Okay, so, in the interest of staying on time here, really pleased to have Bristol-Myers Squibb joining us. To my immediate right is Samit Hirawat. He is the Chief Medical Officer and Head of Global Drug Development at Bristol-Myers, and Robert Plenge, who is the Chief Research Officer at Bristol-Myers as well. We are actually going to be running a bit longer than the 25 minutes that is posted up there. We're actually going for the full 50 minutes, so just so everybody knows, as on the calendar and on the schedule. So maybe, Samit, just to start big picture rather than diving right into some competitive data, let's start with, you know, kind of six months ago, you know, we saw Bristol stock at $40 a share. Sentiment was uniquely cautious. You know, while the threat of generics is unchanged, shares are now trading at $55. From your position in R&D, obviously, what's changed? I think those shares might be a little bit different right now. Yeah, maybe. Might be different. I'll keep it to that. But look, I think a lot has changed since, and I'll start maybe at the end of last year. Our company profile changed, began to emerge very differently. As As we thought about, strengthening our portfolio and how we, take care of what was in front of us, we knew that there are LOEs that are coming through. Also, there was no clarity in terms of the IRA as to how things will land, and now we have that clarity. So those are just the top line. But I think mostly what has changed now is emergence of our pipeline, which is much stronger, much deeper, much broader. We added Mirati, we added Karuna, we added RayzeBio from a portfolio perspective, all in the oncology space, with the intent that we needed to move beyond immuno-oncology, which was the base for our overall oncology portfolio. We added an ADC through collaboration in China, bringing that into it. So, modality-wise, we broadened ourselves and went deeper into small molecules, antibodies, ADC, and then adding a radioligand therapy. In a similar way, we went through the portfolio prioritization and looked at opportunities where we don't need to play because the efficacy was not reading out in the right way, or safety was not there, or when we thought about where we're going in terms of being first-in-class, that was not meeting the vision that we had set for ourselves. So we took out some of those molecules from the pipeline. But very importantly, once we added Karuna into our portfolio, we needed to get that approval, and that approval actually just happened in September. So that was a very, very important medicine that we wanted to add. As we defined our resurgence into neuropsych, remember, 20 years ago we had Abilify, and now we have Cobenfy for schizophrenia. And that's just the beginning of it. We have seven other, six other indications that are to follow after that. We also changed our ways of working a little bit in terms we had done some work the year before and then last year as well, looking at our R&D ways of working in terms of timelines, etc. And we certainly were not the best. And so we went deep into it and reviewed our ways of working, all the way from developing our concept to our execution of clinical trials and then taking them into submission and approval mode. And so we have begun to change that narrative. Two years ago, remember, at R&D day, or was it last year, where we presented that we'll be looking at our productivity from an IND engine perspective, at least 10 INDs bringing into the framework, as well as looking at a median of six and a half years from IND approval to approval for first indications, as well as increasing the positive outcomes from our IND to 20%, where the industry average is 10%-11% right now. And we are on that trend. We are working towards that. As we think about 2025 and 2026, from R&D perspective, these are the years of data generation and certainly data execution. Then 2026, of course, about 10 to 12 or 15 studies that will read out as phase III studies. The overall picture, as we think about the future, we'll, we know that what we have in front of us from a legacy portfolio going down, but we also know a very young first-in-class portfolio that is continuing to emerge now, growth portfolio contributing more than 50% to our revenues. By the end of the year, end of the decade, we also look forward to emerging in an accelerated fashion now. Great. And Robert, maybe you can just chime in on the sort of focusing of the portfolio and working with Samit to, you know, really kind of, you know, streamline the portfolio. Yeah. So, we like to start by talking about our principles that we use for a lot of our decision-making, and that includes principles for starting new programs, for prioritizing programs, or business development decisions as well. And if you think about just the linear sequence of events for drug discovery, you start with a target. And so we refer to picking the right targets as really leaning into human data and particularly what we call causal human biology, then matching a modality to a mechanism. And there it's just about making the right molecule against the right molecular mechanism of action. And third, going from research into early development in particular, that's really when you begin to know if a drug is going to behave the way that you think it's going to behave and see early evidence of clinical efficacy and a good safety profile. So we call that path to clinical proof of concept. And then really, once you begin to see that, that's when you really want to be even more aggressive in terms of clinical development timelines and potentially concentrating risk across multiple indications. And then finally ensuring that you have the right data generation package to position the medicine in the real world so you have the right market access. And of course, a lot of that has to do with working very closely with our development colleagues. You can take those five principles: causal human biology, matching modality to mechanism, path to clinical proof of concept, high quality, not just speed, but high quality clinical development, and then, and market access. You can begin to use that framework for programs that you decide to start in research, prioritization decisions in development, business development decisions. For each and every one, you can say, "Okay, we