Morning, everybody. I'm very excited and it's appropriate that the first panel of our CNS conference this year is with Biogen's Head of Development, Priya Singhal. Thank you Priya, very much for joining me again this year. It was a great discussion last year and now, I have a whole page and a half of questions written out. I'm hoping we can try to get to as much as possible. For everybody joining, you know, you can always feel free to shoot me a note if there are any specific questions you want me to ask. There also should be a link in the webcast too to type in any questions. Maybe we can start and have a full discussion on Alzheimer's, Priya, and thank you again. I think one interesting topical question is related to the lecanemab AdCom. Candidly, I was surprised that there even was an AdCom, simply just because the data looks so unequivocal. To that point, were you surprised that there's going to be an advisory committee and what key topics are you preparing for on your end? Sure. It's a pleasure to be here with you, Paul. Thanks for the question. I think overall we're not surprised that the FDA has decided to hold an AdCom. I mean, after all, lecanemab is currently the first molecule in the class with the potential to obtain a traditional approval and the first with the complete phase III trial results, which could support translatability of amyloid plaque removal to slowing of clinical decline in early AD. We believe that the AdCom will provide the opportunity to review the strength of the data. I agree with you. The Clarity AD data was really rather unequivocal, but it's an important discussion. I don't think we can speculate on what the FDA or the advisory committee may choose to focus the discussion on. I do think that overall, you know, I mean, I think there's a question of whether ARIA is important. I think it continues to be important. It's always about benefit risk, but we've learned a lot about how to manage it. You know, it can be serious and I think, you know, needs to be appropriately weighed in. We think it'll be a totality of questions across benefit and risk, but we don't believe that it's a surprise at all. Okay. Okay, great. We were just talking offline, and I thought I would just throw in one question about it, even though we're gonna focus more on the development side. Just on the, on the NCD, and the CED, you know, I think most investors listening in, right, have followed everything that CMS has said and tried to analyze it very, very closely. I guess on my end, and again if you, if you can't comment much, no worries, but one question that I get regularly is, you know, when we read this recent CMS release and they're speaking to kind of broad access, what do you envision that that might look like? When we think about evidence development, are there any analogs we can look to, or is there any sense of what we can get as it relates to the burden that's going to be on physicians treating these patients? Sure. Let me tackle the first part first, which is, you know, what the access could look like. I think to address that, you know, it's important to kind of underscore that Eisai is leading this discussion and engagement with CMS. They're working very closely. They're sharing the data. They believe the discussions are very constructive. We believe that it's quite positive to see CMS saying that they will provide broader access on the day that lecanemab, if it receives traditional approval. We think this is very positive. Now, as you know, the broader access could be a range of options. You know, a registry, and registries could be really quite light. They could be online. They may not be burdensome. I think we do need to wait and watch on how that is. I see this as a commitment from CMS that they will provide broader access. Okay. And that's what I would underscore at this point. I think beyond that it's hard to tell. Yeah. Okay. Fair enough. Let's switch gears to the subQ formulation. Obviously could be a big deal to kind of broadening access, right? Making it easier for patients that aren't, you know, in cities and at, you know, treated at academic centers to get the drug. Can you just set the stage, Priya, and talk about the various studies and formulations for lecanemab subQ that are under development today? Yes, sure. This is a very important part of, you know, it's a multi-pronged development pathway for lecanemab beyond Clarity, and this is a very important pillar. Eisai has presented the bioavailability data from the phase 1 study that compares the IV versus the subcutaneous dosing. They've also presented modeling and simulation data that illustrates that a fixed subcutaneous dose of 720 milligrams administered weekly may potentially result in a comparable exposure and efficacy to the current IV formulation. The subQ sub-study is currently ongoing in the open label extension portion of the phase III Clarity AD study. This study, the sub-study that is designed so that the individuals completing the 18-month placebo control portion, both the treatment and the placebo group, transition to the subQ sub-study, and they can receive either the IV formulation or they can switch to a direct