathways, and what we're showing you here is the interferon signaling pathway, where CC homozygotes have about 70% reduction in this pathway compared to individuals who have a GG allele. Matching modality to mechanism. Our wonderful BMS chemist made an exquisitely selective molecule that binds to the regulatory domain of TYK2. This is more distinguishing than the active domain of TYK2, but what it does, and this is called an allosteric inhibitor, is it binds to the regulatory domain, and then it locks the active domain in the inactive conformation. And this is how Sotyktu achieves its exquisite selectivity over a related family of proteins called JAKs. Path to clinical proof of concept. Now, you know about the path to clinical proof of concept in psoriasis. In fact, it's now approved, of course, in psoriasis. Here what I'm showing you is the path to clinical proof of concept in systemic lupus erythematosus. Our clinical and translational scientists did a very clever thing. They embedded in our phase 2 clinical trial, a translational endpoint that measures the exact same signature implicated by human genetics. So on the left-hand side, you see the interferon signature, 70% reduction. And what we observe in our clinical trial on lupus is that same interferon signature is reduced by about 70% or more. So again, this is one of the reasons we're particularly optimistic about this mechanism in lupus, and you're gonna hear a lot more about this program, from Samit as we go through the presentation. So again, we are now consistently applying this framework to all of our programs in order to increase the number of INDs with transformational potential that also have an increased probability of success through all stages of clinical development. I wanna provide a new disclosure that really builds on this particular research framework. It is a novel CNS penetrant TYK2 inhibitor for the treatment of multiple sclerosis. To be very clear, this is not Sotyktu, and this is actually not another program that's in clinical development, 322. This is a novel, first-in-class molecule that we believe has transformational potential. Now, the causal human biology here, very strong. It's based upon human genetics. That 1104A variant that protects from psoriasis and lupus, it also protects from multiple sclerosis. And as you can see in the bottom left-hand side of the slide, we also have evidence that the TYK2 pathway is hyperactive in patients with multiple sclerosis, and that's shown in the histology slides, again, on the bottom left. So if you focus on the graphs in the upper right, matching modality to mechanism. Start with the graph on the left. This is a mouse model of multiple sclerosis, where the P1104A variant is introduced in the homozygous state and is shown to protect from disease in this mouse model. So what we did is we made a CNS penetrant TYK2 inhibitor that phenocopies. It basically means that it kind of recapitulates what we saw with human genetics in the form of a small molecule drug, and we actually achieve very good disease protection, again, in this same mouse model. So path to clinical proof of concept. We take all of this data together, and we understand that we need to inhibit TYK2 by at least 70% in the brains of patients with multiple sclerosis. And if we can see this level of inhibition, we think that that will increase the probability of success through subsequent stages of human development. So this is a program that we expect to file an IND later on this year, and of course, a trial to begin soon thereafter. Again, this is our research framework in action. It gives us confidence not only in this program, but all of our other programs. And again, we consistently apply this research framework to every one of our research programs. So I want to give you one more example, and I want to provide this context of this research framework in the context of our solid tumor oncology strategy. So just reading across the top, our strategy in solid tumor oncology is to build a portfolio of foundational assets to address key tumor intrinsic, that's inside of a cell, mechanisms, together with tumor extrinsic, immune cells, stromal cells, other things outside of a tumor cell mechanism, where we believe that combinations will be critical for durable responses and transformational potential. So I wanna start with the tumor extrinsic side of this strategy. So I think as you all know, we have really deep expertise in tumor extrinsic biology. We are the only company with three approved T-cell checkpoint inhibitors. Because of this, we have translational insights to guide the next generation of therapies in a way that we think is incredibly unique and highly differentiating for us. So for example, we use our translational insights to guide the next generation of T-cell checkpoint inhibitors. Our anti-CTLA-4 next gen program, our anti-TIGIT bispecific program, you'll hear about that from Samit, as well as our dual DGK alpha/zeta program. You'll also hear about that from Samit. We also use these translational insights to understand other immune cell types that are important in killing cells, in addition to contributing to resistance, not only to IO agents, but also other standard of care agents. So for example, other immune cell types include T-regulatory cells, myeloid cells, and K cells. And we use our translational insights to understand other components of the tumor microenvironment that contribute to resistance to standard of care medicine. So this includes aberrant stromal biology. On the tumor intrinsic side, we also have deep expertise, and we have an emerging pipeline, both pre-clinically and clinically, to address specific tumor types and specific subsets of patients. Again, we have insights from our translational data sets to guide not only the next generation of tumor intrinsic mechanisms, but also how these will be used in combination with our tumor extrinsic mechanisms in order to achieve durable responses with transformational potential. So for example, we have programs that target certain oncogenic mechanisms. For example, Repotrectinib in ROS1-positive lung cancer, as well as programs in the RAS signaling pathway. We have programs that target lineage-specific targets. One great example of this is our AR-LDD program in prostate cancer, and you're gonna hear a lot about that from Summit. It's a program that we're incredibly excited about. We also have preclinical programs that address certain cancer vulnerabilities, DNA damage repair, as well as synthetic lethal interactions. The real power, the real power of this approach, however, is how we actually combine the tumor intrinsic mechanisms and the tumor extrinsic mechanisms in the context of our research framework, causal human biology, matching modality to mechanism, path to clinical proof of concept. So for example, we have translational data that shows the interactions between approved IO therapies and oncogenic driver mutations. I- I wanna give you an example of the research framework in action, but I'm gonna focus on two programs that target tumor extrinsic mechanisms. How we actually combine anti-PD-1 therapy together with a novel agent, our anti-CCR8 depleting monoclonal antibody that depletes T-regulatory cells. So the transformational potential here is a first-in-class monoclonal antibody that we believe can be combined with anti-PD-1 therapy in addition to other standard of care agents. Causal human biology comes from published data, as well as our own internal data, that show that Tregs in the tumor microenvironment are associated with poor prognosis. Now, we also have internal data showing an association of CCR8 positive Tregs with lack of response to anti-PD-1 therapy in specific tumor types. And this is shown graphically in the cartoon in the bottom left. So the green cells are CCR8 positive, Tregs cells, and you can see that they're secreting suppressive factors that inhibit CD8 positive T cells, even in the presence of anti-PD-1 therapy. As a consequence, immune cells can't invade and tumor cells survive. Now, our therapeutic hypothesis is that if we actually have an antibody that binds to and depletes CCR8 positive Tregs, what happens is you reduce the ratio of Tregs to T effector cells, and effectively, you're removing the brake on activated CD8 cells, and now anti-PD-1 therapy can work. It can actually activate an antitumor response, immune cells invade into the tumor, and they kill the cells. Matching modality mechanism in the upper right, our biotherapeutics colleagues created an antibody which depletes CCR8 positive Tregs, but spares T effector cells. Path to clinical proof of concept. Now, this is a program that's in early development now. So all the data that I'm showing you on this slide are actually from patients in our ongoing clinical trials. In the histology slide on the left, you can actually see in a single patient, depletion of anti-CCR8 positive Tregs in the biopsy of a patient after two cycles. And on the right, what you actually see is a reduction in the ratio of CCR8 positive Tregs to T effector cells. Again, consistent with our preclinical data and consistent with our therapeutic hypothesis. So again, this is a program that's in early development today. We expect to have more data on this next year. All right, I'm gonna change topics, and I'm gonna talk now about our therapeutic modalities. We are, again, really fortunate at BMS to have access to diverse therapeutic modalities. And this is really important because it really allows us to match a therapeutic modality to a molecular mechanism of action. We have deep, deep expertise in small molecule chemistry. I told you about our allosteric TYK2 inhibitor, including our CNS penetrant TYK2 inhibitor. And we also have really great expertise in early discovery screening mechanisms, including AI-assisted screening mechanisms that we use at the very beginning of our drug discovery journey. We also have deep expertise in our biotherapeutics group. I told you about our anti-CCR8 monoclonal antibody, but we also have expertise in more complex biotherapeutics. This includes masking Probodies, immune cell engagers, bispecifics, and antibody drug conjugates. We are very focused in early efforts in nucleic acid therapies, primarily in cardiomyopathy, as well as neurodegeneration. But what I want to spend more time on are two platforms, again, that we believe are highly differentiating: targeted protein degradation and cell therapy. So I want to start with targeted protein degradation. I want to tell you why it is exciting, why now, and why us? So the promise of Targeted Protein Degradation is you can actually have a small molecule that can actually bind to and tag a protein, leading to degradation of that protein. The consequence of this mechanism is twofold. First, we can expand the universe of novel targets, and we can enable clinical differentiation for existing targets. So I want to start with expand the universe of targets, and I want you to focus on the figure on the left. So there are about 20,000 proteins in the human proteome. About 10% or so of these are actually drugged by approved medicines or are amenable to being drugged by conventional small molecules or antibodies. So, for example, you can actually have a protein that's an enzyme, and a small molecule can fit into a binding pocket, leading to enzymatic inhibition of that particular protein. However, more than 20... or more than 50% of the human proteome actually is made up of proteins that are disease-relevant, so for example, as defined by causal human biology, but for which there are no known potent binders that we think can actually be turned into medicine. So for example, there are some proteins that are scaffolding proteins. So these don't have enzymatic function, but what they do is they recruit other proteins to form a complex structure that will exert a biologic function. Other proteins are transcription factors, so they sit on top of DNA and induce a conformational change, to turn genes on or off. It's very difficult for small molecules to get into and bind and inhibit these types of complex interactions. This is the opportunity for targeted protein degradation. Because what targeted protein degradation can do is you can find a binder that can actually bind to different parts of these proteins, and they can degrade them, they can eliminate them, thereby exerting biological function. Now, another opportunity for targeted protein degradation is to achieve superior efficacy for existing targets. For example, to overcome resistance or to achieve higher selectivity. Now, on the bottom right, we're showing an example of a protein that's a kinase, where in the case of oncology, you might develop mutations that lead to resistance of this particular kinase. But we can actually find binders to different parts of the proteins. Shown here is a CELMoD that binds to a different part of the protein, that can then degrade the protein to overcome resistance of established targets. So we believe we are the industry leaders in targeted protein degradation. Why? Because of the breadth and depth of our portfolio and the breadth and the depth of our expertise. We've been doing this for a very long time. There are three modalities that we really focus on within our targeted protein degradation platform. The first are molecular glues, and we refer to these as CELMoDs. Now, the way these work is you'll have a protein called cereblon, a molecular glue will then bind to that molecule and will find proteins inside of a cell, and there are these handles that we call degrons. It'll pull the other target proteins into this complex. They then get ubiquitinated. They go to the proteasome, where they have proteasomal-mediated degradation. Second modality are hetero-bifunctional degraders. We refer to these as ligand-directed degraders or LDDs. Others will refer to these as PROTACs. The third modality are ADC degraders, where we take an antibody and we conjugate a CELMoD or an LDD to the molecule in order to deliver the CELMoD or the LDD as the cytotoxic payload. As you can see in the bottom left, we have a number of external partnerships to expand our approach with these modalities. For example, identifying novel molecular glues or E3 ligases, and to expand beyond proteasomal-mediated degradation, so lysosomal-mediated degradation or autophagy, for example. Now, the other reason we believe that we are industry leaders is shown here. Put simply, we have more programs approved or in clinical development than any other company. Full, full stop. Full stop. So we have 3 programs that are in full development, and you're going to hear more about these from Samit. We have 4 programs that are in early development, including 1 novel disclosure that we will make today, our BCL6 LDD for the treatment of lymphoma. We have 4 programs in IND-enabling studies, including another novel disclosure that we will make today, our hemoglobin F inducer CELMoD program for the treatment of sickle cell disease. And we have more than 15 programs across all three targeted protein degradation modalities and across all of our therapeutic areas. And so taken together, this is why we believe we have the potential to deliver approximately 4 INDs every year across all of our therapeutic modalities. So now what I want to do is I want to describe each of these three targeted protein degradation approaches in a little bit more detail, and I'm going to start with CELMoDs. So again, CELMoDs are molecular glues. They bind to cereblon, they find those handles, those degrons, they bring them in, leading to proteasome-mediated degradation. So we have made major investments to expand our CELMoD library and identify novel protein targets, and that's shown on this slide. So in 2019, if you focus on the scatter plot on the left-hand side, we had a modestly sized CELMoD library. Each of those dots in blue, that was a unique CELMoD that was part of our library in 2019. So what we've done over the last several years is we expanded the size of this library based upon our molecular knowledge of how CELMoDs work, in addition to artificial intelligence and other mechanisms, to use computational approaches to predict chemical diversity. So now what you can see in terms of our library, shown in red, are two things. One, there are many more red dots than blue dots, and you can also see that the red dots are moving away from the blue dots. And what this means is that we have a far more chemically diverse library. So we take representatives from this library. We then profile them across the entire human proteome, and we find novel targets that are actually degraded by the CELMoDs. If you look at the graph in the upper right, what you see is the more molecules we profile, the more novel substrates we identify. If you look carefully at the graph, it's not flattening out, it's continuing to grow. As we find these novel proteins, we're defining new rules of degradation. We're finding new handles. We're finding those degrons that can tell us about how to expand the library further. But what's really important is how we turn these insights into medicines. We take these proteins that are degraded, we apply our causal human biology engine, and we start new drug discovery programs. So, for example, we've actually started about 10 programs for CELMoDs alone in oncology that are now in full discovery or in IND-enabling studies. So I'm going to give you an example of one program that's actually come out of this effort. Again, this is a program that we have not previously disclosed. It's our hemoglobin F CELMoD inducer. Now, a note of caution, this is a pretty early program. It's only now in IND-enabling studies. But we show this as an example of what is possible with this platform. So I think as you all are aware, sickle cell anemia is a devastating disease. The approved oral therapies are largely ineffective, and there are some exciting new cell and gene therapies that are promising, but they're really unlikely to meet to help most patients, given the global burden of this disease. So causal human biology, it's very compelling. They're genetically validated targets that we know lead to an increase in fetal hemoglobin, and that persistence of fetal hemoglobin is associated with good outcomes in patients with sickle cell disease. The matching modality to mechanism, focusing on the right. Through our CELMoD proteomics initiative, we found a CELMoD that degraded one of those genetically validated targets. As you can see in the graph on the right, our preclinical data show a very large increase in hemoglobin F expression, that's shown in purple, in a dose-dependent manner. This is substantially greater than the standard of care medicine, hydroxyurea, and that's shown in green. The path to proof of concept is very clear, right? We want to take this into patients with sickle cell, and we want to see an increase of about 30% or more of fetal hemoglobin expression, because we know this is the amount of expression that is required to help patients with this disease. Again, this is early. It's in IND-enabling studies today. We expect to file an IND next year, but I hope it shows you the promise of this platform and why we're excited about our ambition to deliver four INDs per year coming out of the totality of our total protein degradation approach. All right, so next, I want to talk about ligand-directed degraders, or LDDs. This complements our approach with CELMoDs. So in this figure, I'm comparing and contrasting how CELMoDs work versus LDDs. CELMoD, again, binds to cereblon, binds those handles, those degrons, recruits them to the complex, but some proteins don't have those handles, so there are no degrons that are available. This is how we actually use