really like. We'll probably come back to Milvexian. We really like the target for Milvexian. We have a small molecule against not just Factor XI, but Factor XIa, the activated form. We know that it works in a particular way. We saw and did the right early clinical development work. So we say we see in a venous thromboembolism, a VTE study, a dose-dependent decrease in clots, a surrogate for efficacy, without a dose-dependent change in bleeding rates. We do all the right clinical pharmacology modeling to say this is the dose that we think will be effective in AFib and maybe a different dose that's going to be effective in other indications such as SSP." And then deciding to concentrate clinical development across these three areas and ensuring that, and we can get back to why we increased the sample size, but ensuring that the timeline for readouts for all of those are beginning to become synchronized, which is important for that fifth principle, market access. So we apply those five principles to all of these different decision-making, this decision-making framework. I think that's a very valuable way for us to, I think, make the right sets of decisions all along the way. Great. And, you know, there's, I guess, risk profile in drug development and kind of the consideration of competitive assets. We just got competitive data this morning. What, you know, in terms of your sort of team development approach drew you to Cobenfy, and, you know, what, you know, sort of maintains and sustains your excitement for that program and that product as we enter the sort of full launch in 2025, and, you know, advancing from there? You want to start from Samit? Yeah, I'll, I'll start and then, you know, we can kind of broaden it into the various indications that we're going into. If you go back to those five principles, we had really strong conviction in the M1, M4 direct agonist hypothesis, which is different than M4 alone, different than partial allosteric modulator versus positive allosteric modulator versus a direct acting agonist. That came from the causal human biology of xanomeline in clinical trials in the 1990s. That was the first principle. The second principle, matching modality to mechanism, you can have a brain penetrant molecule that actually is M1, M4 direct acting, but you have the side effect profile that comes with agonizing those receptors in the periphery. That's where trospium comes in. Now you have a very strong therapeutic hypothesis based in causal human biology, xanomeline in patients. We have the right molecule, M1, M4 agonist with the protective effects of trospium in the periphery. Karuna did the right early development clinical studies to begin to see that it was working. Then I think very importantly the, you know, the accelerated high-quality clinical development to control placebo rates, while seeing the benefits. So there's a lot of really important patient selection, just making sure you're monitoring the study in the right way, and then ultimately the approval and making sure we get it to the right patients. And so we can then take those same principles and say, "Okay, we're going to do a number of other indications as well because of our degree of confidence." So adjuvant schizophrenia, Alzheimer's disease, psychosis, etc. And Samit can talk more about those trials. I think from a clinical perspective, you've seen the data come out this morning. It's unfortunate from the patient perspective, because this is a very large indication in market and certainly having more than one modality. We've seen that D2 agonist; there are so many of them and they're all utilized. With that said though, what we see, at least from the first data set that we've seen in the public domain that we've just seen, several things happened. Placebo rates are high compared to what we saw with Cobenfy. However. Just to clarify, we just want to make sure that it. Emraclidine. You're talking about emraclidine. Yes. This is emraclidine. Emraclidine data just came out and they just released on the press release. What we've seen is the placebo rates are high. Change from baseline to post-treatment, patients on placebo have a 16-point decrease, I think, in one of the trials and about the same in the other one. The treatment arms also have not performed as well. That's why the difference between placebo and treatment is two to three points only. One other thing, which is very, no pun intended, atypical for a trial is that the lower dose, 15 mg, actually performed better than the 30 mg. Lots going on over there. As you reminded me earlier today that if we think about Cobenfy, EMERGENT-1, EMERGENT-2, EMERGENT-3, China study, they all very consistently showed similar results from a treatment perspective and the outcomes for these patients' perspective. Now EMERGENT-4 and 5 have given us data all the way up to one-year follow-up from these patients. The efficacy is maintained. Side effect profile doesn't get worsened. We do know that there are initial phases where there is nausea and vomiting, but then that goes away over a few weeks and then patients continue to get benefit. I think lots going on for Cobenfy. Certainly, adjunctive schizophrenia will be the next readout in 2025, followed by ADAPT trials for ADP. Then next year we are starting bipolar disorder, AD, Alzheimer's disease agitation, Alzheimer's disease cognition trials. Then in 2026, most likely autism will come in once we've done some juvenile tox work, etc. Great. And when we just sort of think about the big opportunities, incremental to schizophrenia, obviously, you know, the things that come to mind are always bipolar depression, sort of first and foremost as a major driver of commercial uptake and commercial opportunity. But Alzheimer's agitation is also seeing a resurgence. You know, maybe talk a little bit about the profile that you think Cobenfy offers in Alzheimer's agitation in particular. And then what's the hope for this mechanism in bipolar depression potentially? It's bipolar mania actually that we've been pursuing. Bipolar mania? Yeah, it's bipolar mania because. Is there a profile in or is there an opportunity in bipolar depression in your view? Probably not this molecule, but then there are many other things that one could pursue, going forward. Certainly please feel free to add in. But if you