start of subcutaneous formulation, or they may receive the IV formulation for about 24 weeks and then switch to subQ. It's quite a comprehensive approach to evaluating subcutaneous. There's also an additional phase I study that's designed to evaluate the bioequivalence of the subcutaneous dose of lecanemab via vial and auto-injector in healthy participants. As is obvious, you know, a use of an auto-injector could potentially allow for home administration. It's really a comprehensive plan. Eisai has also stated that they will be ready to file with this package by Q1 2024. They believe that this study will generate and the total package will generate the PK/PD and the safety data that's needed in terms of a regulatory filing. Yeah. Okay. Okay. You know, one interesting question that a KOL raised on a physician panel that we moderated at a conference in January was this idea that Cmax could be relevant for getting more drug in the brain. Like maybe there's some sort of gradient effect and, you know, the subQ obviously has a much lower Cmax and has been modeled more based on C-average and AUC. I guess to that end, you know, what evidence do we have that Cmax doesn't matter for both brain penetration and potential target engagement? Yeah. Basically the exposure response modeling of the phase II data, the lecanemab data, suggests that the C-average is the one that's correlated with PET SUVr. The model predicted that the greater steady-state concentration of lecanemab, the greater the change from baseline in PET SUVr at 12 and 18 months. That gives us a certain degree of confidence. The modeling has also suggested that Cmax is actually correlated with the incidence of ARIA. At similar exposure, subcutaneous lecanemab has a lower Cmax than IV after each administration. It's possible that subQ formulation can give us, if the C-average correlation with SUVr, can give us the plaque reduction, but also result potentially in a lower incidence of ARIA. Of course, we have to wait for the data, that's how we're thinking about it. Yeah. That's the data that we're anchoring this hypothesis on. Okay. When you talk about a bioequivalent study, is that looking at bioequivalence in serum or CSF or both? It's a bioequivalent serum. Okay. Okay. How do you think about the regulatory hurdle? Do you think you can get approved on plasma bioequivalence and safety or do you need to show target engagement and plaque lowering that looks comparable? Well, we believe that, you know, I will just say, you know, that Eisai has stated, I think several times now that they do have general agreement on filing strategy with the key regulators. That the subcutaneous substudy will provide the necessary PK and PD and safety information. PD will really be plaque, you know. I think it'll be a total package. Okay. They will file this by end of Q1 2024. Yeah. Okay. Do you have a view of when it might, when we should expect some data? I guess if they're filing it in Q1, there's a bunch of medical meetings later this year. Is that a realistic expectation? Well, they haven't commented, so really no comment from me on that topic, because they haven't commented. Okay. Fair enough. Maybe separately, you know, I think one interesting question is just about blood-based biomarkers in this space. There's a number under development. We put together a timeline recently of this. I'm not a diagnostics analyst, I'm trying to kind of learn on the job when I look at these and look at some of the data and look at the correlation data. I guess, can you just start by sort of setting the stage on where we are with blood-based biomarkers? In your view, how important is the development of a credible blood-based diagnostic to achieving lecanemab's peak potential if it can truly replace PET SUVr? Yeah. It's a very important question, and really we believe that the accurate diagnosis today is a key challenge. We believe it's a challenge. We think that the availability of accessible diagnostic tests are one of the key contributors. You know, as is common in other disease areas in other fields, when you don't have a lot of therapies that can be meaningful or be disease modifying, you don't see a lot of momentum in diagnostics. We think we're already seeing a lot of diagnostic momentum, and the field is making progress. We're not at the point where a blood test alone is adequate to confirm amyloid pathology for an Alzheimer's diagnosis, which is the target for lecanemab, so that remains very critical. Of course, we have PET imaging and CSF testing to confirm, amyloid beta pathology, but this is hindered by, you know, infrastructure challenges, invasive, burdensome procedures, high cost, limited coverage and reimbursement. The goal really is to achieve regulatory approval and reimbursement for a blood-based diagnostic that can be validated against the gold standard, which currently is PET imaging. That can, I think, really change the potential and improve access for patients and very much streamline. While many challenges are invoked, you know, when you talk about treating Alzheimer's patients, we believe blood-based biomarkers is really quite central. Today, we think that there are very