LDDs. So the way an LDD works, you have a small molecule that binds to cereblon or another E3 ligase, and then you can actually have a small molecule that binds to one of those proteins. There's a linker then that brings the two together. All the subsequent steps are very similar to CELMoDs. That is, there's ubiquitination of the target protein. It gets shuttled to the proteasome, where you have proteasomal-mediated degradation. Now, I've already introduced our early development pipeline. We have two in early development, two in IND-enabling studies. Again, you're going to hear a lot more about AR LDD from Samit, but I want to actually introduce one new program. Again, this is something that we've not previously disclosed before. It's our BCL6 LDD program in lymphoma. BCL6 is a really special molecule in lymphoma. It is one of the few master regulators that's important in malignant transformation. So our transformational potential here is to find an oral small molecule medicine that can treat B-cell lymphomas in those patients that have abnormalities in the BCL6 signaling pathway. The biology for this program, like all of our programs, is incredibly compelling. There are gain-of-function mutations that are somatic in nature, that lead to high levels of BCL6 expression. What's also interesting is if you actually have a deletion of BCL6, it basically prevents B-cell maturation, which is a form of phenocopy in terms of genetics and a pharmacologic intervention. In the figure on the left, what you actually see is a normal process of naive B-cells going into a germinal center and then emerging as a healthy, mature B-cell. If BCL6 is overexpressed in this context, you get shunting of the cell into a malignant cell, for example, DLBCL. All right, matching modality and mechanism, in the upper right-hand side of the slide, we created a BCL6 LDD with exquisite selectivity relative to the entire human proteome. So that figure in the upper right, we call it a volcano plot. It actually measures all proteins in a cell, and what I think you can appreciate is there's only a single protein which is highlighted in green, which is degraded by this LDD, and that's of course, BCL6. Path to clinical proof of concept, we want to correlate exposure of the drug, and here in our preclinical models, I'm showing you plasma exposure in blue, tumor concentration in red, and how that correlates with BCL6 degradation. So that first gray bar that you actually see on the left-hand side of that figure, that's full BCL6 expression. As you can see over time, BCL6 expression goes away. So again, this is data from our preclinical studies. But of course, it's all about clinical benefit, and so what we aim to do in our preclinical proof of concept study is to target patients with lymphoma who also have high BCL6 expression as measured by IHC, and that's about 30% of the DLBCL population. So this program just had an IND approved last month. We hope to begin clinical trials very soon. Finally, a new frontier for targeted protein degradation, CELMoD ADCs. Here, what we do is we combine a clinically validated antibody with a clinically validated CELMoD, or something that we think has the potential to have clinical benefit in patients. The purpose of this is to enhance the efficacy and tolerability of both agents together. That's shown just graphically in terms of matching modality and mechanism on the bottom left-hand side of the screen. This is a program that's in preclinical development, so we're a few years probably away from filing an IND. But what the preclinical data on the right show is that if you take the CELMoD and the antibody, and they are unconjugated, you don't see much reduction in tumor volume. In fact, it's very similar to the vehicle control, which is shown in blue. But if we conjugate the CELMoD with the antibody, and we deliver it at about the same stoichiometric levels, what you see is complete reduction in tumor volume. Again, it's an early program, still preclinical development, a few years away from filing IND, but we show it because our knowledge of targeted protein degradation allows us to do things like this in a way that we think are very creative, very innovative, and creates differentiation from us compared to others. All right. Changing topics once again, I now want to introduce cell therapy. So we continue to evolve our cell therapy platform, and we do so along three dimensions. So if you look at the left-hand side of the slide, you see these three dimensions: next-generation engineering, evolving our delivery system, and optimizing manufacturing. And I wanna walk through each one of these one by one. So I'll start with the engineering. So in wave one, this is for our approved products of Abecma Breyanzi. This consists of a mono-specific CAR, a single binder against a single target. But as we continue to evolve the platform, we can actually introduce additional features. For example, dual targeting CARs, two binders against two targets, but in the same CAR T cell. And in wave three, we introduce a number of additional engineering features, so we can begin to knock things out, and we can knock things in. A consequence of this is we can actually begin to introduce unique features into the CAR cell. So we can introduce logic gates, for example, which we think are gonna be very important for the treatment of solid tumors. We can also change features of the cell that allow for allogeneic engineering. We can also introduce different types of binders. For example, T cell receptor binders on the surface of the CAR, which allows us to access intracellular proteins that aren't easily accessible on the surface of a tumor cell. We continue to evolve the delivery system. Wave one, with our approved products, we use lentivirus. In wave two, we can begin to use adeno-associated virus, or AAV, and this allows us to actually do additional engineering of the cells. And in wave three, we wanna move away from viral delivery altogether into non-viral systems, and this includes electroporation or the delivery of DNA with lipid nanoparticles. And finally, manufacturing. We fully recognize the importance of manufacturing, of delivering these life-saving medicines to patients, and we continue to invest very heavily in manufacturing. We do so to reduce cost of goods, shorten turnaround times, and lower failure rates. Wave one, our two approved products, autologous. You know the products, Abecma and Breyanzi, and we use alpha/beta T cells. In wave two, also autologous, but what we want to do is begin to learn from everything that we've actually seen in the clinic from our two approved medicines, and we begin to improve the manufacturing process. Again, reduce cost of goods, shorten turnaround times, reduce failure rates. We call this our Nex- T platform. In wave three, we wanna move away from autologous into allogeneic. These allogeneic cells could be derived from healthy donors, or they could be derived from iPSCs. Now we can actually begin to make CAR-Ts, not just from alpha beta cells, but also gamma delta cells, and potentially induced cells, like induced NK cells or induced T cells. All of our expertise, as I've described for some of the other programs, it's complemented by our excellent partner network. Some of those are shown at the bottom of this slide. All right, so here is a pipeline snapshot. I don't think we've actually shown our pipeline quite in this way before. In pale yellow are our autologous programs. In light brown, you see our allogeneic programs. In gray are other programs that we have not yet disclosed. So I think as you take this in, I hope you can appreciate the breadth and depth of this pipeline. So, for example, we are the only company with the two approved CAR-T projects-- programs. We also have expertise, not just in hematology, but in immunology and in oncology. You're gonna hear more about a few of these programs from Samit, including our GPRC5D CAR-T program in multiple myeloma. I wanna spend a little bit of time on two of these programs, our BCMA GPRC5D program in multiple myeloma, as well as our CD19 Nex- T program in multiple immunologic diseases. Again, multiple immunologic diseases. So let me start with BCMA GPRC5D. We have a tremendous amount of experience in conducting multiple myeloma trials. We know that there is a very large unmet need in these patients. So the causal human biology here, we know BCMA and GPRC5D are both clinically validated targets. We also know if you combine the two in the form of a T-cell engager, there's clinical benefit. The antigens are expressed independently, and that's shown in the scatter plot on the lower left-hand side of this slide. We also know from our translational data that antigen heterogeneity and clonal evolution are factors limiting the efficacy of BCMA CAR-T, and that's shown in the Abecma trial on the right, where you initially have high levels of BCMA expression at baseline, but over time, BCMA expression goes down in patients with progressive disease. Matching modalities and mechanism in the upper right, we've optimized a bispecific construct, our binders to both of these molecules independently. And we've also optimized the manufacturing process so that we can deliver these products at scale, with lower cost of goods, lower turnaround time, lower failure rates. Again, we have a tremendous amount of experience of conducting multiple myeloma studies, so we know exactly what we want to do in terms of the path to clinical proof of concept. We could go after patients with evidence of early relapse or patients who failed to respond, as shown by the orange and the green stars. So this is a program that we will expect to file an IND later on this year, and also a program that we hope to expect clinical trials soon thereafter. All right, our next program, CD19 and autoimmunity. This is a program that we are just incredibly excited about. We've been thinking about these concepts of sequential immunotherapy for a very long time, and we believe this is one of the first assets that allows us to accomplish our vision of functional cures. So let me say that again, functional cures in patients with autoimmunity. This would be an absolute game changer. Our sequential immunotherapy strategy is shown on the upper left, and there are three steps to this. Step one is to control inflammation. Step two is to reset immune memory, and that's where this medicine comes into play. Step three is to promote homeostasis and repair. Harnessing human biology, very compelling, again, as with all of our programs. This time it comes from an academic study from one of our collaborators, Professor Georg Schett. What he showed in patients with severe refractory lupus, refractory to all previous therapies, and that in patients with high disease activity scores, it's called a SLEDAI, before CAR-T therapy, very high. After CAR-T therapy, complete remission, functional cures. These responses have been shown to be durable. Matching modality to mechanism, we use the exact same CD19 binder and the exact same CD19 intracellular domains that are used in Breyanzi, so we know that this will work. Manufacturing here, autologous, but we've actually improved the manufacturing process, so it's now single train. Again, shortened turnaround times, lower failure rates, lower cost of goods. Path to clinical proof of concept, we wanna expand on the findings from the academic studies in lupus, but we also want to introduce molecular biomarkers that can allow us to determine if the T-cells are actually active and engaged. But we also want to use these biomarkers to show evidence of immune resetting. Again, functional cures, game changer. You're gonna hear more about these from Samit, including how we're actually gonna go beyond lupus into multiple other immunologic indications. All right, so-... Two more points, before I summarize, and the first is shown on this slide, and that's the importance of computational science in all aspects of our research, and this includes artificial intelligence and machine learning. So, for example, we use computational science to pick the best possible targets, to define causal human biology. And I'm showing you an example on the lower left of how we actually model somatic mutations in cancer to define these patient driver states. We use computational science to actually do predictive molecule invention, as shown in the middle of the slide. This allows us to improve quality of the molecules that come from research into development, but also accelerate timelines within research. Our goal by next year is to have every single one of our programs enabled and assisted by artificial intelligence. This will allow us to accomplish our goal of predicting, making, testing, and very importantly, learning. Finally, we use computational science to build mechanistic models, as shown on the right. This is always very focused, fit for purpose, for questions that we think are going to help us understand how our medicines are working, again, to increase probability of success throughout all stages of clinical development. The second point I want to emphasize is the importance of our extensive BD partner network. Throughout the presentation, I've given you examples about how we've actually utilized this partner network, and this gives you a snapshot of our partner network. We have more than 100 active collaborations across all aspects of research. Some of these partnerships deliver data, some actually deliver components that are really important for the success of our internal programs, and others deliver INDs, and in some cases, our partners are taking those medicines into early development. And now I want to summarize. We believe we have the right strategy at the right time to develop transformational medicines to change patients' lives. What I hope I've done is to convince you that we want to build on our strengths, while at the same time improving R&D productivity. We can do this if we continue to have this relentless focus on our three key research principles of causal human biology, matching modality to mechanism, and path to clinical proof of concept. I've given you examples throughout the presentation of this research framework in action. I gave you an example about how we apply it in the context of our therapeutic area strategies, specifically in oncology. As shown in the middle of the slide, we're very fortunate to have access to diverse therapeutic modalities to allow us to match a therapeutic modality to a molecular mechanism of action, and I spent more time on two platforms that we believe are highly differentiating for us at BMS, targeted protein degradation and cell therapy. I've described how all of our programs are enabled by translational insights, computational science, and our BD partnerships network. So taken together in its totality, this is why we can believe we can improve our productivity and increase the number of INDs with transformational potential and increase success throughout all stages of clinical development. That brings me to the end of this presentation, and I think what you'll hear next after the break is all the exciting work that we actually have in our clinical development pipeline. Thank you. Good? Okay. Well, thank you, and, welcome back. Good morning. I'll just wait for 30 seconds for everyone to take their seats, and then I'll start off again. Well, thank you. Welcome back. We're gonna get, into the second part of this presentation. This morning, you heard from Robert just before the break, how we are innovating and bringing innovation into discovery and research, and the way we build our molecules. Now, what I'm gonna try to do today is to walk you through how that innovation is translating into enhancement and evolution of our pipeline, that is, going to bring about transformational outcomes for patients, patients who are living with serious and life-threatening diseases and where the unmet need is very high. Now, before I get into that, I do want to reiterate what Robert had said this morning. Research and development are joined at the hip at BMS. We work together very closely. As we take molecules and medicines from Robert's organization into development, we generate the data, we generate clinical data, biomarker data, and then through approval, we hand it off to a commercial organization that Adam leads. But it is very important that we bring that data back into research so that that reverse translation can occur, and then we can find more targets, more molecules, and target more diseases, because there is a lot to do in the world of science. With that said, I can tell you one thing, my perspective is, that this is one of the best pipelines in the industry at this time. It is deep, it is diverse, it is differentiated. Across the therapeutic areas of oncology, hematology, including cell therapy, immunology, cardiovascular medicine, and evolving in neuroscience. I will not obviously have the time to touch on every single molecule that you see on this slide, but certainly, I would like to direct your attention to some of these that are going to be differentiated, that I believe are making a true difference in how patients live with their diseases today, because there is a high unmet medical need. With that, let's start off with immunology. Already on this slide, you can see on the left-hand side that the modalities are quite diverse. From small molecules to biologics to cell therapies. We have a couple molecules that are already approved for a few indications. We have a deep pipeline from a registration perspective, and we continue to make progress for additional indications, where we are doing proof-of-concept studies that may translate into additional registration pathways. With that, let's start off with pulmonary fibrosis, a disease that is devastating, with fatal outcome sometimes, and with the overall survival that is similar to some of the cancers that are very difficult to treat. If you think about the treatment landscape, only two drugs are currently approved for the treatment of IPF. If you think about progressive pulmonary fibrosis indication, only one drug is currently approved. These are modestly efficacious drugs, but they do have tolerability issues, where many of the patients go off treatment. So naturally, this is an area of high unmet medical need, where we need to bring about quantity and quality of life improvements. Now, how does that work? Well, LPA1 seemingly is implicated in the initiation of the pathology of this disease. Once LPA1 pathway is initiated, that signaling leads to fibroblast activation, secretion of collagen, and fibroblasts and collagen, they work together, they allow lay down that infrastructure of fibrosis that leads to decrease in the functions of the lung and decrease in the, what we call FVC, which becomes the primary endpoint to measure as we look to the future. Now, the good news is, we do have an LPA1 inhibitor. In fact, 5 years ago, we presented first data for an LPA1 inhibitor, which was very efficacious. However, we knew that there was a safety liability that molecule had. Scientists at BMS, chemists at BMS, did an amazing job in bringing about the next generation of an LPA1 inhibitor, and we presented the data for 2 different clinical trials. On the left-hand side, you see LPA1 inhibitor in IPF, randomized control trial, where we've shown LPA1 leads to decrease in that reduction of FVC compared to placebo. On the right-hand side, last weekend, we showed the data in PPF as well. Double-blind receive placebo-controlled trial, once again, showing that 70% reduction in patients with PPF in the decline of their lung function. There's another very important part to understand from this trial. The trial was conducted in patients who were naive