think about Alzheimer's disease and as Robert has mentioned many times before and we've talked about it, one of the things that's happening in Alzheimer's disease is there is a decreased or paucity of acetylcholine. And that's why direct agonism becomes so important, whereas M4 PAMs required that ligand in terms of acetylcholine to be present. And that's what we talked about this morning, that it's difficult to imagine developing a drug that does not have a direct agonistic effect on the muscarinic receptors. So that is the biology that supports us going forward in Alzheimer's disease, psychosis, agitation, and cognition. We also knew that, not all three indications can be folded into one because the regulators wanted to see individual indications being followed with a profile of the patient. With those subjective tools that we have, that's one of the things that I always cringe on that. Neuropsych is running behind and we'll have to do a lot of work in terms of continuing to engage physicians so that we don't fall in the same trap of placebo rates being higher and having the subjectivity taken out of all of this as much as possible. So agitation has a profile that we've already begun to see some of the data emerge from even the early studies in 1997 and then in the schizophrenia program, how patients who are in the psych, let's say spectrum, or psychosis spectrum or agitated, how they are performing. And so, having the profile that fits very nicely in terms of positive symptoms as well as the negative symptoms and some improvement in cognition gives us a lot more in terms of confidence of readout of these studies. But of course, we'll only see it, starting next year and then beyond. And then for, you know, one of the critiques of Cobenfy has been, you know, one tolerability is sort of one critique. But maybe the bigger one that some physicians we've talked to have sort of critiqued is the twice daily profile, and the challenge of treating a schizophrenia patient with a twice a day drug. How challenging is that in your view? And then separately, what are you doing to, you know, basically potentially bring a once daily or perhaps even a long acting? Yeah. The intent is not to convert it to once daily. Because of the metabolic profile of the drug, we certainly do believe that first of all, getting the ratios right was very important. Karuna did a wonderful job in defining the ratio of xanomeline to trospium five to one in the first studies of schizophrenia. Then it did the study in healthy elderly volunteers to look at what would be required for AD psychosis. There the ratio is 10 to one. So that has been taken forward as a three times a day dosing because of the metabolism that occurs. Remember, patients with schizophrenia, they are how many drugs they are already on. Yeah. On an average, they are five to seven drugs they're already on. So adding another one, that has a side effect profile that is very different than what they're taking today, the atypicals. And that certainly bodes well as well as seen differently from physicians' and patient perspective. So as a beginning, we are starting with a monotherapy for Cobenfy, but the adjunctive schizophrenia trial is ongoing, which adds Cobenfy on top of the background therapies. So what we've not heard, and certainly had the data readout differently for Emraclidine, this would've been a continuous dialogue QD, BID, QD, BID. But right now I think BID is what we have. And we have not heard anything major in terms of BID is going to be a detriment to prescribing it, etc. And the easy way to think about it, take it as soon as you wake up and take it as you're going to sleep. So BID fits from that paradigm perspective. And that's the way physicians also think about it. Patients will be thinking about it. We have not heard anything wrong or anything untoward from that perspective. We continue to work on a formulation even for the agitation and psychosis trials, but we want to provide a BID formulation for these patients as well as we go forward. So that should be instituted in the next trials that we start in agitation, cognition, bipolar. And hopefully we'll be able to bridge it back into psychosis as well to convert that into a BID. Great. You know, Robert, you mentioned Milvexian. We got some updates on the third quarter results conference call. Maybe you could just walk us through some of those updates, but also, you know, a little bit of the battle that you've actually had to fight in the wake of another competitive failure. I mean, I would also argue, like thankfully this other, maybe the trial hadn't failed in the midst of your own phase three clinical program, you know, as it relates to Cobenfy, but the Asundexian situation from Bayer really put a, you know, was a headwind for the Milvexian program. Maybe tell us how you feel about it today. Okay. I'll start and then Samit can actually fill in the details on the clinical trial acceleration and the expanded sample size, but you know, I mean, this is such a hard business and to have really strong conviction in those principles that I mentioned at the very beginning, you know, that guides a lot of what we do, so if you take and apply those principles again to Milvexian, Factor XIa, great genetically validated target, and we had a molecule that we believe could actually inhibit it in the way that we thought could actually recapitulate that human biology. But we also did a tremendous amount of work in our preclinical animal models and this rabbit model of arterial thrombosis in particular, where we could actually test Milvexian against apixaban, against Asundexian, against Factor XIa, ASOs to say, all right, this is the level of inhibition that's actually required for clinical benefit with a decreased bleeding risk. Animal models are animal models. These do have predictive value. We published a lot on these animal models. So you can read about them, but you need to get into clinical development. We did really good, very extensive early clinical development, not just in healthy volunteers, but in venous thromboembolism, VTE studies that allows us to test a very broad dose range and depict the right dose for the right indication, where we saw a dose-dependent decrease in rates of thrombosis, surrogate for efficacy here without a dose-dependent increase in any