limited blood tests available. These are now being called lab-developed tests, they're non-FDA regulated, and they have a limited clinical uptake, primarily due to challenges with the ability to correctly predict A-beta status and commercial scale limitations and of course the high cost. All those factors are really, you know, precluding this from getting to the mainstream. There is momentum. We've seen, you know, in the U.S., C2N launched in 2020. C2N again launched in 2022 with an updated version. Quest launched in 2022. In Japan, we've seen tests approved in December 2022. There's more tests that are coming up. We've been hearing more about the Quanterix with Lilly, Fujirebio, Roche Diagnostics. There's momentum, but we need this to really be sorted out for us to achieve the true potential and to get to patients in time. Is this something we could see Eisai and Biogen partner with companies or make investments here? Yes. We actually already have. Eisai and Biogen have been using both in Clarity AD and in the pre-symptomatic AHEAD 3-45 trial. We've been using C2N tests for screening prior to amyloid PET and CSF confirmation. This is an important data source. Eisai, separately, outside of the collaboration with Biogen, has also funded the development of blood tests with C2N, Sysmex, and Shimadzu. Biogen and Lilly are sponsors of the Bio-Hermes trial, which aims to compare blood tests alongside digital and other tools in MCI and AD. That adds prospective data to a test validation. We think that, you know, we are trying to do everything we can, but it will really take a large momentum to get this into mainstream. It's gonna be very important. Of all the data you've seen so far from the tests that you've been kind of, you've been invested in and partnered with and then others externally, have you seen anything yet specifically that, you know, has a high enough correlation with PET that it could be ready for prime time, or are we really just not there yet? I think we're not there yet, but we have seen a lot of important data, and this has been shared, you know, for example, with the plasma Aβ42/40 ratio. That has been very important at C2N. That this has yielded very important data about how long do you continue to treat and why would you continue to treat. We're seeing that. Can it replace, you know, PET and CSF? We're not quite there yet. 'Cause you have to think about the fact that this is a serious disease. You know, when we talk to physicians, they do want to limit any false positives because they will be putting a patient on a beta amyloid therapy. That's really the question here. Okay. Okay, great. Thank you. You alluded to my next question, which is one of my favorite topics in this space, and it's the whole concept of dosing continuously, non-continuously. I feel like, by the way, I've lived this story twice now with, you know, following Sage since they IPO'd with zuranolone and that whole debate as well, which we can get into. I guess, how do you think about the need for chronic dosing with lecanemab? I mean, you have the data, and we can talk about the data, but just, like, more broadly, did you ever consider treating to PET negativity? What data is there that suggests that giving this chronically is the right way to go? maybe I can just kinda keep it open-ended and then follow up. Thanks. Sure. It's a very important question. I mean, I think it's both a scientific question and of course then you have to follow that through with the therapeutic strategy. Overall, I think it's very important to remember that there's the aggregated amyloid plaque in the brain that gets visualized by PET and picked up by CSF and of course, also by blood biomarkers, hopefully in the future. There's also the soluble oligomeric species that's specifically the protofibrils, that literature shows that these soluble oligomeric amyloid species impact synaptic function and learning and memory, and these can't be visualized. When lecanemab was designed, it was actually designed to address not only the plaque, which is aggregated and can be visualized, but also the soluble species. We believe that that's the therapeutic strategy that can, in totality, address this disease progression. The data that we have that supports that you need to continue to treat with lecanemab even after removal is the data that's important. I'll sort of touch on that data. Eisai presented the data from the lecanemab phase IIb study that included a gap period. The average time off drug was about two years. Before previously treated patients resumed or placebo patients started treatment in the open label extension for the phase II study. What we saw was that lecanemab resulted in fast and deep plaque clearance during the 18-month placebo control period. We saw an increase in the plasma A beta 42/40 ratio during this time, which is indicative, we believe, of a reversal of the disease biology. You know, the hypothesis here is that Aβ42 gets sequestered by the amyloid plaques in the brain. When you remove the plaques, it allows more Aβ42 to circulate. You pick up an increase in the plasma Aβ42/40 ratio. When plaque reductions appear to have been maintained, what