to prior treatment, as well as in those patients who were already on standard of care treatments. Therefore, we have to think about safety profile in that context when we think about LPA1. The safety profile looks very good, whether given as a single agent or in combination on top of the standard of care. These are the data that led us to design two phase 3 clinical trials, one in PPF and one in IPF. These trials are right now in the process of initiation. By the end of this year and beginning of next year, we'll be initiating both these phase 3 trials, with the data expected in 2026 for IPF and 2028 in PPF. Now, turning to Sotyktu and turning to systemic lupus erythematosus. Robert Pleng touched on systemic lupus erythematosus, but let me reiterate. Systemic lupus erythematosus is a complex disease. It's a very heterogeneous disease, leads to organ dysfunction, leads to comorbidities that come because of those organ dysfunction and organ failures. Very few drugs approved, very hard to treat disease. Therefore, it is quite exciting to see when we look at these data from a randomized control trial, once again, of Sotyktu as an oral molecule, safe to deliver. What you see over here are a couple of the endpoints that we talk about, but as we can see from the published data, as well as presented data, very consistently, we see not only the primary endpoint being impacted, but consistent results across all secondary endpoints as well. Again, the drug was very well tolerated. We start to see efficacies coming up at the very lowest dose tested of 3 milligrams BID. Not only that, it is very important, as we always say, we have to pay attention to the quality of life of the patient, and we see that each of the domains, in this case, the skin domain and the joint domain, also saw improvements when patients were treated with Sotyktu. On the right-hand side, you see the skin impact that SLE has on a patient, and then after treatment, there's a clearance of those skin lesions. And that is certainly, if you think about a patient, the impact on their quality of life and their psychology when they are afflicted with this disease, how important it is to be able to manage those and impact those. Once again, these were really promising data, led us into designing two phase 3 trials that we initiated earlier this year and is currently in enrollment, and we anticipate the data from these phase 3 trials in 2026 as well. Now, SLE is not the only disease where the biology applies, but we learned from this trial, and we think that because of the similar pathophysiology that is engaged in other diseases, such as Sjögren's syndrome, it is important that we pay attention to that. And taking this biology and taking these clinical data, we have now looked at Sjögren's syndrome, another area of high unmet medical need, and designed a phase 3 trial that is just initiating as we speak, and these data will be available in 2027. So taken together, for SOTIG2, it is not just about psoriasis, a disease that we already have an approval for, a disease where we've already raised the bar for what an oral molecule needs to deliver from an efficacy and safety perspective. We also have additional indications in psoriatic arthritis, where the phase 3 trials are ongoing, and we'll be seeing the data over the next couple of years. We've initiated the programs in SLE and Sjögren's syndrome, but we have an opportunity to further extend that through alopecia areata, where we are conducting a phase 2 study... as a proof of concept, and looking forward to the readout next year and to extend that indication possibly. Now, SLE, as I said, is a complex disease, and we have multiple drugs that are used for the treatment of this disease. However, there are patients who are relapsed or refractory to those medicines. As Robert said earlier, we have an intention to look at SLE and immunology in general as sequential therapy. What we have shown thus far in immunology is how we decrease that inflammatory response in immunology. But we truly can now reset the immune system, and these are the data that he already spoke about, so I won't belabor the left side of this slide, which you see the seven patients' data that we recently published, with longevity of those responses, and these patients are treatment-free for a long time. But on the right-hand side, you see the true nature of that, the proof of mechanism and principle of resetting of the immune system. You see the naive B cells coming into circulation, and that's what we want to achieve as we look to the future of treatment of patients with severe SLE. We have a mechanism to do that. You heard about the next generation CAR T cell, or NEX- T, CD19-directed CAR T cell we have in our pipeline. We've already known that this is a good molecule, a good platform to develop, because we generated the first data from this platform in hematological malignancies. We knew the safety profile is similar to the best-in-class, Breyanzi, and we knew that this is an efficacious way to treat diseases as well. Now we know that applying automation, applying the philosophy of in vivo proliferation and expansion of the cells, and decreasing that turnaround time, we can take it into additional diseases, and that becomes very important as we think about autoimmunity. Taking all of those principles into account, we have recently initiated a phase one trial in severe SLE patients. Right now, this trial is enrolling patients. We are in the dose escalation phase. As we go through the dose escalation phase, once we have found the dose, we'll be doing a dose expansion, meeting with the regulatory authorities as to what the regulatory package would look like, what the designs of the study should look like, so that we can take it into very accelerated fashion into registration mode when the data are available and if the data are supportive. We also know that B cells are implicated in additional diseases, multiple other autoimmune diseases, as you can see on this slide. We are in the process already to amend our ongoing SLE trial that I just talked about, to add additional cohort to treat other diseases, such as myopathies. We are also preparing an additional IND that we'll be filing later this month to start our phase one program in multiple sclerosis. Our approach, as Robert said earlier, is not only just about our excitement, but really the need to bring about transformational treatments availability to patients with autoimmune diseases, and in this case, we are making good progress on that, and you'll hear more about it in 2024 and beyond. So overall, as I think about immunology, we are continuing to build our platform and continuing to build our pipeline from a differentiation in terms of modality, in terms of transformational outcomes for patients with multiple diseases. And right now, we are in the process of initiating programs with LPA1 for IPF, accelerating the development of Sotyktu in additional diseases. And certainly, this is not all. We do not talk about Cendakimab today. We do not talk about Zeposia today, just because of lack of time, but these are also studies that are currently enrolling, and we'll start to see the data in 2024, as well as in 2025 for some of these diseases. Let me just continue on with our promising pipeline in hematology now. In hematology, very well known, the overall differentiation in the profile of the drugs that we have. Many of them, first-in-class molecules, as you can see on the left-hand side, many of them best-in-class technologies, as we've talked about Breyanzi in the past. We have multiple indications already approved, very serious diseases being targeted as you look in the middle of the slide for registration programs, and additional proof of concept trials that are ongoing for additional molecules. Again, I will not be able to touch on all of them, but very promising future as we look at the growth of this pipeline. Let's start with Reblozyl, the first and only erythroid maturation agent approved for treatment of anemia, not only associated with beta-thalassemia, but also for myelodysplastic syndrome. Just a few weeks ago, we had the approval of Reblozyl for the treatment of first-line as a first-line treatment for treatment of anemia associated with low risk MDS. And this was based on the outcomes of the data that we saw from the COMMAND study, where there was nearly a doubling of the transfusion independent, as opposed to erythrocyte-stimulating agents or ESAs. But that is not the application that we are excited about. We are now conducting a study in non-transfusion-dependent anemia associated with MDS. But beyond MDS-associated anemia, there are other opportunities that we have to think about. And this is another one, which we have a phase 3 trial ongoing, looking at the combination of Reblozyl with a JAK inhibitor, Ruxolitinib, in patients with myelofibrosis. This is a phase 3 trial that is anticipated to read out in 2025 and may be extending the label for Reblozyl even further. But myelofibrosis is a really high unmet medical need disease, and we need new agents in this class, in this particular treatment. Here is where we are—we have a BET inhibitor that we are developing right now in phase 1, which could potentially be the best-in-class BET inhibitor. We are right now conducting a phase 1 trial, both in combination with Ruxolitinib in the first line setting, as well as with Fedratinib in the second line setting. And as data, these data evolve in 2024, we have a potential to take this molecule into registration trials for myelofibrosis patients as well. Now, pictures are worth 1,000 words, and this one truly lives up to that. On the left-hand side, you see a PET scan of a patient with disseminated follicular lymphoma. On the right-hand side, with single infusion of Breyanzi, you can see the outcome and interpret for yourself. These are the types of transformational data we have generated with cell therapy. We are truly excited about Breyanzi because it has the best-in-class profile and the broadest program as we think about lymphoma indications. On the left side, in the bottom of the slide, you can see we already have the approval for second-line and beyond treatment for large B-cell lymphoma. We have already presented the data for mantle cell lymphoma, the transformative outcomes in patients with CLL, and even more so in patients with follicular lymphoma, as we await the data for marginal zone lymphoma patients. We are in the process of obviously submitting many of these indications for regulatory review and approvals. We are also looking forward to initiation of the next trial in earlier line setting for patients with follicular lymphoma, and overall, truly excited about Breyanzi and its potential as we look to the future. Now, beyond that, lymphoma, again, is a disease which requires many more treatment options. And from our protein degradation platform, we have a CELMoD that we have started to generate data for, and that is called Golcadomide. Previously, you might have heard of CC-282. It is the same molecule with the name now. We already know that as a single agent, it has activity in heavily pretreated patients with diffuse large B-cell lymphoma. Now, we are generating the data of the combination. We are conducting a trial in late-line setting in combination with rituximab, but here you can see the data in the first-line setting, very well tolerated with the standard of care treatment of R-CHOP. These data are small in number of patients treated to date, but very promising, very exciting, where you start to see 100% clinical remission or complete remission rate. Now, these patients are, of course, being followed for a duration of therapy. We're enrolling more patients in these trials to generate more data, but these are very promising data as we look to the future of development of this molecule, bringing into registration trial after we have discussed the trial with the regulatory authorities in 2024, with potentially data available at the latter part of this decade. Beyond this, you heard from Robert, we have the opportunity to potentially bring BCL-6 also into the foray as we think about the future of development of new therapies for patients with diffuse large B-cell lymphoma, and not only that, maybe also bring in patient selection if that works well for BCL-6 inhibitor. Now, moving from lymphoma over to multiple myeloma, we have multiple therapies, multiple modalities in development for multiple myeloma. We have the leadership, and we want to continue to evolve in terms of refurbishing our portfolio and bringing new therapies for patients with multiple myeloma. Let's start with Abecma. Abecma was the first CAR-T cell therapy approved, which was BCMA-directed for relapsed refractory multiple myeloma patients. We have the approval in the late-line setting, and we also see the data emerging from the real-world side. We have generated the data in an earlier setting through the KarMMa-three trial, which is right now under review in the U.S., Europe, and Japanese health authorities. Our intention is now to take Abecma and move it further up in the line in the post-transplant setting through KarMMa-nine trial, and I'll talk a little bit more about that in just a sec. But what I want to really talk about initially is to look at what is happening in the approved indication in the late-line setting for Abecma. The data were generated by an independent group of investigators and presented, which show that we can replicate the data that we saw in the clinical trials also in the real-world setting. Not many people can say that that is true for most molecules, especially when we talk about competitor CAR cell therapies, that we maintain and maybe numerically higher rates of overall response, also complete response. We also maintain the overall safety profile for Abecma in the real-world setting. We also see that our manufacturing success rates are very high. We also have seen the data that CAR cell therapies are potentially much more beneficial if treated before or used before other modalities of BCMA-directed. So overall, the profile of Abecma remains very stable and very promising data continues to emerge for Abecma. Now, beyond that, though, we have looked at the data from one of the cohorts of KarMMa-2 trial. These are the patients who had newly diagnosed multiple myeloma, then went on to receive transplant with high-dose chemotherapy, but they did not experience an adequate response, meaning they did not get a complete response, they did not get a very good PR, PR. When these patients were then treated with Abecma, you can see the conversion of their responses to very high rates of CR as well as VGPR. What we see in the middle of the slide is the durability of those relapse-free intervals, which now have most of the patients followed through about 2 years and beyond. On the right-hand side, you also see the overall safety profile. And what we see on the safety profile is hardly any CRS of grade 3 or higher, minuscule in terms of numbers for neurological toxicity. These data have given us confidence in addition to all of the other data that we have generated for Abecma, to design and we are about to initiate the phase 3 randomized trial of Abecma, followed by Revlimid maintenance, compared to Revlimid maintenance alone in patients who have received a high-dose chemotherapy and transplant and did not achieve an adequate response to their transplant. These data should be reading out in around 2027, and we are truly excited to bring the promise of Abecma to the earlier settings for patients with multiple myeloma. Now, there is another way of targeting BCMA, through the T-cell engagers. Now, one would say that there is already a BCMA-directed T-cell engager that is already approved, so why are you developing a T-cell engager again? Well, we believe in Alnuctamab, we have a differentiated profile. Number one, from a construct of that antibody, which targets two antigens at the same time, meaning two BCMAs at the same time. Number two, when we look at the clinical data in the middle and the left of the slide, most of these patients are ongoing, but here, what we are looking at is the way we infuse or we deliver or administer Alnuctamab. The duration between subsequent infusions of Alnuctamab are much longer, as opposed to what you see a weekly infusion or weekly administration of other T-cell engagers. And that most likely is translating that longer-term efficacy, as well as the safety profile that we see emerging for Alnuctamab in terms of the infection rates that we see in this molecule. But again, these are open label trials that we are seeing the data from, so we have to test it out on randomized trials that are directed towards registration. The promise of this molecule we are taking into earlier settings of relapsed refractory multiple myeloma. Looking forward to initiating a phase 3 registration trial early part of next year in 2024. But beyond that, since we have a rich pipeline in multiple myeloma, we are also initiating combination trials of Alnuctamab with GPRC5D-directed CAR cell therapy that I will talk about next, as well as in combination with our CELMoD platform over here, a combination with Mezigdomide. Now, GPRC5D. A little bit on GPRC5D, certainly a very important target, a validated target, because there is a T-cell engager that is approved that targets GPRC5D. So then again, why are we building another one to target the same antigen? Well, we've taken a different approach. We believe repeatedly giving an infusion or administration of a T-cell engager to that targets GPRC5D, leads to constant pressure on that target, and that ultimately leads to what you see from a safety profile. As you know, there are nail changes, there are skin changes that patients have to live with for a long period of time. We've taken a CAR T-cell approach, which is a single one-time infusion, and what we see from that single one-time infusion is the response rate and the overall efficacy that is depicted on the left-hand side of this slide. You see high response rates in patients who have received prior BCMA-directed therapies, whether it be the CAR T-cell therapies or non-CAR T-cell therapies. You also see high response rates in BCMA-naive patient population. On the right-hand side of this slide, you see that there are no grade 3 skin changes, there are no grade 3 nail changes. There are low-grade skin and nail changes that are transient in this particular case. And because of this profile, because of these attributes of this CAR T-cell approach, we are now looking forward to initiation of phase 3 program for GPRC5D as well. In 2024, we are looking forward to initiation of a trial directed towards registration in quadruple exposed late line treatment of relapsed refractory multiple myeloma, as well as looking forward to bringing it further up the line to do a randomized trial versus standard of care. And thereafter, we are also looking, as I spoke earlier, to combine that with Alnuctamab or our CELMoD programs to generate combination data, to continue the growth and continue to change the outcome for patients in the long run as well. And the last part of multiple myeloma modality, what—that I want to just touch on is Iberdomide and Mezigdomide. Because we've talked about the data for Iberdomide and Mezigdomide in the past, I will not show you the data again. But suffice it to say that Iberdomide and Mezigdomide have shown already high response rates and durability of those responses in single-arm, open label studies, phase 1 and phase 2, as doublets and triplets and quadruplets. And those are the data that form the basis of initiation of these phase 3 trials that you see at the bottom of this slide for Mezigdomide, as well