bleeding. So now we have, we think not just the right target, the right molecule. Now we've done the right early clinical development study. We did a tremendous amount of clinical pharmacology modeling to say, all right, here are the exposures, here are the responses. We take that back, look in the animal model data, compare it to apixaban, and ultimately we say these are the right doses. Of course, at that point you are placing an enormous bet down on what you think is the right dose for a very large, expensive phase three study. But that's the, that's where conviction matters. And suddenly you say, okay, we believe we have the right molecule, the right dose, and now we're going to do the large phase three clinical trials. And Samit can provide the details, but you know, it's, it's moving in the right direction, I think. I think the only thing I would add to what Robert's saying, number one, three times now in the last just few months that it has happened that gives me conviction that we've got wonderful scientists in the lab, wonderful drug developers, because it's not that we didn't look at the competitor molecule when we were looking at Karuna. We did. And we decided to go with Karuna. Milvexian came out of our own labs. LPA1 came out of our own labs. So thankfully we are making progress in the right direction with the right aptitude, right thinking, right conviction, right science behind it for all the principles that Robert talked about. So hopefully it continues. And I would rather be on this side of it than the other. Yeah. For Milvexian, I think what we learned from the data that were presented earlier this year was truly the right phase two trials are so important to pick the right dose. We did a 16-fold range in terms of looking at the various doses and then said, okay, there is a differential dose that we'll need to pick for atrial fibrillation as opposed to when you're combining with a background therapy of antiplatelet agents, so we went with a single agent as in 100 mg BID for AF. If you remember the competitor molecule, the maximal dose tested was 50 and they just went with 50, and then for ACS and SSP, we went with 25 BID with a background therapy of antiplatelet agents. They went there as well with 50, so we'll see what happens ultimately. But we are confident. We continue to enroll in our trial. You just saw that we increased our sample size because our event rates are very low, and so to catch up on those event rates, we've increased the sample size so that we can keep the overall timelines in 2027 readout. Right. And your confidence and conviction that the result is just absolutely like clearly is not an Asundexian result seems extremely high, at this point. Can you just remind us why it's so high? So what we saw in our clinical trials, as Robert pointed out, we did see a dose-dependent increase in efficacy without a dose-dependent increase in safety or bleeds. Second, the preclinical experiments and now of course we've seen the clinical experiment as well. Asundexian had three times the event rates for strokes and thrombosis as opposed to apixaban within the same study. Apixaban actually overperformed compared to what the assumptions are. If you recall, our assumption in our clinical trial at the end of the study would be 1.33 events per 100 patient years. Apixaban was 1.03. Asundexian was 2.33, I think. And so when we look at our trial, our event rate, blended event rate overall in a blinded fashion is running much lower. So as we go forward, picking the right dose without added efficacy, safety issues because the DMC continues to look at the data, gives us confidence that we are in the right direction. And they said, they didn't say no to us increasing the sample size as well. So I think overall we feel good where we are. But of course, when the phase three reads out, then only we'll know what ultimately transpires. In previous conversations, you mentioned, you know, it is important to keep in mind this is a non-inferiority trial design. Yeah. You know, can you just help everybody understand why, you know, it's okay in a non-inferiority trial design to increase the size of, of a study and not be concerned? Yeah. So non-inferiority really means that you, both your drugs will be similar in terms of the efficacy. But we are, our hope over here is that from a safety perspective, this will have a better profile. Now, as we think about the event rate, as we said, we were hoping for 1.33. Right now we are running behind. There are only two ways to keep watching it. Now, either you just wait for events to happen, but then it'll read out much later, or you can increase the sample size so you can accumulate more events. So we wanted to keep the 27 timeline, in hand. The reason for doing that is we wanted to have the three studies read out in close proximity to each other. And the other two are running as planned and they should read out in 2026. Getting AS, SSP, ACS in 2026 and AF in 2027 gives us that ability to bring all of this together. We've always talked about, you know, in the era of IRA, it is going to be important to have the maximization of that commercial potential starting right at the beginning so that you're not losing at the backend from an ROI perspective. Great. Maybe we'll shift gears a little bit. We have some data, earlier data coming up very soon, maybe even the middle of this week, at ACR. Can you maybe just help us understand the profile and the opportunity that you see for CAR T therapy in immunology in particular? Do you want to start and then? Yeah. I'll start. I always like, Sam had heard this a bunch, but I always like to start with, I used to practice clinical rheumatology. I saw patients with these serious autoimmune diseases, including lupus. It is really hard for a patient who's in their early 20s and 30s to be told they have to take immunosuppressive therapies for the rest of your life. The unmet medical need here is to be able to get patients off of all immunosuppressive therapies and to have a functional cure. That is a massive unmet medical need for these patients, and not just for lupus, but for a variety of autoimmune diseases, whether it's inflammatory myositis, scleroderma, multiple sclerosis. And so what was shown a couple of years ago is the potential for a CD19 CAR T to be able to reset immune memory. And