we saw was that they appear to have been maintained during the treatment gap period. This ratio declined, indicating that the Alzheimer's disease biology was returning. When lecanemab was restarted, we saw the trend reversing. Our conclusion at this point, based on the data that we've seen, is that while plaques remain relatively stable during the treatment gap period, we do see signs of returning disease biology. As we think about, you know, what's the... We have a molecule that addresses both these aspects. We've got the data that shows that, yes, it does come back, sort of the soluble species start coming back. The question now really on the table is how often do you need to administer lecanemab after the initial 18-month period where you get to that, you know, amyloid negativity, as you referred to it, and you remove majority of the plaques. Do you need to continue it? We believe, yes. How long and how often do you know, provide lecanemab is the question. This is being answered. We believe that you need data for this. This is that other pillar of the clinical development plan for lecanemab, and it's being evaluated in the phase II open label extension. The two, you know, maintenance dosing is being tested as Q4 or Q12. That also, Eisai has stated that they expect to submit a regulatory filing by the end of Q1 2024. Hopefully that answers the, both the scientific hypothesis, how lecanemab addresses it and what we're doing to generate data to really evaluate the question. Okay. Okay, great. One last Alzheimer's question that just came in before we switch gears and talk about zuranolone was just how do you think the sub-Q is most likely gonna be positioned in the real world? I know you kinda covered some of this earlier on the different studies, but do you think it's going to be something where when it's used in the real world, it's a switch from an initial IV course? What are your thoughts there? Well, I will say that the data that we're generating right now, that Eisai is generating, will allow evaluation of all the situations, because as I mentioned, the sub-study is testing three aspects. One is you just start, you continue on IV and you switch, or you start on sub-cute. Remember, people, patients who were on lecanemab during the 18-month period, they're gonna switch to sub-cute. That is gonna give you all those, sort of, you know, use options. You will be able to see what the data shows in each of these situations. Now, how it'll exactly get adopted, I think remains to be seen. Certainly we'll be launching with IV and then we'll be filing with this. There's a period where, you know, just the IV will be available, and by that point we'll have this in review and, I think we can then comment on how it could be used. The way the data is being generated, I think it could answer a lot of the questions that are outstanding today. Yeah. Yeah. Okay. Great. Maybe let's flip back to zuranolone. You know, it's interesting, right? Like I followed this drug since it was in phase I and phase II, and the whole concept of non-continuous dosing with this drug on the Wall Street side, right, became a kind of bull case, an optimistic case. As the data accrued and investors got focused on the effect size and some of the day 42 stuff, it's almost flipped back and there's a lot of skeptics who think that it's a challenge with this product. I guess in your view, you know, what makes you confident this is the right way to dose this drug? You know, how do you envision zuranolone being used in the real world? I think we think that there's a very significant opportunity. I mean, obviously, you know, we all know that the data from major depressive disorder is that there's millions of patients who are currently on therapy and are in need of, you know, a drug that can add to their treatment plan. That's one aspect. The other is that we have seen repeatedly across the entire LANDSCAPE and Nest programs for both MDD and BPD that the rapidity of onset of action by day three is really very meaningful. We also believe that it is sustained and that it is durable, and we believe that we have data to show that the safety and tolerability is really consistent and it does not come with the SSRI and SNRI burden of safety effects. We believe that this is really potentially can be a paradigm shift where you could have a patient with MDD who needs treatment once and potentially twice in a year. Because that's what we've seen with SHORELINE, which is the largest naturalistic study that's been done in, you know, in MDD. With the 30 milligram, I believe it was 4.5 months that we saw for patients who needed a secondary treatment. In with the 50 milligrams it was eight months. We think that that is really meaningful and that is going to add value to both HCPs and patients who are looking to, you know, have benefits and disease modifying treatment in this area. We think it's very meaningful. Yeah. With regards to PPD, it's the same thing. It's highly prevalent, highly underdiagnosed, and we think that the data are compelling. Obviously you know that, you know, FDA had given a Breakthrough designation. We did a single filing to make it very simple, and