as for Iberdomide. These trials are enrolling well, and we are looking forward to enrolling and reading out these data in 2026, and the post-transplant maintenance setting in 2029 for Iberdomide. Now, one could say you've got a CAR T-cell therapy, you've got a T-cell engager, you've got a small molecule in multiple myeloma. How does that all come together? Well, you know, multiple myeloma treatment is really sparse, and meaning it's fragmented. Patients go through multiple lines of therapy, and there is a journey that a patient with multiple myeloma currently has to go through. So the way we look at our overall multiple myeloma platform or multiple myeloma franchise, we want to have a solution available for every patient, no matter where they are in their journey for their multiple myeloma. Whether they are newly diagnosed in the post-transplant setting, they have had 1-2 prior lines of therapies, or they have exhausted all therapies and now are in need for a CAR T-cell therapy approach through either BCMA-directed CAR T-cell therapies or GPRC5D therapies. And that's the intention of being able to develop multiple molecules simultaneously or at the same time. Overall, what you've heard from me today for hematology, we continue to expand our ability to add more indications for Reblozyl. We are not done yet with Reblozyl. There are additional opportunities that are available. In the multiple myeloma space, I just told you that we have, again, not only the modalities, but also the ability to help every single patient, no matter where they are in their journey. At the bottom of the slides, you can see how we are continuing to evolve and develop our presence in lymphoma and extending that with a differentiated platform through protein degradation as well. Now I want to go through oncology before we go into a break. In oncology, it's very important to understand that we have an approach that is continuing to build on our leadership in immuno-oncology with differentiation that we are bringing about in the immuno-oncology approach, as well as differentiating ourselves beyond immuno-oncology through protein degradation, as well as through the kinases, which are specifically directed against mutations in the tumors. Once again, a pipeline that is quite broad and quite promising as we look to the future. Let me start with Opdivo and Yervoy. If you think about immuno-oncology, you have to know that this has brought about true transformation in the outcomes of patients with very serious and life-threatening cancers. Opdivo and Yervoy, of course, have been tested and are already approved across multiple tumor types, multiple indications. But once again, we are not done yet. We have a lot to do as we think about the readout of the pending studies in the metastatic setting, as well as in the early stage of the disease through adjuvant programs that are ongoing. Now, we do know that when we deliver a nivolumab in an IV setting, there is a burden on the patient, there is a burden on the healthcare system, there is a burden on the nurse and the physician, and there is a chair time that is utilized. We want to certainly continue to improve the burden that is already on the patient, and the physician, and the healthcare system. That was the intent of developing the subcutaneous formulation, where we decrease the administration time to just 5 minutes. That philosophy, that mindset, led us to building and developing a subcutaneous formulation of nivolumab with Halozyme technology or combining that with hyaluronidase. That phase three study started a couple years back. Now we are anticipating the data to read out in the next couple of months, and if data are supportive, we'll be able to take it to the regulators, get the approval, and usually these approvals, because of biologic studies that we've done, will be applicable across indications, and therefore we will be able to provide benefit to the patients across indications, not only right after the approval within this decade, but continue that on in the next decade as well, and you can see at the bottom of the slide how we think about it. Now, beyond Opdivo, there is Opdualag. Opdualag is the fixed-dose combination of combining Opdivo with a LAG-3 inhibitor, Relatlimab. We already raised the bar in terms of how patients with melanoma in the first-line setting should be treated. We have an ongoing or a couple of ongoing programs in the registration phase as we think about MSS colorectal cancer and adjuvant melanoma. We are also building our understanding and the data sets for additional indications, such as first-line hepatocellular carcinoma, as well as non-small cell lung cancer. Why do we have conviction in adjuvant melanoma? Well, this is just a glimpse of what we have seen from early data that have been presented through investigator-initiated trials or investigator-supported trials. On the left-hand side, you can see that single-agent nivolumab does produce pathological complete responses in the setting of neoadjuvant setting of melanoma. But when nivolumab is combined with relatlimab, you can more than double the pathological complete response rate in this small study. In the middle of that slide, you see that these pathological complete responses are long-lasting with no relapse. There's only 1 relapse in the combination setting. These data sets are giving us the conviction that as we look towards the readout of RELATIVITY-098 study, that these could be really extending the treatment opportunities for patients with melanoma. In a similar way, we had seen the data in patients with MSS colorectal cancer. In MSS colorectal cancer, we know that single-agent PD-1 inhibitors do not work. This is an example of a patient where we have a patient who has been pretreated with multiple other therapies, experienced the metastatic disease to the lung, and when treated with Opdualag, leads to a partial response at 3 months, continues on at 9 months, and then continued on for 11 months or beyond. We have conducted this study for relatlimab plus Opdualag, or rather in Opdualag, and we are now awaiting the data for overall survival in 2025. If data are supportive, certainly a promising therapy and transformational outcome for patients with MSS colorectal cancer. Now, beyond these indications, we are continuing to generate the data, and we're looking forward to some of these readouts in 2024, early and mid phase in terms of hepatocellular carcinoma, and early 2024 for first-line non-small cell lung cancer that is looking at triple combination of Opdivo plus relatlimab plus chemotherapy. These data, when available, will pave the way for additional indications to pursue for Opdualag. But beyond Opdualag and Opdivo, there is the TIGIT program that Robert also mentioned. We've taken a slightly different approach. We've taken a dual approach of bispecific antibody, and this is the first disclosure of the second target of that bispecific. That is CD96. We believe that dual targeting at the same time is much more important, because when you inhibit TIGIT, you leave the second pathway open, and that may lead to either decreased efficacy or resistance to TIGIT inhibitors. As you can see on the right-hand side, there are two different ways of targeting these two. You can either do it through the monospecific way and combine the two monospecific antibodies, as you can see on the right-hand side, but the efficacy or activity is not that pronounced. It is only when you put both of those targets on the same antibody, make a bispecific antibody, and that pink bar actually shows you that, that that efficacy is good in terms of the T cell response. Now, of course, many of the competitor trials are ongoing. Those data are evolving, and we are also generating our own data with this bispecific antibody in combination with nivolumab at this time, with also looking forward to then combining it with chemotherapy. And our initial tumor types that we are looking at in terms of thinking about the future development are such as non-small cell lung cancer and gastric cancer. But of course, there are many more opportunities that also could come by as supported by data. Another molecule I want to talk about is the oral administration of a DGK alpha/zeta molecule. Now, this is very interesting molecule as we think about the future of development of immuno-oncology molecules or immuno-oncology enterprise. An oral approach to a checkpoint inhibition, again, a molecule that primes the CD8 cells, so to say, converts those cold tumors into hot tumors, so that these tumor cells are now available for cell kill when they're targeted with PD-1 inhibitors. So this is again, a phase 1 trial that is ongoing. We have just initiated the combination with nivolumab. So in 2024, again, a data-rich period, where we'll start to see these data emerging, and hopefully, we'll be able to bring it to the medical community to then plan for a future development. Now, as I said to you before, that immuno-oncology is not the only approach that we've taken. We want to go beyond that, and that's where protein degradation, and especially when we talk about, ligand-directed degraders, that's where it comes in. What we are talking about is a disease that is new from our portfolio perspective, is prostate cancer. Now, in metastatic castration-resistant prostate cancer, it's a devastating disease. In men, the overall survival rate in the metastatic disease is only 35% at 5 years. Now, how are these patients treated today? These patients are treated with hormonal therapy, which reversibly only inhibits AR, and then resistance occurs in these patients because of amplification of the androgen receptor, because of mutations in the androgen receptors. So what do we need? We need something that is more efficacious, that is safe to deliver and hopefully convenient. And that's where AR-LDD in our portfolio comes in. AR-LDD, we've taken an approach to irreversible degradation of AR. We have thought about it from a perspective of no matter whether it's a wild type androgen receptor, a mutated androgen receptor, or an amplified androgen receptor, that we can target all of this. We also are looking forward to seeing whether we can combine this with the current standard of cares. And with that in mind, we initiated the phase 1 program, again, a couple of years back. We've gone through the dose escalation phase. We are right now in the dose expansion phase for a couple of doses because we have to ensure that we have the right recommended phase 2 dose for this program. And I do wanna show you just a couple of examples of what we are seeing. This is the biopsy from a patient, pre-treatment and post-treatment. Very clearly, you can see on the left-hand side, the upregulation of AR expression that is shown in the brown staining over here. With one cycle of treatment with our AR, AR-directed ligand, directed degrader, you can see the, the androgen, receptor has been degraded, and you do not see the brown stain on the right-hand side. Now, that does translate into clinical benefit as well. As you can see from this particular patient's example, 69-year-old male, multiple prior therapies, that have been used to treat this disease, again, comes in with AR, amplification in the tumor. When treated with AR-LDD, within a month, you see a precipitous drop in that PSA level, and these drops are then maintained for six months or longer in this particular case. So overall, a very promising profile that is evolving. We are continuing to generate this data. We are planning to initiate registration trials. Of course, we'll talk to the regulators, what the appropriate trial would be for such a molecule, and that then take this forward into not only the castration-resistant prostate cancer, but open the opportunities in the earlier setting, in the castration-sensitive prostate cancer setting. So taken together in oncology, we want to continue to expand our presence and leadership in immuno-oncology field, with differentiation coming through oral administration as well, and extend beyond that to the bispecific approach of TIGIT. Then, of course, in protein degradation, we want to use AR-LDD as the first approach, but then there are many others that Robert already talked about that we can bring about. And last but not the least, a specific directed approach of kinases and repotrectinib, where we're looking forward to the PDUFA date in the US. of November 2027. Overall, a large unmet medical need being addressed to this portfolio. With that, since I've shared with you a lot of information, I'm pretty sure you wanna digest that. So we'll take a 10-minute break, and we'll be back to talk about the rest of the portfolio. Thank you. All right. We'll just wait for about 30 more seconds as people trickle in and take their seats. All right, well, welcome back. Still a very good morning. And here we will start off after listening to what we talked about this morning already through immunology, oncology, and hematology, and cell therapy. Now I'm going to start talking about cardiovascular medicine. On cardiovascular medicine, we've taken a very focused approach. We already are leaders as we think about anticoagulation, but we want to extend our leadership over there through the anti-factor XIa inhibitor, that is Milvexian. Secondly, we have cardiomyopathies that we want to really extend our leadership with the first and only approved therapy in Camzyos, but want to bring in myosin inhibition as the way to treat multiple other diseases beyond symptomatic obstructive hypertrophic cardiomyopathy. With that in mind, let's start off with Milvexian. Milvexian, a factor XIa inhibitor. We want to extend our ability to treat more patients because there are many, many patients out there who are in need of better efficacy and better safety profile when it comes to anticoagulation. With Milvexian, we can extend our approach to not just treat the venous side of the disease, but also the arterial side of the disease, as we think about additional indications of secondary stroke as well as acute coronary syndrome. We have conducted a robust phase 2 program that gave us the confidence to initiate the largest phase 3 program called Librexia, where we have three indications being pursued in secondary stroke prevention, treatment of acute coronary syndrome, as well as for atrial fibrillation. We also have fast-track designation for each of these indications, so when the time comes, we will have the ability to have rolling submissions for these indications to certainly accelerate the process of regulatory reviews. Now, taking an, a page from Robert's file and talking about how Milvexian discovery occurred, how the development has gone by. From a genetic basis or causal human biology perspective, we think about hemophilia C. Patients have a deficiency of factor XIa. What happens in those patients? Well, first of all, there's a lower risk of ischemic or thromboembolic diseases or ischemic strokes. Secondly, spontaneous bleeding is uncommon in those patients. If you think about Milvexian, it is an oral modality that is highly specific for the inhibition of factor XIa. And then overall, from a proof of concept perspective, as we have shown, we've conducted two clinical trials, one in patients who underwent total knee replacement. That's where Milvexian was used as a single agent for up to two weeks, and showed a dose-response relationship when we think about efficacy, the efficacy that was superior to the active control of enoxaparin. Secondly, we do not see serious bleeds over here. We do not see a dose-response relationship from a safety perspective. So overall, this program has led us into initiation of the single agent administration of Milvexian in patients with atrial fibrillation, and that large phase 3 trial is currently underway. The second study that we conducted was for secondary stroke prevention. Now here, when these data were presented, you posed several questions to us. You said that the trial did not meet the primary endpoint, so why are you so confident in going into phase 3? You said: We don't understand what the 200 milligram dose over here means. You said: We don't understand how these data relate to acute coronary syndrome, and where you're going with that program. Well, let me walk you through one by one. Number 1, if you think about the primary endpoint in the phase 3 trial, that is about reduction in ischemic strokes, as opposed to the combined endpoint that we had, or composite endpoint that we had in the phase 2 study, but which looked at not only the ischemic strokes, but also combined that with cohort infarcts. So if we separate that out and look only the effect on the ischemic strokes, we see a 30% overall relative risk reduction in the phase 2 study that we conducted. Secondly, we also see that dose-response relationship, albeit starts early and plateaus out very early at the 25 milligrams BID dose, and that 25 milligram BID dose is the one that we've taken into the phase 3 setting. And that, what that really means is that we don't have to worry about the 200 milligram BID dose, which is an outlier. Now, to your last point about how does this matter for ACS? Because if you think about the pathophysiology in acute coronary syndrome, it is similar to what we see in the arterial disease of secondary stroke. The treatment paradigm that is currently utilized for ACS is the same, dual antiplatelet therapy. And now that we have the data from the secondary stroke prevention trial of combining safely adding a factor 10-A inhibitor to antiplatelet agents, this gives us the confidence to initiate the phase 3 program that we have across the three indications that are currently enrolling, and we are looking forward to the readout of these studies in 2026 and 2027. We are, of course, working very closely with our partners in Janssen in terms of conduct of this study, and we'll continue to see how we accelerate this program to bring these data even faster, even earlier across the indications. Now, talking about Camzyos, truly a transformational therapy, the first and only myosin inhibitor approved for treatment of obstructive hypertrophic cardiomyopathy. We already have a very strong launch for this indication in terms of symptomatic obstructive hypertrophic cardiomyopathy. We are extending the opportunity and potential for use of this medicine for treatment of patients with non-obstructive hypertrophic cardiomyopathy, as well as working with companies that have generated the AI algorithms, such as Viz.ai, that you might have seen the approval coming through. We are looking forward to increasing the diagnosis because there are many patients who are still undiagnosed and living with underlying disease, and therefore, applying these artificial intelligence methodologies and algorithms, and in reading the ECGs or EKGs, we can pre-diagnose these, or we can diagnose these patients and get them to the physicians as soon as possible. Beyond that, we want to test out the theory of applying myosin inhibition to other diseases such as heart failure, and I'm gonna touch on that in just a little bit. But we do believe in the truly disease-modifying potential of Camzyos as we think about obstructive hypertrophic cardiomyopathy. I have no intention of making you read our ECG tracing over here. But what I do want you to look at holistically, first of all, the left side ECG versus compare it to the right-hand side ECG tracings. The number one thing that you notice is truly the high peaks and low valleys on the left-hand side, meaning the voltage that you see is very high as the heart is hypertrophied, so electrical current takes a longer time to traverse those hypertrophied walls. And therefore, the current. The voltage that you see is much higher