we now have clinical data. The abstract I think has four patients with lupus, and we'll present more data later on this week on additional patients with lupus. And you know, consistent with what others have shown, we are able to reset immune memory. That doesn't mean that you know, every single organ that was damaged previously gets better. So if there was prior kidney damage, almost certainly that kidney damage will remain. So it's not as if it's reversing all of those damages, but patients are getting off all of immunosuppressive therapies. So that's really exciting. It's still very early. So we. Give you an idea of where the drug really is needed as a high unmet medical need, so these are relapsed refractory, rather refractory to treatment patients who've got severe disease. So you'll want to see the baseline characteristics of these patients, high SLICC scores and the organ involvement that Robert was talking about. But then post-treatment, what happens to them? Are we causing a B cell depletion or not? Are these B cells then again restarting to repopulate? And what is the profile of these B cells? What's happening to their background therapies that they're on? Are they going off of that or not? Are their clinical signs and symptoms improving, and as they're improving, what's happening to their longevity and that? So not all patients, remember we only started the study in November of last year. It's about a year that the first patient was infused. And then is the profile emerging from a safety perspective that would be tolerable and acceptable? So all these four or five things you want to observe now, and then you want to obviously continue to see if others are having the same thing or not. As Robert said, kidneys are not liver, so they don't regenerate. So some of the things that kidneys cause when they're harmed is proteinuria and all that. So we have to keep in mind that this is not magic, right? This is going to be important treatment for these patients, but some of those, organ dysfunctions that are present may last. But what does that really mean from a patient perspective? Yeah. Does that really matter from a patient perspective? Those are going to be the critical parts that we'll have to keep in observation. Yeah. It seems pretty high impact would be an ability to just sort of sustainably reduce or even eliminate prednisone, some oral prednisone, things like that. Exactly. Not just prednisone, but all immunosuppressive. All immunosuppressive. I mean, if you're a young person who has to be on immunosuppressants and when I give these patients these medicines, you have to go through the long list of potential side effects, whether it's infections, cancer risk, you know, how they actually have to just sort of manage their lives, not to mention all the adverse effects that come with prednisone and the medicines. I like that. That's a big deal. So to be able to say that you're off all immunosuppressant therapies, and you have a functional cure, I mean, that changes the way that people approach their lives. Great. In terms of, you know, sort of other assets, there's a lot going on at Bristol. Maybe we can sort of take a quick step back and, you know, go through, you know, Sam and I, we went through this earlier, so we can go through the family tree of assets that are coming. But, you know, if you, if you wouldn't mind, maybe walk us through the assets that are most important and then it'll give us an opportunity to walk through LPA1. Yeah, absolutely. So I maybe I'll change my family tree a little bit because the big brother I said was Milvexian, but this morning I think it's Milvexian is now twin brother with Cobenfy. Yeah. Which is already there. And both of them are going to be very, very critical. And I think the way to think about it is for Cobenfy, there is pretty much a readout for an indication every year until the end of the decade. So next year we are looking at ARISE. The year after that would be ADAPT. The year after that could be agitation. The year after that could be bipolar. The year after that could be cognition. The year after that, autism. And, and of course in between whatever else might come because, even in AD psychosis, there are two indications. There is the acute and then there's the relapse prevention, for example. Both studies are ongoing right now. If you think about Milvexian, we've talked about in 2026, two studies readout, 2027, third study reads out. This year itself for Sotyktu, you have the readout of psoriatic arthritis, two studies, before the end of the year. And then in 2026 will be SLE and 2027 will be Sjögren's. If you think about Camzyos, next year, first half, non-obstructive hypertrophic cardiomyopathy. And then we have Reblozel reading out next year for myelofibrosis, the independent study. And then there will be a lot of the phase one data that comes out. 2026 is a big year. 2026 we'll have the radioligand therapy, first phase three study that should read out. GPRC5D, multiple myeloma study should read out. Iberdomide, one study should read out. Mezigdomide, at least one of the studies should read out for multiple myeloma. SLE, I've already talked about. What else am I missing? Golcadomide. You meant Golcadomide is late though. Golcadomide would be late because that's first line diffuse large B-cell lymphoma, and then once we start the other studies, then they will, it'll add on, so early pipeline will start a lot of studies next year as well. PRMT5 will go into phase II studies that could lead to regulatory discussions and as to how to conduct these studies. EGFR HER3 ADC starts phase III studies next year, so that will start to contribute towards the back end of the decade. AR LDD will start phase III study next year, so that'll contribute to back end of the decade. Fuc-GM1 in small cell lung cancer starts phase III study next year. That'll contribute to the back end of the decade. That's why I was saying at the beginning of this conversation that as you look towards the back end of the decade, our reversal back into, from a revenue perspective, is a very accelerated reversal, obviously dependent on the successful outcomes of these. Maybe an unfair question. And by the way, CD19 CAR T for SLE is probably. Right. For sure. The readout. And maybe a little bit of an unfair question, but, you know, we