now we have Priority Review with the PDUFA date of August 5. Priority Review is also a very, you know, good outcome in terms of where the FDA has started their review on the potential that the drug could add in terms of impacting or being a meaningful, and significant, you know, difference between currently available therapies. I'll stop there. Happy to answer any other questions. Yeah. Great. Thank you, Priya. On, you know, one thing that, you know, when we try to forecast these drugs and model them, is I've had a little bit of trouble trying to figure out. Like, I know the SHORELINE data, right? Just figuring out how it's gonna be used in the real world, what line of therapy. If you look at the launch of Axsome's drug, right? Payers naturally have pushed this into the treatment-resistant depression population. When I think about zuranolone, I don't know if this, you know, non-continuous dosing approach really makes sense for patients in that line. I guess can you talk a little bit about Biogen and Sage's sort of strategy for positioning this drug? Cause it does seem like based on SHORELINE that, you know, this could be very clinically successful in the earlier lines of therapy. I worry that maybe if it gets stuck in TRD, it's not gonna get that escape velocity because the initial experience might not be as favorable. What are your thoughts there? Yeah. I think that is very important to note that zuranolone has not been evaluated in treatment-resistant depression. If approved, I think that both Sage and Biogen were already working very hard on what our launch educational strategy is going to be, how we're gonna approach physicians, what's the patient journey, who are the physicians who are gonna be treating. We're looking at that very, very carefully, and we're looking at the appropriate use of zuranolone supported by the clinical trial data thus far. What's really important to note is that in this LANDSCAPE and Nest program, specifically for MDD in the LANDSCAPE program, zuranolone has been evaluated as a monotherapy, adjunctive therapy and add-on. You know, and co-initiation. I think that gives physicians and data has been generated across all those. That gives physicians a lot of data to rely on as they look at the patients who walk in through their clinic. I think that's going to be important. While we don't, you know, we can't speculate on what the label is gonna say. At the moment we are really focusing on patients who might be needing a switch or an add-on and, you know, where they need more power. We believe that this GABAergic mechanistic action is going to really be important for those patients. Yeah. Okay. Do you, One thing with SHORELINE, right, and I understand it's described as a naturalistic study, but I do think one thing that's different about that study versus, you know, how a physician might have the impetus to care for a patient in the real world is that between courses of therapy, I think patients weren't allowed to redose for six weeks. How do you kinda think about that in terms of how it will impact, you know, psychiatrists' approach to the drug, the psychology around it? I guess, do you expect that restriction to be in place in the real world, or do you expect it to be more open-ended? Can't speculate really on the restrictions in the label. I think we'll have to wait for that. I think the important information that SHORELINE provides us is how zuranolone could be used in the real world if approved. The 50 milligrams approximately cohort in SHORELINE, approximately 80% of individuals who responded to the initial course received only one or two treatment courses in total during their time in the one year study. Majority of the patients actually received only the initial 14-day treatment course. Then I already quoted the data to you of, you know, what was the time to retreatment if patients went on to get another retreatment. We think that these underscore the potential and provide data. The other piece I wanna definitely add here is that as this is a very important launch for Biogen and for Sage, of course, and we are focusing very deeply on what is all the real world data we need to generate. We are looking at this very carefully. We have a very systematic and comprehensive plan. We'll continue to generate data to help physicians really understand how the drug works and fill in any gaps. It's not like this will be it. We have an educational strategy that we're approaching and also what's gonna be our approach to generating real world data. Okay. Like what would be something that, you know, would be your first inclination on an additional question to help answer for physicians? Well, right now what we're doing is we're speaking to a lot of physicians and we're gathering that, and we're prioritizing all the questions that we're gathering both from the Sage and Biogen side so that we can decide how we would approach it. We're also looking at, you know, whether this would be, you know, what kind of networks we might tap into. We're looking at it very comprehensively. I'm sure we can share more, you know, in future meetings. We're also looking at additional indications, ex U.S. strategy, so