on the left-hand side. That is the pretreatment ECG of the same patient that you see on the right-hand side, where those voltages have come down, therefore, telling you about the remodeling of the heart. Number two, as you can see in the circled part of the ECG, there is a ST segment, and there is a wave that is called the T wave. You see the inverted T wave, especially in the lower circle on the left-hand side. When you compare that to the right-hand side, once again, you see the ST segment have come up and the T wave is now upright, once again, telling you that the repolarization defect that was there has now been corrected. So overall, truly a disease-modifying outcome when we think about Camzyos from an ECG perspective. We are really thankful to Dr. Matt Martinez from Morristown Memorial Hospital, who provided us this tracing as well as this particular echocardiogram from a patient. Now, of course, I don't want you to read it, but what I want you to focus on is the circled area. What you see on the left-hand side is a sluggish moving heart. In general, you see the walls are thickened. In general, you see that the septum that is separating the two black holes that you see on the upper part of this left-hand side... That is also thickened. You also see a valve that is very sluggish because of the hypertrophied valve, walls, and that sluggishness of the valve that valve that when it opens, it also blocks the aortic side, and that's what is called the obstruction of the tract. On the right-hand side, you see a heart where the walls look more normalized, where you see the valve opening normally, and therefore, you're truly remodeling the heart, and that's what patients experience. That's what you heard in the video right at the beginning of this program. That's what probably patients are experiencing when they what they are telling the physicians and the physicians telling us, that a patient who goes on Camzyos never wants to come off of Camzyos because they are truly experiencing the effect that they have on their disease because of Camzyos. Truly proud to be able to bring that first therapy that truly addresses the underlying cause of the disease in obstructive hypertrophic cardiomyopathy. These are the types of data, combined with the data from the non-obstructive hypertrophic cardiomyopathy trial called MAVERICK, that led us into designing the Phase 3 trial in non-obstructive hypertrophic cardiomyopathy, that is right now enrolling patients, and we anticipate to see the data readout in 2025. Now, another approach that we are taking to seeing what we can do with myosin inhibition is in heart failure, specifically in the heart failure with preserved ejection fraction. Now, I'm not gonna go into the details of what types of heart failures there are. There is a picture over here. We've given a little bit of a summary of what heart failure looks like. But in general, about 7 million patients in the United States suffer from heart failure, and there certainly is a paucity of treatments that are available, which are effective and safely delivered for patients with preserved ejection fraction-associated heart failure. The pathophysiology over here is akin and similar to what we see in non-obstructive hypertrophic cardiomyopathy, with stiffening of the ventricles as well as the ventricular hypertrophy that we see. So we want to take that hypothesis and apply myosin inhibition on top of that, and we have an ongoing study called EMBARK, where we have begun to see the data in-house. What we see is an impact on the biomarkers, NT-proBNP, as well as troponin. What we see is the physiology changing a bit over there, and these are the types of data that we are taking forward in designing our next study, a phase 2 trial of MYK-224, another myosin inhibitor from our pipeline, that we want to test out in a randomized fashion in the phase 2 trial that will pave the way for then take this forward into patients with HFpEF indication. So overall, as we think about cardiovascular disease, a focused approach to continue to extend our leadership in anticoagulation, and then, of course, trying to help the patients with obstructive hypertrophic cardiomyopathy, non-obstructive cardiomyopathy, and extend potentially the label for myosin inhibition into patients with heart failure, with preserved ejection fraction. More to come as data evolves in the future. The last therapeutic area I want to touch on is neuroscience. Truly, truly, truly excited about this because over the years, working with our external collaborations, we have continued to build on our pipeline. Now where we are is that we have 22 programs actively in the phase of discovery. Not only that, we have more programs in clinical development. You heard from Robert, we have a CNS-penetrant TYK2 inhibitor for which we are looking forward to filing an IND later this year. But we've already generated some data in terms of single ascending dose, multiple ascending dose studies in healthy volunteers, as we think about our anti-tau program, as well as for our eIF2B activator program. There's a third program running very closely behind, as in the FAAH and MAG lipase inhibitor. Talking about tau, tau inhibition. Tau is another one of those protein that gets accumulated in the brain and probably even more pathogenic as opposed to the beta amyloid that you've been hearing about, that you have heard about, against which therapies have been developed. But tau, maybe, as I said, is even more pathogenic as we think about what it leads to in terms of Alzheimer's disease, time of start, severity of the disease, and the detriment that occurs over time. So it is important to find therapies that can potentially get rid of tau as well as stops the internalization of tau into the neurons. And that's the approach we are taking for anti-tau therapy that we are developing. Now, of course, one could say, "Well, other therapies have failed. Why are you developing anti-tau therapies?" Approaches taken thus far have targeted the N-terminus as well as the C-terminus of that gene that we show over there. What we are doing is approaching the middle part of the MTBR gene, and that's where we're looking at specifically the R1 domain, which is implicated in the disease. When we look at the preclinical models, they do tell us that when specifically targeted, this is what is leading to better outcomes when we think about animal studies, in terms of stopping or inhibiting that internalization of the tau protein into the neurons. And that philosophy is what we are now testing out, and we have done the phase 1 healthy volunteer studies. We know that we can get linear concentrations as we increase the dose in healthy volunteers. We know that the drug does penetrate the CNS and blood-brain barrier and get in the CNS. We know we do not generate anti-drug antibodies, and therefore, these concentrations are maintained, and we see robust exposures in the CSF of healthy volunteers. Taking all of this data, we are about to initiate our phase 2 randomized trial in patients with Alzheimer's disease, starting early next year, with two different doses compared to placebo. We will allow background therapy with beta amyloids in this population again, so that we can start testing out the safety profile and combinability of this drug with the approved therapies. Another program that I want to touch on, which is novel, is eIF2B activator. Now, what is eIF? eIF means eukaryotic transcription initiation factor. If you remember your Biology 101, transcriptions means DNA to RNA, RNA to protein. That transcription is DNA to RNA. Translation is RNA to protein. So what happens if you stop the transcription or initiation of that DNA to RNA, RNA to protein? Well, you get abnormal proteins, folded proteins, misfolded proteins. Misfolded proteins means they will accumulate that lead to degenerative diseases. Degenerative diseases, such as neurodegenerative diseases specifically, lead to amyotrophic lateral sclerosis. That's where it's implicated. ALS is a devastating disease. We know that. About 2- to 4-year survival once the symptoms occur. So we need to find therapies for these unmet medical need, serious diseases, and that's exactly where we want to bring about an activator of eIF2B so that we can get rid of these misfolded proteins and get that back to normalization, and hopefully impact the disease and its outcomes. So overall, if you think about the neurology pipeline, we are making progress. We want to be the leaders again in neurology, and initial starts look very good from the diseases that we are targeting. And when we are able to talk about 5 MAG lipase in 2024, we'll be able to show you that multiple other diseases that can be approached to the third target that we have in development at this time. But having a pipeline that is that rich, that deep, that diverse, but not having the ability to deliver that fast, that would not be good. So we want to be responsible from that perspective, and we are taking approaches to further improve our productivity. We've again taken the AI and machine learning approaches and built platforms so that we can accelerate the development of our pipeline. In the initial phases of development of our protocols, we have developed a platform called Solera. What we do with that is we take our clinical trial designs, we run simulations for those clinical trial designs to have the most appropriate protocols that can be executed in the clinical trial sites that decrease the burden on the patients. We can run about 1 million simulations now in only 20 minutes, which used to take days for even doing 500 to 1,000 simulations when statisticians were designing these trials. In the middle part, where we are generating the data, enrolling the patients, we have again developed a new platform called Da Vinci, that allows us for real-time access and review of the data, so we can generate the queries, get the queries cleared, and further accelerate the development of our programs. We then also have digital protocol solutions that we are building that will help in automation in terms of writing our protocols, as well as writing our responses to health authorities, as well as writing our submission documents. Again, shortening the time from data readout to submission of our documents, thereby decreasing the time that it takes to get the drug approved. Overall, truly excited, working towards further acceleration of delivery of these molecules. We are applying all of these learnings from AI and machine learning tools, to also be able to select the sites, as well as to be able to analyze the big data that we have collected, to make sense of it, to appropriately try to design trials. And if we have to go after patients that are selected patients in the clinical trials, we can make sense of that. So overall, once again, we are taking all of the available tools to us, continue to build our understanding of these tools, and apply them in the appropriate nature to be able to accelerate the development of our pipeline. Taken together, what you've heard from me today is certainly the opportunities that are available to us in further extending the opportunities associated with the launch products. You heard from me how we are taking more and more products into registration programs, and the new molecular entities that we can generate from there as we look to the back end of the decade or the second half of the decade, as well as how we are progressing to evolve and certainly enrich our pipeline from the new molecular entities that are entering into the early phase development and transitioning from early phase to the mid phase of this development. Our intention is obviously to increase the number of INDs that you heard from Robert about, of, approximately 10 INDs per year. We certainly want to increase our probability of success of converting the molecules that enter the first in human trials to getting ultimately to approvals, as well as to shorten our development cycle times to a median of six and a half years for the drugs that we take into full development. I can tell you that when we look apples-to-apples comparisons across the industry, we have a much higher positive success rates in the outcome of our phase 3 trials as compared to the others. That is what makes us feel proud. That is what encourages us to really continue to build our pipeline and bring the transformation to patients with serious diseases, life-threatening diseases that have an unmet medical need. With that, let me pass it back to Chris to take you to the conclusion, and then we'll get into the Q&A after that. Thank you. Thanks, Amit. We have obviously covered a lot of ground today. So as I step back, though, and look at what we presented, a couple of things are pretty clear. First, over the last four years, we have done a really good job of building a highly productive, innovative engine. That's an engine that is bearing fruit today, and hopefully, you saw that in the discussion that we've had this morning with what we've accomplished to realize the power and to begin to bring forward the power of our protein degradation and cellular therapy platforms, how we have broadened and deepened our presence in hematology and oncology and immunology. How, as you just heard from Amit, we've strengthened our position in the cardiovascular space, and how we have begun to rebuild the company's presence in neuroscience... The second thing that's pretty clear is as we look forward and continue to execute on the strategy that we've talked about today, I'm confident that this R&D engine will be a core building block to our growth story in the back half of the decade. So I started the discussion today with this slide that talked about some of the specific levers that we have to pull going forward, and let me just rearticulate a few key points that, hopefully stood out to all of you. First, we see very tangible opportunities for us to extend our base business in immuno-oncology. And specifically, we talked about the opportunity that we have to bring forward our PD-1 subQ program, and you saw the benefits that that can bring forward to patients as well as to customers. And we're happy that the potential launch indication for this product covers upwards of two-thirds and potentially up to three-quarters of Opdivo, Opdivo's business today. And of course, that subQ program is further enhanced by Opdualag, as well as potentially earlier stage IO assets, such as the bispecific TIGIT program, that we touched on this morning. As expected, we continue to de-risk the long-term potential for our recently launched, portfolio of assets. You can see here the milestones that we've achieved just up to this year, as well as the numerous additional catalysts that we expect over the next 12-18 months. And all of these bring into a sharper focus, that long-term potential that we see with this portfolio of products. We've continued to advance and broaden our pipeline with a clear line of sight today to move from the 6 assets in registrational studies that we talked about in January, to now being able to articulate double that, with 12 assets over again, the next 12-18 months or so. And of course, we have many additional proof of concepts coming behind that. And what I can tell you is that these assets are being developed in areas of high unmet medical need and in commercial markets that are large today and are growing over time. And we talked about how we are making progress with a number of our platforms across therapeutic areas. We talked specifically about 2 platforms, in particular, cell therapy and protein degradation. In cell therapy, you heard how we are continuing to make progress on the manufacturing side. We're making progress in terms of improving product supply, strengthening vector supply, advancing next generation technologies. All of which, of course, are important for our existing assets of Abecma and Breyanzi, but they also are important for the exciting pipeline that we're bringing forward. And on that front, you saw how we're advancing programs to strengthen our position in hematology. But importantly, we're also advancing this exciting modality into areas like immunology and neuroscience. And to be very clear, we intend to lead in that effort. We're also leading advanced new technology in cell therapy, and we talked a bit about some of those as well, including our dual CAR program and our allogeneic program. And if you take all of this together, we think these efforts position us at the center of an innovation that is really among the fastest-growing modalities in our industry, and it also positions us to be the partner of choice in cell therapy. And with respect to protein degradation, we talked about how this is a platform that we believe is ready for prime time, both in terms of the number of INDs that it is capable of generating, and you hopefully saw that, in Robert's presentation, as well as in the exciting proof of concept that we are seeing again, in key areas outside of malignant hematology. And both Robert and Samit gave examples and shared important progress in areas as diverse as prostate cancer and sickle cell, both of which I think you can appreciate, are areas of significant unmet need. So if you add it all up, we have a strong track record. We have a portfolio of high-quality assets, a clear focus that you saw across both Robert and Samit's presentations of improving the productivity and effectiveness of our R&D engine. And we, of course, have a capacity to continue to enhance all of what we talked about today, not only through organic efforts, but also through business development. And we believe that we have the ability to continue to bring forward very exciting first and best-in-class medicines, and to leverage this R&D engine as a driver of growth as we navigate the back half of the decade. And so with that, again, want to thank all of you for being with us, both here as well as online, and we have plenty of time now to commence Q&A, and we look forward to getting your questions. With that, I'll invite my colleagues up, and we can get started. Thank you again. Great. So I see a hand up from Chris Shutt over on this side. And can we get a microphone to Chris, Charlie? Great. Thanks so much and appreciate all the info today. Just 2 questions for me. Maybe just first on Opdivo subQ. I think you talked about duration on that asset to the early 2030s, and I'm just interested, why only that long? And is there any pathways that this could be impactful, maybe beyond the early 2030s, as we think about just kind of the impact to the business there? And then maybe a bigger picture question for Chris. I guess given the pipeline you laid out today, I'm just interested in the role kind of BD in the balance sheet plays for the company. It seems like you've got a number of near-term launches. You've got now this growing mid to late-stage pipeline. The street's still clearly very worried about the late 2020s. I guess, is there a sense of urgency to add later-stage pipeline assets that could maybe more directly contribute to that window of time? Or is the thinking more smaller transactions like we've seen in the last year or two, you know, maybe more capital return and just kind of wait for, you know, continue to develop the internal pipeline and wait for some of these assets to mature? I'm just trying to get a sense of, like, how you're thinking about, you know, that element of the, of the story. Yeah, let me take both of those questions. So with respect to Opdualag, the subQ program, rather, sorry. Obviously, we feel that this asset has the potential to have a significant impact on patients as well as customers. We designed this program, obviously, before we had any discussion of IRA. We think