Great. Thank you. Good morning, everybody. It's my pleasure to be hosting this panel with Priya Singhal, Head of Development and now also Interim Chief Medical Officer at Biogen. Priya has done this panel with me a couple of years in a row, and there's always a lot to talk about. So we really appreciate your time, Priya. Thank you again. Maybe just to kind of kick things off, it would be great if you could just give, like, a 10,000-foot view of the Biogen pipeline. Things have been sort of reshaped, right, with the leadership change at the company over the past, say, year and a half. I guess maybe on a forward-looking basis, you know, how satisfied are you with where you're at, and what areas or technologies are you looking to kind of increase your exposure to as things continue to unfold? Sure. Thank you all for having me, and, you know, happy to be here. So before we begin, I just wanted to point out that I'm going to be making forward-looking statements. These are based on our current expectations and beliefs. And they are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors that are in our SEC filings for additional detail. I believe that we've made significant progress over the last year, bringing about kind of a new Biogen as we've prioritized our pipeline to invest really where we believe we can deliver the greatest returns and enhance value. We've also completed the Reata acquisition, and we've realigned the company structure and overall cost basis to support the best future growth. On the commercial side, we see that this is an execution year relative to our new product launches, you know, Alzheimer's, Friedreich's ataxia, postpartum depression. On R&D, I wanted to focus on the fact that we continue to establish Leqembi in the marketplace. We have an opportunity to build on the launch of Leqembi with potential subcutaneous formulation, maintenance dosing, as well as preclinical AD. We are also continuing to expand our leadership in Alzheimer's disease with advancing assets targeting tau, and we believe that tau could represent yet another aspect of the future of Alzheimer's disease. So this is our focus on our ASO targeting tau, which is BIIB080. We also think that we have a significant opportunity in lupus, where we've got multiple programs in SLE and CLE with the potential to contribute to revenue in the back half of the decade. There's a lot we believe to be excited about the Biogen pipeline, and there are a number of inflection points this year that we can speak about, you know, during the session. But I wanted to share that one of our goals is really to continue to increase the productivity of the pipeline to help ensure that we have a regular cadence of drug launches. As a leadership team, we understand, you know, there's more that we can do on this front. We also have a very keen eye towards evaluating external opportunities. I work very closely with the head of research, the head of corporate strategy, and we think there's a lot more potential to expand beyond neurology, into immunology and the rare disease space. We also think that, you know, while we did a very concentrated effort last year on R&D prioritization and it's substantially complete, I expect this to continue to be a dynamic process that is data and evidence-driven. So that will continue to evolve. And from a pipeline perspective, you know, we're focused—you asked about technologies—where we have the expertise on small molecule, biologics, ASOs. And Jane Grogan, our new head of research, also brings in a lot of expertise on cell and gene therapy. So we'll be continuing to watch and evaluate the potential of all of these spaces as they mature and evolve. Sorry, taking myself off mute. All right. That's an excellent overview. I, you know, naturally have a lot of questions on different programs that you've that you've laid out. I think the one clarification I would love to kind of think through just in your aspirations and the business development side is, you know, what's your updated thinking on within immunology, which areas are adjacent, right? We can talk about maybe at one end of the spectrum, MS, which is just, like, purely synergistic, and at the other end of the spectrum, you know, mass market immunology like psoriasis. So kind of where can Biogen fit within there? And similarly, on the rare disease side, right? We could talk about rare neuro like you did with Reata, or we could talk about, you know, the lysosomal storage disorder space that's completely different. How do you kind of think about expanding while also sort of overlapping with your preexisting expertise? Yes. Overall, what I can tell you is that, we believe that, you know, we've been in the immunology space. We have a lot of expertise internally. And we have two very large programs in SLE, one with additionally in CLE, as you know. In addition, I would say that we are looking at neurology, specialized immunology, as well as rare, not necessarily as individual verticals, but they could also intersect. And this is where you see us playing with specialized immunology, SLE, and also CLE, where there hasn't been a treatment in more than 70 years. Moving from that, you saw us do the acquisition for with Reata, where we are looking at Friedreich's ataxia that is rare, but it's also neurology. So we are really bringing all our collective expertise. And here, I would say it's not just in the disease area, but it's also to leverage the tools that we believe we've been quite successful in. For example, with, you know, advancing amyloid as a surrogate biomarker, we believe we pioneered that, you know, within Alzheimer's disease. And then the neurofilament light chains, which is a very important surrogate biomarker and now accepted, with the approval, accelerated approval, of Qalsody for genetic ALS, SOD1 ALS. But we believe that this has ramifications beyond. And in fact, we recently presented data, in SMA from the RESPOND study where we showed that, patients who were on gene therapy, SMA patients who received Zolgensma and were, you know, wanted to have more additional benefit went on to Spinraza. The baseline, neurofilament levels were high, and almost all patients, this is, of course, a small study, but almost all patients, their neurofilament, levels went down significantly. So we continue to pioneer across the diseases, and we are looking at biomarkers. Because just to go back to what I said earlier, Paul, our goal is to pioneer, but also kind of to drive the results. So we're looking at what is our expertise, what's the domain, for example, in neuro, neurology or immunology that we're really good at, and bringing it all together. All right. Excellent. Thank you. Appreciate it. So let's kind of go through programs and catalysts maybe one by one. I obviously have a bunch of questions on lecanemab, but I thought it'd be interesting to start with Angelman, given that that's been an area of super high interest with the progress Ultragenyx has made. And it looks like it may be your next readout. Do you want to maybe talk about that program? And I guess as it relates