it's a very comprehensive approach. For zuranolone, we believe that this is a very important opportunity and we wanna do the right thing for both patients and physicians. You know, I think Sage generated some data in bipolar historically. They also have some subset data in patients with high levels of anxiety. You know, if you could pick one, is there one psych indication that you're most kind of intrigued by for this? Well, it's early days because we're still looking at the data. We're kind of evaluating them very, you know, in their entirety in terms of what the plans would look like and how we would develop these. I think generalized anxiety disorder is important. We've already seen that zuranolone is, you know, is beneficial to patients with MDD with a high level of anxiety. We're looking at generalized anxiety disorder by itself, but we're also looking at bipolar disorder. We're looking at a lot of these, and I'm sure we'll be able to share more data soon. Okay. Okay, great. When I met, when I met with Mike, and Mike, CSCFO and, or Michael and Mike, CFO and IR in December, you know, I like to ask, you know, what's the one R&D pipeline drug that, you know, you feel like it's most underappreciated or I don't know exactly it was phrased, so maybe I shouldn't quote them, but most under the radar. They talked about lupus, oh, five nine. Can you just talk about this drug, you know, and also, you know, Chris has talked about immunology as a potential area for business development. Like, maybe talk about this drug and just kind of your broader interest as the R&D portfolio is shaped in, you know, getting more into immunology after that wasn't more of a core area when you were doing a lot of drug development in MS. Yes. You know, we have two phase III programs in SLE. We have two programs. One is DAPI in collaboration with UCB, which is also a phase III anti-CD40 ligand antibody fragment in phase III for SLE. BIIB059 is also called litifilimab, and this is a monoclonal antibody that's targeting the human BDCA-2, and it's a homegrown asset. You know, we're very proud to have brought it to phase III. Both assets have the potential to be first in class molecules in SLE, but litifilimab is also in phase II/III for CLE, which is a skin-based autoimmune disease and can exist in the absence of systemic manifestations. No real treatments approved in the past 70 years. A very high burden of disease, specifically in the diverse underserved populations, impairing quality of life, severe skin damage. We believe this is right in our, you know, sort of our mission of going after diseases of a high unmet need with an asset we believe that has the biology that impacts the biology for this disease. Now, the hypothesized mechanism of action and data is coming from the phase II LILAC study where we generated proof of concept. This was published in The New England Journal of Medicine last summer. Essentially what litifilimab is a humanized monoclonal antibody against BDCA2, as I mentioned, which is a protein that is predominantly expressed on the surface of what we call pDCs or plasmacytoid dendritic cells. What these plasmacytoid dendritic cells do, that they are innate immune cells and they rapidly produce high amounts of type I interferon as well as cytokines and chemokines in response to immune complexes in lupus. What you see in lupus is pDCs accumulating in target organs like skin, kidney, and joints. Litifilimab comes in, binds to the BDCA2, and leads to the BDCA2 internalization and inhibition of type I interferons, but also of other cytokines that are implicated. We saw the proof of concept. I won't go into the details, but in part A of the LILAC study, we saw it in SLE, and in part B, we saw it in CLE. This is really important. I think that overall, you know, we believe that the pathogenesis of lupus is quite complex. There's a constellation of symptoms, and, you know, many mechanisms of action are important. We believe that this actually, the litifilimab inhibition of pDC actually works to preserve the protective type of interferon response to viruses in other cells. It works on the pDCs, but it preserves the other cells, and that's important as you think about benefit risk. We need to wait for data, but we're excited about litifilimab. That phase III is reading out in 2024. Is that right? No, it's later than 2024. I believe it's 2025 or 2026, but I can come back to you and confirm the date. It's all good. It's all good. Okay. Yeah. Thank you. And then. Actually, I didn't answer your second part of your question, which is, you know, we think that we have been experts, obviously, in MS for many years. We think it's an autoimmune disease. It gives us a lot of legitimacy to explore and potentially move deeper into immunology. We've already generated a first in class asset like litifilimab, which has progressed to phase III. We believe we have the expertise and the capabilities. We've got a good foundation with three late-stage programs in CLE and SLE. I think as Chris has stated, you know, what we're trying to do is the first half of 2023, we're focusing on looking at our current programs and capabilities, but this is an