are a week away from the election, but a lot of the molecules you just mentioned are small molecules. Mm-hmm. Is there from your perspective any chance, hope, that one of the real, I think, disconnects in the IRA legislation, does have a chance of being corrected, which is the small molecule, you know, sort of, disentangling the nine-year versus 13-year discussion? I don't think any one of us has any clue. Okay. Nobody has a magic eight ball to really predict what that would mean and how that would happen. With that said, as we think about clinical development and the pipeline, we do believe that all modalities are going to be important. As we think about small molecules, we'll just have to get better and better in terms of thinking, as we were talking about Milvexian. The reason I say that we have to bring together the three readouts in close proximity is to maximize that return on that investment. There are also going to be places where we will not be able to recoup, and then we will have to make decisions that we won't. We talked about it already. Even two years ago, we talked about Iberdomide, that we can't do a de novo newly diagnosed multiple myeloma study because the readout for that study is 10 to 12 years. Yeah. If our clock starts in 2027, there's just not enough time to do that. That'll happen again and again as we think about earlier application into adjuvant settings for some of the studies, and especially if you really need good data, as well as Project Optimus comes into it when you have to pick the right dose for adjuvant. It just delays the start of these earlier studies. Then of course there will be an impact. I feel bad from a patient perspective. I feel bad from an innovation perspective, but the reality is going to hit us that way. I hope that there is an opportunity to engage in that dialogue. I hope that there is a differential thinking, coming in from a policy perspective, but that's just a hope for now. So let's maybe move back to immunology. There were some programs that you didn't mention in immunology that I think are worth talking about. You know, you have a positive cendakimab result. It was just presented at a recent meeting in EOE. You know, maybe just give us your thoughts on that program. And you know, you conducted a robust program according to the opinions of the experts. It's a fairly robust result. What are the plans for, you know, IL-13 in that regard? And if there aren't plans to advance that, what's the sort of commercial argument? Yeah. So right now. It's an unfair question because we're not talking about commercial, but the clinical. Sure. Commercial. No, I think the way to think about it that we presented the data, as you said, that trial did meet its endpoints. And now, the discussions that we are having is putting in the context of what is the incumbent right there. Yeah. It's a very strong incumbent that's out there. We'll have to put all of that in that framework as we think about conversations on regulatory paths and moving forward. I don't have an answer for you as to what the timelines are and how it looks, but those are the discussions that we truly have to have on the table. That's why we have to keep in mind the commercial opportunity, what it truly is, and then make the decisions on the timelines and what the next steps would be. Okay. You, Robert, in immunology, maybe just sort of bring us back to, there's a vast array of mechanisms. We're starting to actually see for the first time combinations that are working. And what I mean by that is my recollection is all the way back to the IL-1RA. Yeah. Combination with TNF, which was just disastrous from an infection perspective. Yeah. But now we have IL-23 in combination, you know, with TNF that's starting to show some really intriguing results in areas like IBD. How do you think about the opportunity for combinations versus sort of single mechanisms in immunology going forward? We've put forth this paradigm that we call a sequential immunotherapy paradigm. We published on it a few months ago in a Nature Reviews Drug Discovery article. The idea is if you are a patient coming to your physician, you almost always present in the setting of acute inflammation. Step one in this paradigm is to be able to control inflammation largely with immunosuppressive therapies. For many diseases, there is this efficacy ceiling. In order to really do better compared to standard of care therapies, you likely either have to go into much more precise patient subsets, whether it's genetically defined or some other biomarker, or to your question, you have to use combinations. But the combinations have to be done in a way that's safe because you can't just do one inflammatory cytokine on top of potentially another overlapping inflammatory cytokine 'cause maybe you're hitting it too hard. But that's step one, controlling inflammation. Combinations, potentially patient segments, are one way to get at that. Then step two is what we talked about a few minutes ago, which is to be able to reset immune memory. So basically sort of turning your computer on and off to reboot the system to hopefully get rid of those pathogenic, autoreactive cells, whether they're B cells or T cells. We're seeing promise in that with the CD19 CAR T approach. But there are potentially other ways to reset immune memory. And we're exploring those and I know others are as well. But then once you reset immune memory, there's an open question about whether those autoreactive cells come back, or whether you have to either repeatedly dose these step two medicines or is there an alternative way to promote homeostasis, and repair. And there are a few different ways in which one could consider that. But that's sort of the paradigm where step one, control inflammation, step two, reset immune memory, step three, promote homeostasis and repair. And I think we're gonna really see in the next five to 10 years a lot of those clinical studies play out in terms of how you mix and match all these different mechanisms together. But it's a pretty exciting area, and I think it offers a lot of hope for patients. And right now in the portfolio, we have drugs that are part of each of those three pillars that Robert just described. If you think about Sotyktu, it takes care of the inflammation. If you think about CD19 CAR T cell