there's real value for this product in the marketplace. The way we look at it today, based on our understanding, both of the IP as well as how things are playing out with respect to CMS, is we think this has an opportunity to extend into the early 2030s. Beyond that, we'll have to continue to follow and see how things progress. But we're excited where we are today, and we think this program really does have value to both customers and patients, and we're excited, obviously, to see the data later this year, and then we'll continue to follow the external environment as well. With respect to kind of how we look at capital allocation and business development, let me just say at the outset that the way we are approaching capital allocation is largely unchanged. Business development continues to be the primary objective that we have, or the first important objective that we have with capital allocation. The criteria that we look for in opportunities is also very similar to what we've talked about previously. We're gonna look for opportunities that make strategic sense for the company, that make scientific sense in that we can be a leader in that space, as well as obviously, that it needs to make financial sense. I think, though, what we would also be looking for, and hopefully you saw it in the discussion today, is potentially using that lever to do a couple of things. First, if there are areas where we feel like we've got gaps in our existing pipeline, potentially to use business development as an opportunity to fill those gaps, but also, of course, to continue to enhance and strengthen the growth profile of the company. And so I would say those two things become increasingly important. But I think in its totality, business development has been the primary focus for us from a capital allocation standpoint, and it's going to continue to be. Of course, we remain committed to the dividend and growing that dividend, and we continue to look at buybacks as opportunistic. Great. I see Luisa has a question, Nina. Thank you. Luisa Hector from Berenberg. I've got two questions, please. The first on all the presentation, all the way through, we could see how critical these three parameters are for improving R&D productivity, and it was really helpful to see that with examples, so thank you for that. I just wondered at what point, as these products transition into development, you start applying the commercial lens so that you're sure that the science translates into raising the efficacy bar or improving the patient experience when the asset potentially reaches the market. And the second question would be on Milvexian. You laid out the details of the dose selection in SSP and ACS, but how have you selected the dose for AF? Can you share the dose with us? In AF, in terms of endpoints, could you just confirm, are you looking for non-inferiority on efficacy and superiority on safety? Maybe, Robert, you start and then some. Yep. Yep. Well, I'll start with the first part of the question. So, you know, I think in terms of the parameters of productivity, when we think about number of INDs, probability of success, speed through clinical development, doing all of that efficiently. But as you also point out, a really important parameter is the value that those medicines actually bring. And so we really engage with our commercial colleagues, Adam and others, right from the very beginning. I mean, these are part of our teams. And so from the discovery process all the way through to early development, and of course, late development, we know we consider what those commercial opportunities are. You know, from a basic science perspective, we really think deeply about those three kind of areas: understanding human biology, matching modality to mechanism, path to clinical proof of concept. So we know we're at that inflection point. And in terms of the understanding human biology, we really think, you know, we sort of put on our physician's hat, and we think about what is the unmet medical need for patients, and that's really the starting point for us. But of course, as the closer and closer we get to a launch, we refine that commercial potential. But the short answer to your question is we start right from the very beginning with very close collaborations with Adam Lenkowsky and his team. If I could just add one thing to that. I think that that collaboration is gonna be increasingly important in a post-IRA world, because making sure that we get those insights into very early decisions about investments that we make is gonna be critically important. For Milvexian, since we also have our colleagues over here from our teams, I'll ask Roland Chen, who leads the cardiovascular therapeutic area, to talk about Milvexian, the dose, and the way we selected the dose. ... I'm Roland Chen, Cardiovascular and Neuroscience Development. Specifically with respect to atrial fibrillation, the dose will be 100 milligrams BID. When you think back about the rationale for, for the dose, which you asked about, it really goes back to trying to identify the dose that optimizes the benefit risk. So I'll walk through some of the considerations. I think first, you have to think about the history, about how you select doses for, for agents that are used in atrial fibrillation, for example, with rivaroxaban and apixaban, which the alliance has a great deal of experience with. I think secondly, you look at the data that we have. That is, we take our phase 1 data, our modeling data, as well as the phase 2 data, which were intentionally designed to provide very complementary sets of data. And then third, the need to show non-inferiority against an established agent, a good agent, apixaban. And then finally, again, how do we go about with the pathophysiology and what we know about the disease? And so when you step back, we intentionally did not want to do a phase 2 study in atrial fibrillation. Specifically, because those studies are hard to conduct and get enough events to actually see whether you actually have efficacy. So we intentionally studied 2 complementary treatment contexts. First, in SSP on top of dual antiplatelet therapy, but also in our TKR study, where we studied it in monotherapy. Why, again, if you think about it, the history tells us you can use this study to help actually define a dose because there is a good model here to help model what you can see in atrial fibrillation, where monotherapy is typically the standard of care. This is the TKR model, which helps us. The SSP data is complementary because it helps you with actually providing insight in those patients who might actually, in the real world, have AF and actually need antiplatelet therapy. So when you think about it and put it all together, it's about trying to show non-inferiority or better against Eliquis. It's about trying to establish a safety profile that is better than Eliquis. And when you think about our data with TKR, you can go up to 100 milligrams, where you see the efficacy plateauing. You don't need to go higher. But I think that's complemented by the data from our two other studies, that is the TKR and the SSP study, where you can see that there isn't a dose response with consequential bleeds, which gives us confidence to be able to go to 100 milligrams. And so I think 100 milligrams BID. And so with those two things in combination, gives us confidence that we're looking and gonna be able to optimize the benefit risk. It's great. I see Andrew Bana's hand up over there, Charmi. Raul, thank you. Thank you. It's Andrew Baum, Citi. Two questions. Samit knows my interest and excitement over CAR-Ts in autoimmune. So I'm gonna start with a softball question. Perhaps you might like to frame the magnitude of the commercial opportunities, given the breadth of indications, and also comment on the prevalence of multi-refractory patients across autoimmune, just so that excitement translates into financial terms. And then perhaps you could share some of your early discussions about what the regulator wants to see in terms of the durability of follow-up, the design of trials. Do you need a control arm? What are you doing with preconditioning? All of which may impinge upon the magnitude of that benefit. And then a second question, separate entirely, is on the IRA. Obviously, Bristol has a number of small molecules addressing elderly patient population that falls in Medicare. To what extent does a multiplicity of small molecule approaches on the same target through what may have called backup, but maybe you reframe it as differentiated fast followers, enables you to ameliorate the impact of the IRA by pursuing different indications with different molecules, albeit directed with the same target and all being small molecules? So thank you. Yeah, maybe I'll start with that question, and then Adam and Samit, you guys can cover the first question. So let me just sort of maybe level the IRA question up, 'cause I suspect IRA is on many people's minds. So a few things from our perspective. One, we've anticipated IRA coming. Two, we have built very strong capabilities in the company to understand the implications of IRA for our existing assets, but also, as I alluded to in the previous question, to connect back to other parts of the organization to ensure that we are informing key decisions that need to be made, including in research and development. Third thing I would highlight is that we have consistently said that we do not believe that there's a broad swath reaction to IRA. So there's been some discussion, maybe you stop doing small molecule development, you focus on large molecule. We don't think that's the right way to approach this. We think we wanna continue to follow the science as a primary objective, and then make sure that we are looking at the implications of IRA for investment decisions, not even at an asset level, but it's really at a program level within an asset. And that's how we've designed the infrastructure that we have in order to help inform those decisions. And clearly, IRA and the implications will inform potential investment decisions that we're going to make. And as you point out, it could also inform how we think about sequencing our pipeline and the types of assets that we bring forward. I think the point is that we've designed an infrastructure which allows us to make a lot of different trade-offs and a lot of different decisions based on the implications of IRA in a given therapeutic area, in a given disease, and with a given asset. That's how we're going to approach it going forward. I think, as you hopefully saw today, we've got a diversity of assets in the portfolio, and if there's anything that is almost an unequivocal no-regret move with respect to IRA, it's more diversity in your pipeline, and hopefully, that's what we presented today. Adam, do you wanna start and then Samit? ... Thank you for the question. We're very excited about our CAR-T, our Next T CD19, for a number of reasons. First, when you look at the profile of that asset, it is very similar to what we see with Breyanzi. Really, we believe this will be another best-in-class efficacy and safety profile, and it's exciting to now bring CAR-T from hematologic malignancies into, immunologic disorders is an incredibly exciting opportunity for the company and for patients. So when we think about SLE, we're obviously developing, Sotyktu in that marketplace in an earlier line treatment. And so Next T CD19 will be developed in a later line patient population, and we anticipate about 50,000 patient eligibility for Next T there. But Samit also talked about a broader program into auto disease states like MS, myositis, and that could yield, you know, another potentially 100,000+ patients in immunologic diseases. So very exciting. It's still early to tell, but we're looking forward to bringing this into immunology. On your last part about the regulatory discussions, very early to really comment on that, because we have to generate some data as we approach the regulatory authorities. And of course, Andrew, you know, I will always say, I cannot tell you what we talked to the regulators about. Right. We've got a microphone over to Steve Scala. Nina. Thank you. Steve Scala from TD Cowen. An obvious protein degradation target might be breast cancer, but it's either apparently not being worked on or you are working on it, but didn't say so. Can you tell us your thoughts on that? And a little bigger picture, but you stated areas where Bristol intends to increase the gap versus the industry average, including increased probability of success and decreasing development time. But of course, no company aspires to do the opposite. So the question is, what are the companies that Bristol believes will fall behind, either doing or not doing? To judge strength, it's helpful to know what weakness looks like, so it'd be helpful to know what Bristol thinks on this point. Relatedly, thinking back in history, I think Bristol has always been a player, but really seldom a leader. I'm just wondering, what has lit this spark now, and what will keep that spark lit? Thank you. Yeah. Why don't I, why don't I start? I might just start with the last part of your question. I mean, one of the reasons we believe that we're gonna be leaders are all the people in the room here. I mean, I think we have, you know, a great pipeline, great scientists, great committed clinicians, and I think that's, that's why we are going to, not just continue to lead, but expand our leadership. And so in terms of targeted protein degradation, I think we outlined our, our, our strategy, and we apply that, whether it's a cell therapy, targeted protein degradation, small molecule, biotherapeutic, et cetera, which is we think very deeply about the science. And it's not just the science in animal models, it's science in humans, and that's why we define this term, causal human biology. Hopefully, we were able to describe how targeted protein degradation brings a unique approach to matching a modality to that particular target, and that it can degrade or get rid of it. So to your question, we actually think about all targets, and we think about what that opportunity might be. You're right, we do not have an estrogen receptor degrader in the clinic, but these are all things that we're constantly thinking about and constantly worrying about, because patients need these medicines. So that's how we approach it in general, in terms of targeted protein degradation. And maybe I can take the second question, but also, you know, two years ago, if we go back and we were in the same room around the same time in November of 2021, we showed you what we were working on. And hopefully, what you see today, you've seen the translation of that promise into the reality of today. So we have continued to move. So what I would say is that that spark has turned into a controlled fire, and that fire is turning into productivity that we see right now. If you think about what we have in the pipeline, that is what is keeping that fire alive. And it is really a very promising pipeline. I truly do believe in it, and I have talked about every single therapeutic area where we are going with this. But what, what we are doing is obviously continuing to keep an eye on what we should do versus what we should not do. And if you look at quarter to quarter, when Tim and Nina shared the slides with you, you see that our pipeline continues to evolve. But there are things that we also take off of that pipeline because the science is not supporting that, and so we should not continue that. In terms of how we, then continue to accelerate that, that's where our new ways of working are very important. And where, where many companies falter and fail is when they don't pay attention to execution of that pipeline, whether... And every single thing counts. In fact, just recently, we divided up our development of any clinical protocol into eight different small pieces and looked at what is our current time and where do we need to get to. It's quite interesting what we observed from where we were spending a lot of time, and we need to get better. For example, how we select sites, how we approach the sites, how we do our contracting, how we enroll our patients, how we follow our patients. That's why what we talked about earlier, the Solara platform, the Da Vinci platform, and applying the AI and intelligence of our clinical trial sites, how we select them, what we can provide to the investigators, all of those things help, and that's why we have to approach it from a holistic way, not on a specified way of a single point. ... But you're right. I mean, I think that at the end of the day, the reason we have highlighted it so specifically here is that we believe this is gonna be an important dimension of what will make the company successful, and in our ability to continue to drive growth as a company and ultimately deliver value to shareholders. I think that what we've seen is a couple of things that are really important. One, when we break it down, there are some areas where the company is exceptionally good today. I highlighted our regulatory side. Some had highlighted when you look at the data on phase 3s, for example, we're very, very, not only competitive, but we're actually out in front, we believe, of most of the competitive set. There are other areas we obviously need to continue to make progress. Again, this is going to be an area where you're not just skating to where the puck is today, but you're also gonna have to be mindful that every company is going to be going through a journey like this. I think from our perspective, this is an area we're gonna have a healthy degree of competitive paranoia. We're gonna pay attention to what's happening in the marketplace, and our commitment is to be not only achieving the objectives that we have today, but continue to push ourselves to do better, go faster, improve the probability of success, and deliver more. Great. Thank you. Geoff Meacham has a question over here. Great. Thanks. Geoff Meacham from Bank of America. I have a couple. So one, on the neuroscience end of things, as you guys build out the pipeline, how much of a role will BD play, and is there an intended focus maybe on more novel targets, either internally or externally? I guess, so what I'm looking for is, you know, how do you think Bristol could be different in this disease area with, you know, decades of pretty anemic, I would say, innovation? And then on some of the newer targets in IO, when you think about, you know, the combinations with Opdivo, would you say subQ is maybe a more default route of administration as you look to IO combos? In other words, I'm trying to get a sense for how external factors like the IRA, route of administration, like, could play into the development as you try to extend Opdivo and kind of run the runway out a little bit. Thank you. Maybe Robert, then Samit? Yep. So I'll start, and then I'll ask Richard Hargreaves also to comment on our neuroscience portfolio. But you're right, I mean, neuroscience has been a very tough area over many, many years. I think, you know, what's different today is, you know, we do have a much deeper understanding of the causal human biology because of factors like human genetics and single-cell sequencing and all sorts of other advances in science and technologies. And so we actually believe that we have greater insight. So it wasn't... You know, at one point, you could say it was tau. Now it's the R1 domain of the microtubule binding region of tau. So that's a very specific therapeutic hypothesis. You know, before it was amyloid or tau, and now it's actually biomarkers to track specific epitopes of R1, for example, in patients, and there are now data to do that. So I think the science