area where we may supplement and build on our foundational, you know, expertise in specialized immunology. Yep. Okay. What should we expect, Priya, in terms of just an R&D update from Biogen this year, after you're done kinda taking a closer look at your current portfolio, the risk, the risk profile, and, you know, how your positioning of things might evolve going forward? It's a very important and central initiative. You know, Chris is very much supportive and also wants us to continue to do what we've been doing all through 2022. It's an ongoing effort, because what we're trying to do is look at our portfolio, look at the inflection points for data internally, but also scientific advances externally, and help us guide how we would either go to next decision point and spend until that point, or we might actually terminate or accelerate. I'll give you a few examples. We are kind of dynamic prioritization. First, I'll just speak a little bit about how we've approached it in the process. We wanna essentially rebalance the risk profile, but also increase the productivity. We wanna prioritize the programs with the highest risk/reward profile. To do this effectively, we've taken three high-level steps. Number one, we've identified the programs where we believe we have the highest attractive risk-reward profile, and we've developed what we call internally a clinical investment framework that helps us guide decision-making. Helps make sure that our spend is commensurate with risk and that we are being very clear about what's the de-risking experiment and how we can get to that very quickly. This is primarily for our pre-proof of concept portfolio but also applies to our, actually our pre, our discovery and research portfolio. We have identified programs where we are committed to investing to win. BIIB080, which we haven't talked about, which is our anti-tau ASO, is one of those where we are really investing to win. We've also discontinued programs where we believe that there's significant challenges either with the development, commercialization or regulatory or fit. One is, you know, vixotrigine in neuropathic pain, the other is oral tolebrutinib in MS. The second piece here is that we've taken a lot of steps to increase the productivity of the pre-POC pipeline because we've noted, right, we failed certain pre-POC programs. The question is: How can we do better? What we've had is genetic targets. We are increasing our translational science capabilities to increase the focus on generating value by focusing on the translational biology, the totality of it, not just the targets, versus operational milestones. The final one is that as we do this, as we kind of bring assets forward or retire some, what we're trying to do is build, you know, areas beyond neuroscience, like neuropsychiatry, specialized immunology and rare disease. All of these are built on foundations that already exist. So with zuranolone, we've already got neuropsych. With litifilimab, as I spoke, we've already got specialized immunology. With SPINRAZA, we've had a very successful run in rare disease. We're building on all our expertise to kind of branch out. The reason to do that is not because we don't wanna do neuroscience, which remains very important, and we will continue to do that, but we just wanna make sure that we balance it so that the risk/reward, maybe in the other areas, is not as steep. The risks are not as steep. We'll still continue to take, you know, very calculated and informed targets and biologies forward and be pioneers. I mean, you know, you've seen the example with amyloid. Hopefully with tau, we're taking that to the next level. You've seen it with neurofilament and ALS and tofersen. That's how we're trying to think about this. Okay, great. Last thing before we wrap up. My expectation from hearing what you said, from hearing Chris on the earnings call, was that maybe on the Q1 call or the Q2 call, we may get some kind of updates on how you're reframing things or reprioritizing. After that, the deck is clear to maybe do more business development in these core areas. Is that the right interpretation? I think business development is always on the table for us. At any given time, we're looking at a lot of assets. I think it needs to have a combination of the high science, and it's gotta be really attractive, and it's gotta be at the right economics. I think that what Chris. I'll just quote him here. He said, you know, "We don't have that high desperation quotient. We'll continue to evaluate the business development opportunities. Yes, you're right. In the first half of the year, we really want to do everything we can to streamline within. Yes, our focus might be higher in the second half. We're continuing to look at it at any given time. We don't anticipate, you know, a specific hard line, but yes, it's gonna be more and more important. Okay. Okay, great. Well, hey, thank you so much. This was an awesome conversation. Thanks to everybody for joining. I'm excited to be talking to Ryan Watts from Denali in just a couple minutes. Hopefully everyone continues to hang out. Thank you again, Priya. Thank you, Paul. Thanks, everyone. Bye-bye.