therapy, that's about resetting the immune system. Alnuctamab, we are going to be testing out actually starting next year and a couple of indications there as well. And then we have drugs for the homeostasis part as well. So I think our pipeline has the ability to do that, but of course we'll continue to observe how the space evolves. Great. Multiple myeloma, the level of expertise there is obvious, unquestionable. The dynamics in the market in multiple myeloma, I think, are interesting. But when you look at the pipeline, you know, Robert was talking about segmentation. How important is segmentation going forward in multiple myeloma and how's Bristol approaching it? Yeah, I think it's a natural segmentation because of the modalities and because of the need as things start to become used earlier and earlier, unfortunately, because the disease is not being cured. You're accumulating the prevalence population as you go later and later. As we think about, we just saw the data of CD38 getting into a newly diagnosed patient population. What happens as we look to the future as cell therapies like Iberdomide or Carvykti move earlier? What happens after that? As T cell engagers move earlier, what happens after that? I think we are only talking about biologics right now, but small molecules will have their own space because combinations are just easier with the small molecules. It's hard to combine Carvykti with something. It's hard to combine T cell engagers for their profile with something right now. So we'll have to continue to find what is the best way to continue to provide combination therapies for better outcomes when efficacy and tolerability for these patients. And that's why we've taken a multi, multi-modality approach to it. First we have the small molecules. We were developing a bispecific, or rather the, yeah, the T cell engager, alnuctamab, which we took away because we were not going to be first. In fact, we were going to be fourth or fifth. So we took that away, but we have the broadest cell therapy approach to it. So Iberdomide was the first one. GPRC5D is the second one. And the third one is a dual CAR, which is the BCMA and GPRC5D on the same CAR. So that's the third one. We hope that GPRC5D applicability pre and post BCMA is going to be equally important. But if we can then further improve on that, maintaining the safety profile with a dual CAR, taking BCMA and GPRC5D, that would, that can be a game changer if the safety profile is tolerable because, you know, both nodes are important. You know, we've seen the data when the two T-cell engagers were combined, the response rate was like 97% or 96%. But the problem was the safety profile. So if we can get the same outcome with a better safety profile, that could be a real game changer in this patient population. Right. And coming up, we've got ASH. It's, you know, right around the corner, it feels like. But it will still probably feel like it's decades away. There's so much happening. Exactly. Can you maybe just walk us through, you know, what's coming at ASH? Are you excited about anything that could be presented there? Yeah, with the portfolio that we have in hematology, we have to be excited. There's so much happening, and there will actually be an encore, by the way, although it's not a rheumatology meeting, but there will be more data presented for the cell therapy CD19 in autoimmunity at ASH. But beyond that, I would say watch out for Golcadomide data, further updates on the large B cell lymphoma, as well as I think follicular lymphoma is there as well. If you think about Mezigdomide, more data being presented over there, especially novel combinations. As we think about the Mezigdomide cell therapy, cell therapy data should be there, additional cell therapy data, including GPRC5D updated data that'll be presented over there. What am I missing? BCL6 LDD, and then we have a hemoglobin F inducer that'll be presented as well. That's pre-clinical, right? The pre-clinical data, but it's a pretty remarkable pre-clinical package, including non-human primate data on the HbF inducer. Okay. Great. Maybe we go to some other assets. HFpEF, the EMBARK study you mentioned, the opportunity there, and, you know, I guess with a second gen 224 asset, can you just talk a little bit about what sort of separates the two, what you think is gonna really, you know, differentiates 224 from Camzyos? Hey, before we get there, we went a little too quickly over BCL6. Oh, sorry. I feel like it deserves just a little bit more time because I think it's a really interesting asset. So then we'll come back to this one. But so this is been. You can see the passion here. Yeah. So this has been one of these, you know, transcription factor oncogenic drivers for a very long time. It's been very difficult to drug, so there's very strong causal human biology. We now have a ligand-directed degrader, otherwise referred to as PROTAC, and you know, we are showing that we're actually getting degradation of the target, and you know, we're beginning to see, I think, promising signs of clinical activity as well. As a single agent. Yeah, as a single agent. So, so this is one where it fits all the principles that we've actually talked about: strong causal human biology, very unique modality, matched from molecular mechanism, very clear clinical proof of concept study, and we're beginning to see how that data will actually present itself. And then, because we're in a very unique position of having Golcadomide and other agents in lymphoma, we can now figure out how to position this particular medicine in a way that I think is pretty unique. So now let's go back to HFpEF. But I just wanted to make sure that we spent a little bit of time on BCL6 LDD. That's great. Making a very hard turn from hematology to cardiovascular disease now. So I think, MYK-224, we did a study in obstructive hypertrophic cardiomyopathy to define and differentiate what it looks like. The data looks pretty similar from efficacy perspective. Yeah. But certainly gives an opportunity for the second, cardiac myosin inhibitor to bring into cardiology. And so EMBARK study has already shown from a principle perspective, we can decrease the NT-proBNP in substantial number of patients. And there is a class change from an NYHA perspective. So heart failure is improving in these patients with