in neuroscience has actually evolved quite a bit, and we actually have internal and expert external expertise and allow us to pursue these ideas. But, Richard has been doing neuroscience for a very long time, as the best in the industry, so. I'm Richard Hargreaves, the Head of Neuroscience. And yeah, I think that we—our pipeline has come through really using the flexibility of business development and finding the best opportunities wherever they are in the world. We have a small internal neuroscience group, but what we do is we leverage our BD colleagues and look for opportunities anywhere we can find them. And, you know, when you say, "Well, what are we gonna do next?" I think you saw in some slides that, you know, as we delve, one of—I think leaders should do what only they can do, and the CELMoD collection gives us an enormous advantage. I don't think any other company has a library like that. As we're beginning to look at that library, we're finding molecules which will degrade factors, transcription factors, proteins that are involved in neurodegeneration, which will take us into a completely new space. On the combinations in IO space, so what you saw today is we have multiple new molecules that are coming into the pipeline that will require that combination with Opdivo. So certainly, having a subQ formulation that decreases the burden on the patient and the healthcare system is helpful. So if you think about DGK alpha/zeta molecule, that's an oral molecule, but if you have to sit in the chair for 35 minutes to get another infusion again, maybe not as good, but 5 minutes of administration would be better. So we'll look at that. In addition to that, we are already developing, for example, fixed-dose combinations with Opdualag, right? And we already have a subQ program for that as well, that we're running, and we'll hopefully see the data in the coming time. But taking the same ideology, same thinking around it, we'll also look every single time that we build a new molecule that is gonna be combined with Opdivo, how we can get to a fixed dose combination, and how do we go from IV to a subQ formulation so that we can continue to utilize that backbone. Thank you. Great. Dave Risinger's got a question. Great. Thanks very much. Dave Risinger from Leerink Partners. So a number of my high-level questions were already asked, so I just had a couple of dosing questions, please. The first is, with respect to the LPA1, in phase 3, you're evaluating the 60 milligram dose that you studied in phase 2, but you're also doubling it. So just curious, on the doubling of the dose to study the 120, in phase 3. And then, regarding Sotyktu-2, the efficacy in SLE was very encouraging, but there was a lack of dose response. I don't know that it was quite inverse, but total lack of dose response. Could you just discuss that and whether the 3 milligrams is right, or it should be 2 or 4? That would be helpful as well. Thank you. I have my colleague, Jonathan Sadeh over here. He leads the immunology therapeutic area, so he'll address those two questions. So first, LPA1. So, you asked about how we got to the higher dose. So I think it relates to some extent to what Robert was describing before, that, you know, we, we take our data, our clinical data, and, and go back and do some reverse translation, trying to understand what our clinical data means to, to the patient, what it means to biomarkers. And that's exactly what we did here. When we saw our phase 2 data, we saw that when, when you looked at exposure response, we saw that the higher the exposure was, the higher the response was. And response, you remember, was, slowing down the rate of FVC decline. And that's really critical because FVC decline correlates with morbidity, and importantly, very linearly relates to mortality. So the higher the inhibition of that FVC response, the more efficacy you're gonna get, and our goal here is to completely flatten that FVC decline. So when we looked at that exposure response, we saw that higher doses would potentially translate into that increased response, and that's how we got to the 120 mg dose for LPA1, and that study is starting right now for both IPF and PPF. Your second question was about lupus. So really important points to make here, really important indication. First, I wanna say that no company has more experience in SLE development than we do. We have done a lot of studies in SLE, and we have the deepest and broadest portfolio in SLE. So we think we understand here what is required, you know, dosing and clinical development path for approval in SLE. Now, when we looked at our phase 2 study, we did a pretty wide dose-finding study. We tested several doses here, and we saw that the optimal dose was the 3 milligrams BID dose. You pointed out that it is somewhat in inverse an inverse dose response. That's something that has been seen in other programs. If you've if you remember, the Anifrolumab program actually had a very similar dose response. We have some theories about why that is, and, you know, actually, again, in collaboration with our-- with Robert and his teams, we're trying to evaluate that, understand that. But the bottom line is that it's very clear that the optimal dose from an efficacy, safety perspective is 3, 3 milligrams BID, and that's why we've taken that dose forward, and phase three study, as Samit described, which started earlier this year. I think maybe just to kinda amplify a message of that, I mean, there's this whole thread between starting with the genetics, thinking about the preclinical models, seeing what we see in the clinical outcomes. And it's not just the clinical outcomes, it's all the biomarker translational data and how it all actually fits together. So we actually take that totality of data, we model it, we think very carefully about it, and that's how we actually select our doses for both of the studies that you actually referred to. And it's, you know, why we're quite optimistic about going higher with LPA-1, but also we feel like we've got the right dose for lupus. Great. I see Mohit has a question behind you, Kate. Thanks for taking my questions, and then thanks for these presentations. So a couple of questions from my side. Could you help us understand with the TYK2, now you are not pursuing it in ulcerative colitis. Can you help us understand the data you have seen and the thought process behind this? And is it the TYK2 you are not pursuing, or is it just so TYK2 you are not pursuing? If you understand my question here. The second question is regarding HFpEF for 2, 2, 4. If memory serves, MyoKardia was also testing mavacamten in that indication or planning to test. Did we ever see any data? Because there was some improvement in NT-proBNP there. So what were the learnings from those trials, which would help you inform about 2 to 4? Thank you. So I'll also again ask Jonathan to take the first question, and then Rohan, if you can talk about the second one. Okay. So the first question about IBD. So as you know, we have done three trials now with Sotyktu in IBD. We had a really good theory here, hypothesis, scientific hypothesis, that TYK2 inhibition will correlate with improvement in symptoms in IBD. We tested it in three trials, first in Crohn's disease, second in ulcerative colitis, in three and six milligrams, and then went higher in a second ulcerative colitis trial, Sotyktu. And in all three, we're seeing that there isn't really the response that we were looking for, and so we decided not to move forward with Sotyktu in IBD. I think it's important, though, to describe, again, going back to Robert's points here, they're about causal human biology and why we believe in this, in this, in this asset. There are multiple indications where we do see a very strong correlation between causing human biology and response. Remember, we have already approval in psoriasis, three phase three programs ongoing and multiple other phase two proof of concept studies that will be coming on. So we think there is a very bright future for Sotyktu, but it's not gonna include IBD. Thanks for the question about HFpEF. I think you heard from Summit why we're so excited about cardiac myosin inhibition in patients with HFpEF. ... I think what, one of the things that's important to point out is, as Summit mentioned, the, the data that we got from Maverick with mavacamten in the non-obstructive form of HCM, because it shares a number of similarities with patients who have HFpEF. Now, I think we're excited about the EMBARK study. Summit also alluded to that. That's a study of mavacamten in patients with HFpEF. And, you know, that study is continuing on. But what we've seen is very encouraging with respect to biomarkers, as was mentioned, and other parameters. I think what, what brings us to MYK-224 is, you know, we are currently studying that in the obstructive form of HCM. That's a condition we know a lot about based on the data we've gotten from mavacamten. We think that the knowledge of bringing forward study in oHCM, as well as in HFpEF, really gives us a leg up in terms of how we think about accelerating development in this area, specifically with MYK-224, as Samit mentioned. We're, we're excited because ultimately, this shows the benefit of having two agents, that is MYK-224 and Camzyos, as a part of our cardiac myosin inhibition portfolio. Thank you. Great. Seamus has a question. Maybe get a mic over there. Thanks. Seamus Fernandez from Guggenheim Securities. So, a couple questions. Maybe just first on Camzyos and 224. Can you just help us understand and frame the opportunity in HCM versus oHCM? And I guess one dynamic incremental to that is how has IRA actually-- or has it played at all into your decision processes as it relates to 224 and advancing that into HFpEF versus otherwise? And then, you know, separately, the CCR8 antibody, can you just help us understand a little bit of the, I guess, the clinical risks, the safety risks of actually targeting Tregs aggressively, and, you know, how that might result in immunologic reactions that could maybe mimic CRS? Are you able to avoid that by targeting CCR8 specifically? Thanks. Sure. We can start off with the opportunity- Yeah. Adam, do you want to start with the opportunity, and then we'll go- Great, yeah. Thank you for the question. So when we look at the opportunity, the largest opportunity by far is our current indication, which is in the, you know, the obstructive HCM. It's about 75% of the patients fall into that category. 25%, roughly, are in the non-obstructive, which is the study that it's ongoing right now, and why we're excited about Camzyos, because that product is largely de-risked into what we said would be a $4 billion plus number. And we're very pleased what we're seeing week in and week out in terms of number of patients who are coming into the top of the funnel into enrollment. You know, as Chris alluded to, and you saw in the video, you know, the feedback that we're hearing from patients has been phenomenal in terms of how they're feeling just a few weeks after Camzyos treatment. Yeah, and just on the MYK-224, as well as Camzyos both being developed. Look, I don't think IRA is the only way to look at it, that's just one component of it. But ultimately, we'll make data-based decisions, and having the optionality that Roland was talking about, of having two molecules for obstructive hypertrophic cardiomyopathy, non-obstructive hypertrophic cardiomyopathy, and then HFpEF allows that optionality of picking the right drug and making, making it happen. So we'll continue with that. We are initiating the phase 2 program with MYK-224, generate the data, and prolongs that ability to develop the drug and take it forward in that indication as well. As far as CCR8 is concerned, I'll start off, and certainly Robert, if you want to add beyond that. We have one very special feature in our company. We are an oncology company, we are also an immunology company, so we can upregulate and we can downregulate at the same time. We have that ability. We've shown that with CTLA-4, we, we've done that for PD-1, we can do that for other molecules. So I think from a T reg perspective, because it's a dose escalation and combination trials, and because we have the translational science resources available to us, I think we can fine-tune how much regulatory T cells need to go down to really convert the cells, cells such that they are now prone to killing by combining them with a PD-1 inhibitor. So we'll have to obviously test that out in the clinic and then bring back the science to the bench so that we can do the translational work and take it back where the efficacy and safety are then managed appropriately. I don't have much to add. That's, that's, that's pretty complete. I think we understand a lot about Treg biology, and we understand it from our preclinical models. I, Michael Burgess is in the front row. I mean, I don't know if you want to make any comments with, you know, the, what we've, you know, where we are in clinical development and, and other thoughts that you actually have, especially on regards to the- Yep. to the translational side, where we can look for these things. I don't have a lot to add. I would just say, back to causal human biology, I think we know that T regs are an important component of the tumor microenvironment, that half of the slide that Robert was showing, where they're part of, associated with resistance to IO therapy, actually in both solid tumors and in hematology. So we have a number of programs actually targeting T regs, and it may be that different approaches have a different safety profile. And so we have good, you know, on-patient biopsies where we're trying to show T reg depletion, and then pick a dose where there's a good safety and combination, as Samit said, and we're in those combination dose finding now. Chris Shibutani. Let me get something over to Chris. Thank you. Chris Shibutani from Goldman Sachs. Two questions kind of on things that were not brought up, or not quite answered. First, on the one that was not brought up. Obviously, this is an R&D day, and I recognize that the November 21 was an investor day. David's not here. At that investor day—oh, well, David did not have a moment on the agenda. Hey, David. You framed your expectations in terms of the revenue contribution in 2025 from these new products and pipeline assets, and also your aspirational range of targets for 2030. As we go home from this day and contemplate our models and think about, and I think it was expressed and articulated before, that there's more ambivalence or debate about the ability to get to the 2030 numbers. What would you say is the thing that we should really center on when we think, coming from today's takeaways, that maybe you would back and say, "Watch us at the next analyst meeting, this will enhance your confidence in the 2030?" Then my second question relates to not quite something that wasn't answered, and my friend and esteemed former colleague, Steve Scala, had asked about the R&D productivity side of it. Maybe I'll take a slightly different tack. You brought up the question of artificial intelligence. I think this is a bit of a phenomenon and a theme across the investment sector. I think the argument that discovery cheaper, faster, quicker makes a lot of sense. It's harder for us to perceive and measure, and generally, for companies of your scale, we don't pay as much attention. I would argue probability of success on clinical development does seem to be the metric that we care. How should we measure whether or not you are actually achieving your goals? And perhaps, is there a different measurement that you think is important? Because we're all sort of comparing the different companies across each other. So that was my effort to sort of maybe reapproach Steve's question that I don't think was responded to before. Thank you. Samit, do you want to start with that question, and then- Sure. I'll come back. So I think probability of success measurement is not a data point in time. Now, of course, if you want to look at it, you can look at the back or, or retrospectively, what our conversion rate has been from first in human to getting to a, a approved product on the market. And what you will see when you do that apples-to-apples comparison to anybody else, our conversion rate is much higher. So you can do that exercise pretty easily because data are available. But if you think about what we are doing now in terms of the IND filings, because of the way we are doing the research now, we're paying more attention to generate the right molecules with our understanding of causal human biology, the mechanistic approaches that we're taking, and what we understand about the disease and biology of that. That will take time to be able to demonstrate that our success rates have gone up, because any IND file today, as we talked about, you will see the data generated over time, 4-6 years, to say 7 years, depending on the disease. But one thing is true: we are no longer interested in developing additive therapies that are going to make minuscule changes. You know that the time to approval is the shortest when the magnitude of improvement is the largest, and we have several examples right in our own pipeline. If you think about the 9 products that we got approved, what is the shortest approval time? Abecma, Breyanzi, Camzyos, Opdualag, Zeposia. Reblozyl was a little longer, but because we were trying to get to a disease that was a little bit harder to recruit. Onureg was the large time it took, and Revlimid took even larger time to took. So you can imagine what the impact of the outcomes of these therapies was on the patients, and that's what led to faster approvals, faster reviews, et cetera. So what we have targeted really in our pipeline is that probability of success of conversion, and then trying to prove that with large magnitudes in our trials, so it shortens the time to develop. Hopefully, that helps. Chris, the other thing I would add is you can break that problem down. I mean, we've talked about the probability of an asset that enters the clinic, ultimately becoming a medicine on the back end, but obviously, that can be broken down into the probability of success of moving from one phase to another. You can break that problem down by therapeutic areas or classes of drugs. And so I think that, you know, as I said earlier, as we do that, we see in some areas we're already well ahead of where other competitors are. In other areas... And by the way, that translates also into specific types of drug categories, where we feel like we're pretty much on the right end of the curve already. There are other areas we need to continue to make progress. So I think that the way we think about it, and perhaps the way it would be helpful for you to think about it, is it's not, we're not looking just at that totality, but we're also breaking that problem down into its component parts that feed up to and level up to that overarching goal. With respect to your first question, I think that a few things I would pay attention to. Obviously, when we talk about the 2030 opportunity that we have, we've talked about that with respect to the new products that we just recently launched. We've talked to you about, in the middle of the decade, what we anticipate those products delivering. What we showed today that I think is encouraging, and that we're gonna continue to talk to you about, is the de-risking events that we have seen since we talked in January to where we sit today. When we look at those, those have largely broken in our direction, and so we feel much better about the opportunity associated with that portfolio. We also articulated between now and 18 months from now, we have a lot more de-risking events really across that portfolio that we're gonna continue to provide updates on. As those updates play out, that, that 2030 objective will continue to get into sharper focus. But while that new product portfolio is an important dimension of how we look at what the profile of the company looks like in 2030, hopefully, what you take away from today is that there's more substrate beyond that. We've advanced a number of new products into registrational development. Obviously, we have to see how the data play out, but those become an important component as how, how we think about 2030. We have an exciting early stage set of assets that will get proof of concept, continue to move forward, hopefully into registrational development. Those will begin to play out towards the back end of this decade and into 2030. And of course, as we've said, we've still got the optionality and considerable firepower from a business development standpoint. ... Would you mind if I just add a little bit to the probability of success? Of course. So if you can't tell, this is something that we're all incredibly passionate about and all incredibly committed to. So, you know, I would also encourage you to think about this in terms of this thread between the biology, the target, through to clinical proof of concept. And, you know, if we really recapitulate some of those early findings in clinical development, you know, that's an inflection point, and that really gives you a sense if this is gonna be successful or not. We very deliberately pick programs where we hope, you know, we could actually demonstrate that. So if we see 70% or more inhibition of TYK2 in the central nervous system of patients with MS, that has a much higher probability of success. If we see 30% induction of fetal hemoglobin in patients with sickle cell, that probability of success goes up. If we see near complete degradation of BCL-6 in patients with high BCL-6 expression of lymphoma, probability goes way up. So it's this thread that we really try to do for all of our programs, and it's why, you know, everyone in the front row, everyone sitting up here, we all try to work together to think about all components of that. Because, you know, it's a bit of a soft, soft answer, but it's that which actually is going to lead to ultimately successful clinical trials. Okay. Robyn has a question behind you, Kate. Thanks. Robin Karnauskas from Truist. So I thought it was really interesting, you were talking about MS and the brain penetrant TYK2 and the next T. And my question for you is, you know, how do you develop these drugs for MS? You know, where do you think that they would not work? Like, could you get, like, stage patients to benefit for either of these, and how do you pick and choose for how you develop which? And then also for TREG versus CAR T, I see you're developing those. You've gotten an agreement with another company on the TREGs. Like, where do you think one will work versus the other in the immunology setting? I'm in agreement with Baum over here that I think it's really exciting going after this module and this indication. Yeah. Why, why don't I start? I actually also might ask Francisco Ramirez-Valle in the front row to kind of, so comment. So we, we, you know, we think about this concept of sequential immunotherapy, and it's not just, you know, one medicine at one time, but it's the right medicine at the right time. So controlling inflammation, resetting the immune system, and then promoting homeostasis and repair. But, but Francisco has thought a lot about this problem, and maybe you can actually comment a bit on that sequential immunotherapy strategy. Yeah. Thank you, Robert. Francisco Ramirez-Valle, Head of Immunology and Cardiovascular Research. And as Robert mentioned, we have this rubric that we call the sequential immunotherapy approach to really understand and give choices of targets at different times of a patient's journey, similarly to what Samit suggested for multiple myeloma. And so we have a variety of targets that go after blocking inflammation when a patient is coming to the clinic with active disease. That's our step one. Our step two, that we're very excited about, is the resetting the immune system, and so that's what you heard a little bit about the CD19 CAR-Ts and how we think about them in resetting the immune system in B-cell mediated diseases. That will work in a variety of diseases, but it won't work in all. It won't work in T-cell mediated diseases, for example. And that's where the engineered TREG could be a useful tool to reset the immune system in that other type of autoimmune disease. And so, as you alluded to, we have a collaboration with GentiBio on an engineered TREG asset to promote tolerance and immune reset in IBD, which is not a B-cell mediated disease. And beyond that, we also have step three, which is to promote homeostasis and tissue repair. Some of the other modalities may not address some of those underlying, you know, barrier defects in the skin or in the gut, and so we have additional mechanisms that address that part. And so we really can target a patient across whatever part of the disease course they're in in their autoimmune disease with a sequential immunotherapy approach. And I think for the CD19... sorry, for the MS question, is I'm gonna have to- Yeah, I will- Uh. Yeah, exactly. Yeah. Yeah, thanks for that question. I mean, the, the genetics tell you that if you had it from birth, then the incidence of MS is lower. So it tells you that really what we want to do is to think of MS really as a smoldering disease, and the early inflammation that you have, the sooner you intervene, the more likely you are to change the course of the disease. So the way we develop it will be find proof of concept for the molecule centrally, but then, you know, the potential is to move it early, and in that way, you may actually prevent the later stages of disease. I mean, the, the split of MS into, you know, RRMS, secondary progressive MS, progressive MS, is sort of arbitrary, really. It's a single disease process. It starts early, and it, it continues throughout. The TYK2 genetics, they go early, and that's what we'll be thinking about. I think, between Francisco and Richard, you've covered the whole gamut, so I don't have to add anything else. Great. Matt Phipps has a question. Thanks. Matt Phipps, William Blair. A couple cell mod questions. Have the mezigdomide phase IIIs passed the Part I dose optimization? And what is an acceptable level of neutropenia or febrile neutropenia for that? And why not test iberdomide in the KARMM-9 post CAR T instead of lenalidomide? And then lastly, the golcatamide phase III, are you just looking at ABC subtype, or are there any other learnings from robust that you're incorporating? Thank you. Let me start off with the first one. In Mezigdomide, the study is currently enrolling. ... and no, we have not passed the part one yet, but soon enough as we enroll the study. And then we can talk about, you know, depending on who's treating the patient, these hematologists are very used to looking at neutropenia. Neutropenia in and of itself is not the issue. It will become an issue if it is a febrile neutropenia, and patients have to go off treatment and completely discontinue the treatment. So that's not what we observed in the phase two trials. So as data emerges, as data evolves, we'll continue to keep an eye on that as we go along. I'll pass on the second question because I'll ask Anne Kerber in a little bit to answer that question about the combination of CAR T-cell with Iberdomide. The third question was related to, and I forget now. The robust to Golcadomide phase 3- Yeah. So for Golcatamide, again, we've done just a phase one part, and we are still continuing to generate the data. Right now, our focus is on all patients with Diffuse Large B-Cell Lymphoma that we'll be looking at. We also have Follicular Lymphoma, relapsed refractory state that is in focus as we generate the data, and we are now planning the phase three study. So we'll look at it from a design perspective, and if we need to really look at specific population or can we go in all comers. So those data are being generated, and we'll make the decisions then. Maybe Anne Kerber, who leads our cell therapy therapeutic area, will comment on. Yes, thanks for the question on Iberdomide and Abemaciclib. We do agree that the combination has a lot of potential. If you look at where these products are, we are running a maintenance study with Iberdomide, also post-transplant, but this will address an all-comer population. And for Abemaciclib, we chose a setting where we think that consolidation is desperately needed. So in other words, in patients who don't achieve a CR. At this point in time, lenalidomide maintenance is still the approved and established standard of care regimen. So this is why we chose lenalidomide and not Iberdomide in that context, because this is what will be important from a regulatory perspective. An Iberdomide combination right now will create a lot of questions around contribution of components because it's not the established treatment. But certainly, we are generating data on that combination. Nevertheless, we don't do it in the context of our pivotal studies, but we do it in the context of ISRs, for instance, where we are looking into the combination approach. Great. Thanks, Anne. I see Evan has a question, Sharmi? Hi there, Evan Seigerman from BMO Capital Markets. So two questions. One, Samit, on your discussion regarding the advancement in neuroscience, you talked about layering on anti-tau therapy plus anti-Abeta therapy. Can you talk to me about the rationale, but more importantly, the safety, just given what we've seen with donanemab and lecanemab? And my second question is, I noticed there wasn't any mention of NASH. I know that was a program highlighted in your second quarter deck. Can you talk about maybe what happened with that? Is metabolic disease still an area of interest, just given kind of the enthusiasm in the broader market? Thank you. So we'll start off with the neuroscience part, and I'll start off and then certainly, Richard, if you want to add on to that. As I said, the trial that we've designed allows both patient populations to be entered, meaning who are naive to beta amyloid, as well as patients who are already on that therapy because it's approved. Because we want to generate the data and start to understand the overall clinical profile of a single agent as well as the combination, because the real world is going to be such that both patients are available. From our overall combinability and what the effect could be, maybe, Richard, you want to comment on that as well? Do you want to come back to NASH? Well, okay. Go ahead. Well, I mean, I think you've got the sequencing of the pathology with the Alzheimer's, with the A beta preceding the tau. In fact, the best correlation for the cognitive deficits is with the tau protein as well. And so you can argue, actually, if you look at the A beta data from the anti-N-terminal antibodies that's already come out, you can see that they actually impact tau as well. If you look at tau imaging, you can see that the accumulation of tau goes down. So wouldn't it be funny if it was the tau effect that we'd got with the A beta lowering? But, you know, who knows. So I think there's an argument for the sequencing of pathology, where you could put the two together, and you may see different things. I think them being in the trial is just is a practical issue. You'll get experience with them in there, but for the biology, it actually doesn't. It, it makes some sense as well. And then from the NASH perspective, as you had seen, we used to have the FGF 21 inhibitor, and then we tested it out. The data was not supportive of continuing that program, so we discontinued that. Does that mean that we are not in the metabolic space? At the current time, you saw our pipeline, that's pretty full and very pretty deep. Opportunistically, if we see something, if then we can act on it as required or as needed. I see Olivia's got a question. Nina? Hey, guys. Olivia Bennett from Br enneth Richardson. Appreciate some of the comments you made around the Alzheimer's program and moving into phase 2. So, I guess my question is, you know, maybe you can give us some color on how you came to the decision for the 2 dose levels in phase 2, and can you actually provide what those dose levels are versus what was studied in your phase 1? And then I did want to follow up on some of the comments earlier made around your CD19 CAR-T Next T program, and maybe frame the question a little bit more from a regulatory and commercial lens. You know, I think there's obviously a lot of interest in lupus. There's obviously a lot of interest in MS, and I know there have been multiple questions today around that. I guess my question is: Is there maybe more of a straight path forward commercially from a regulatory lens in lupus versus MS or one or the other? ... Yeah, so maybe I start off, and then I'll pass it on to, to Adam as well, to comment on the commercial path for cell therapy. But starting off with neurology, we are not right now disclosing the doses that we are taking forward in the neurology part for anti-tau program. The way we think about it is that we have to do a dose-ranging study to really select the doses for the next iteration or the registration trials, and therefore, more than one dose is being tested. Just like we've done in other programs and other disease areas, and as have been done with other neurology programs by other companies. So it's a similar philosophy of doing a clinical trial design, but we have not yet disclosed on dose number 1, dose number 2, and over time, when we are ready, we will be able to share that with you. As we think about cell therapy and in terms of what we think about the regulatory pathway, as we said earlier, we've not—it's early time right now. We've just initiated enrollment of the trial in SLE. We are adding additional cohort for myopathies. Then we are also filing an IND to initiate a phase 1 trial in patients with severe MS. All of that will lead to generation of data. Appropriate time, we will also engage the health authorities to talk about the registration program, what they should look like. Do we need a control arm? If yes, then what is the control arm, et cetera. But let me ask Adam to comment on the commercial opportunity and how we approach that. No, I don't have much more to add, just because it's early in terms of the data, but what you saw from Samit's presentation, you know, it's really exciting from the German cohort. We showed, you know, remission in patients with lupus, which has been one of the toughest to treat disease states. And so when we think about, you know, where we're headed as a company, just across cell therapy, another, you know, key takeaway from hopefully you're leaving this meeting with, is when you look at cell therapy today with our two leading agents, Breyanzi is a best-in-class product, Abecma moving up lines of therapy and moving outside of hematologic malignancies now into immunology and beyond Next T CD19, you know, we also have. We talked about today, GPRC5D. We talked about today our dual CAR opportunity. So, you know, we've got probably the most robust CAR T development program in the industry, and the CAR T commercial opportunity, which is relatively modest today, is gonna grow substantially into the future. And when you think about in the 2030 timeframe, we're in a very, you know, strong position to lead in cellular therapy across a host of disease areas. I think, I think it's that Dane I see at the back. It's a little hard to see. Thanks, Tim. Dane Leone, Raymond James. So, two questions for me. One, could you maybe provide a little bit more color around the strategy of Camzyos versus MYK-224, specifically to whether MYK-224 solves for some of the drug accumulation issues that have been experienced with Camzyos, and that might be a reason for pushing forward in HFpEF with that compound relative to what you might have seen in the BARC study. And then secondly, on that point, is there a clear view now from your clinical team on how to separate out non-obstructive HCM from HFpEF, given the overlap that we do see in those patient populations? And then an unrelated question, could you elaborate a little bit more in terms of what you mean with your neuro build or rebuild for the company? You focused a lot on neurodegeneration today, but do you also envision a build-out in neuropsych as well, and what would that look like? Thank you. Sure. For the first question, I'll ask Roland Chen to address the MYK-224 and HFpEF, and then we'll come back here. Yeah. So, so thanks for the question. With MYK-224, again, you know, we are, we are very excited about this molecule. I'm not gonna get into the details, but what we've seen in phase 1 data, what we're seeing in data that is starting to accrue in our oHCM Phase 2a study, we're very, we're encouraged about the properties and of the characteristics that we're seeing in patients who have received this drug right now. What I would say is that, you know, the, the promise of what we're also seeing in the EMBARC study, give us added enthusiasm about how we can take forward what we think is a very promising molecule that is MYK-224 ahead in HFpEF, as Samit said. You know, as far as nHCM and HFpEF and how we're thinking about those conditions, they're very distinct and definite criteria that we use to help to define and identify patients with nHCM. Of course, we're looking to see how we can further enhance our ability to diagnose those patients, but those are very distinct criteria. I think HFpEF, as you know, is much more heterogeneous, and we wanna make sure this is part of how we're looking at the disease, of looking at the right subsets of patients with HFpEF. But again, to separate out those with a broader phenotypically defined set of characteristics, who would respond to a cardiac myosin inhibitor versus those who specifically have the diagnosis of nHCM. So we're looking to do that, working these questions through as we move forward. With respect to the neuroscience question you had, you know, we showed you today where our pipeline is today in neuroscience, but the way I would think about it is, we're certainly open to additional adjacencies and opportunities to expand beyond that. We'll evaluate those on a case-by-case basis, and we'll, of course, look at how the science evolves, but also what's the commercial opportunity, and we'll make decisions accordingly. Obviously, the company has a history in broader neuroscience, and I, I think we're open to adjacencies. They just need to make sense for us, and we'll evaluate them as they come. More questions? Okay. Okay. Over to you to close, Chris. Well, so again, I just wanna thank everyone for the discussion that we've had today. It's been a robust discussion, a lot of questions. I appreciate you all hanging through what was very dense content, and I know it's quite cold in here, so hopefully no one got hypothermia. But anyway, hopefully you saw through the discussion a number of things that make us excited about where this company is going. And certainly, you hopefully can appreciate why I'm incredibly excited to be taking over as CEO, why we are incredibly optimistic about the future of the company, and why we believe that this R&D engine that we've talked about today will be a core component of how we generate long-term sustainable growth as a company, and obviously, how we translate that into long-term shareholder value. With that, again, thank you very much. We look forward to continuing the discussion over lunch, and thanks again for coming.