HFpEF. So now we have the proof of principle from Camzyos. Now we want to test it out in a larger population with MYK-224. Those studies are ongoing. We've treated three cohorts. A fourth cohort is gonna start soon now. That data reads out end of 2025, early 2026. And that will pave the way for a later stage development. Remember, in HFpEF, we have only three or four drugs to date. And there is a lot of unmet medical need. There it will then provide opportunities to see if there are combination approaches that we can take forward. We are seeing emergent, emerging data in with the GLP-1s as well. Many of the patients who we are enrolling in our trials, they're coming into the background of GLP-1s as well. We'll be able to see what we are adding or what we are differentiating on, what the data will be differentially looking in these two different populations. There's a lot to learn over the next one year from this program. That will then define what we do for the phase three. Great. This is sort of like a random walk down Wall Street, conversation on the very robust portfolio of choices that we have to go to. But LPA1, we haven't talked about yet. Let's kind of go through the opportunity in IPF and PPF, as well as, you know, again, what differentiates your LPA1 program from some others that have been challenged, separately. Okay. So we've got, I think a lot of good causal human biology around this node, not just from some genetic support, although indirectly for LPA1 as a target, but most importantly from the first generation molecule, which had good efficacy in an IPF study. There were some liabilities of that molecule. So we went back and made it a second molecule and it brought it forward. And that's the current molecule that's now in phase three. So we corrected the liabilities, but we repeated a phase two study that showed very consistent effects on clinical improvement for forced vital capacity. So it's not just really one phase two study. It's really several and not just in one indication IPF, but in a related indication PPF. And in the latter in particular, you see a dose-dependent improvement in forced vital capacity. So I think there's a lot of good causal human biology to support the target. A very good molecule. We have a lot of early clinical data to help us with the dose. And then this leads to, I think, how we select a dose going into our phase three and then maybe just a quick comparison to competitor molecules as well. And so we did. You'll notice a theme with all of this, which is we did a lot of really good clinical pharmacology work to say this is a dose that we believe is going to be effective. And we actually did even a higher dose in the phase three study to make sure that we had the right inhibition of the target. And this is different than what others had done. So with the competitor molecule from Amgen Horizon, where there is a different profile of protein binding, so you do not have the same level of exposure, so effectively, their dose is several fold less than the dose that we've actually taken into our clinical study, which is why we have confidence going into our phase three study, but good target, really good molecule, a lot of clinical data to support not only the indications, but the doses that we've gone into, and the phase three study is going really well so far. Yeah. The only thing I would add is we also have the ability to look at the data for background therapy because that's allowed for these patients. And second, we didn't want to leave any efficacy on the table. So we've actually, although we didn't test it out in the phase two studies, so we took the maximal dose from the phase two study, 60 mg BID in the trial, but then we also put in a 120 in there. And so we've looked at the safety for part one, and it looks pretty safe. So we are now enrolling very well in the phase three portion of this study. Great. So I think we only have two minutes left. Slightly wrong up there. But, you know, maybe just, I think we went through a little bit of the family and the grandchildren as well. But, you know, if you were to just sort of say, okay, you know, these are data sets that, you know, I'm particularly excited to see in the next 12-18 months, in the sort of phase two plus timeframe. What are you most focused on? So, I've mentioned a lot of them in terms of the phase threes. So all of those are gonna be important from a company perspective and our own drug development prowess and research perspective. Beyond that, so beyond the general ones that I've already spoken about, Milvexian, GPRC5D, Cobenfy, and SLE for Sjögren's. And so all lifecycle management in the phase three program. The ones to watch out also are going to be the anti-Tau molecule. It's in randomized phase two study right now. That is, 2026 and 2027 timeframe. And it's because it's a long follow-up that you need for these patients. So that's gonna be important. Another drug that we are taking into phase two is FAAH and MAGL lipase inhibitor. Again, dual inhibitor. Everybody, there are lots of others who are doing it as singular inhibitors. The dual inhibition approach that we are taking in Alzheimer's disease is gonna be important. So watch out for that. Again, 2026, 2027 timeframe. Some of the early data that is gonna be emerging in next year and the year after would be the radioligand therapy in breast cancer and small cell lung cancer. That's gonna be important. As well as, I think 2026 will be GPC3, hepatocellular carcinoma for radioligand therapy. That's gonna be important. I think from cell therapy next year, watch out for data for, not only continuous emergence of SLE, but as we think about data from, the sclerosis or scleroderma perspective, myositis perspective, and then hopefully MS as well, that'll come out. So I think these are ones that we don't normally get to talk about. And one molecule that I know out next year as well. So that will then hopefully give you a little bit more confidence as to why we planned the study, the way we planned it, and execute on the phase three. I'll apologize to all the people who are looking for a laundry list of BD development targets from Bristol-Myers Squibb. I didn't even get to that question because there's plenty going on. Thank you so much for joining us. Really thrilled to have both of you here with us today.