to this phase 1/2 study, you know, it's open label. When you think about clinical endpoints on the neurobehavioral side, there can be an element of subjectivity. How are you planning on analyzing this data, and what would you view as an encouraging outcome that would embolden you to advance? Yes. So just to step back, you know, Angelman syndrome is a rare neurogenetic disorder, again, sort of in that rare neurology with a genetic basis for disease. It occurs in approximately 1 in 15,000 live births worldwide. If you kind of approximate, you know, there are ranges out there, but it's about 500,000 people worldwide. Now, the important thing about this, you know, it's a childhood disease. It's diagnosed in early childhood. It's characterized by symptoms like severe developmental delays, speech impairment, problems with movement and balance. And it can also involve seizures, which can be quite a burden of disease. There's no treatment that has been approved so far for Angelman syndrome. And patients and individuals with Angelman syndrome have a near-normal life expectancy. But they could generally require continuous care. They are unable to live independently, which naturally places a huge burden on families, caregivers, and society, and of course, the patients. The biological basis of the disease is that the paternal allele of the UBE3A gene is silenced in neurons, leading to expression (this is normal. This is a normal individual) leading to expression of only the maternal allele. Whereas in Angelman syndrome, that maternal allele is either absent or is inactivated through genetic mutation, leading to a loss of the UBE3A gene expression. Therefore, there's an impairment of the synaptic connections and brain network activity, which you can see would result in all the symptoms that I described. This can also be visualized (and this is important) by an increase in slow brain waves or delta waves when compared to neurotypical individuals. What BIIB121 aims to do is to remove the unsilencing—the silencing—of the paternal allele to restore the expression of the UBE3A gene. So that's the causal basis of disease, and that's how our antisense oligonucleotide aims to act. That's really the mechanism. Now, you're right. The phase 1 study that is known as the HALO study, it is an open-label study. It's a multiple ascending dose study across multiple age groups and dose levels to look at safety and tolerability, as you would in any phase 1 program and phase 1 study, of BIIB121 in Angelman’s. But what's important is this is in patients. So that's the first point to remember. It's across very important age groups and different doses. And importantly, the study also utilizes two key aspects that I want to mention. One is clinical measures that we can look at, assess, to look at therapeutic potential. The other is EEG assessment. So speaking about the clinical measures, they are the Bayley Scales of Infant and Toddler Development, Part 4, which is a direct measure of functioning across multiple domains like cognitive functioning, functioning, growth, and fine motor skills, as well as symptoms of Angelman syndrome, Clinical Global Impression, which is another, you know, scale that captures the clinical impression of the patient. We're also looking at EEG. So we're collecting EEG data on all patients. So we can look at these measures. There is natural history in this disease area because not all disease areas have that. And we can assess whether we are seeing an efficacy signal. So this is a phase 1b study. The ideal situation would be that we have an idea of whether we are seeing a signal or not seeing a signal because that brings us to a decision point, and we can opt in. Once we opt in, we would be generally aiming to go to a pivotal trial in this rare disease population. So we are looking to isolate a signal that we believe is real. We're going to do that based on clinical measures as well as EEG findings and put it all together to compare it with natural history. We also, this study, just to remind you, is a multiple ascending dose portion, but we also have a long-term extension of various cohorts. So we'll have the opportunity to examine longer-term data as well. Overall, thus far, what we've seen is no disturbing trends on safety and tolerability. It looks okay. And EEG data that Ionis had put out a press release early showed a trend towards slowing of delta wave activity. And the clinical assessed, you know, clinician-assessed endpoints show a majority of participants demonstrating some level of over improvement in overall functioning. So we've seen those very early results. Now we're in the process of really taking that cut and looking at it holistically. And that's when we'll make our decision on go/no-go. The other important thing is that we're very disciplined. And we at Biogen, we do design our own go/no-go criteria, a priori. And this is in consultation with key opinion leaders and others in the space on what would be clinically meaningful across these different scales. And these are the scales that clinicians use. We believe, while of course a lot of work lies ahead, if we truly see a signal, you know, it's achievable and addressable as we go forward because it would be a pioneering effort. There isn't another precedent here. That all makes sense. I—one follow-up question, Priya. In Angelman, how variable is the course of disease? And I guess when you think about, you know, in an open label study, if you saw some level of improvement, you know, do we see some patients continue to get better over time naturally, some patients stable, some worse? Like, what's the spectrum of that? And I guess maybe to put that into context, like, how much better do you need to be than natural history to be confident that an efficacy signal is real in a study like this? Yes. It's a very important question and one that we consider all the time when we look at trials like that in rare diseases with open label data. So one is—we are curating natural history. So we know what that variability is. And we have the opportunity to design our own go/no-go that gives us confidence that this is not noise. So that is important. And, you know, we won't be doing this alone. We have external input. We have internal expertise. So we'll be kind of coming up with those holistic criteria that help us get confident that we're seeing the change. The other thing is that we'll be looking at EEG findings as well. There is variability, and there's different variability across different age groups. So that is something we are keeping very much in mind. Okay. Makes sense. Now, if you move forward here, how do you think about a pivotal study and an endpoint in a pivotal study? Do you need to create a new scale? I think others have talked about that. Or do you feel like the endpoints that you're currently looking at in this phase 1/2, you know, one or multiple of them could actually be suitable? Well, currently, you know, when based on our engagements with experts in the space, we believe that these are the scales that they use. These are the scales that could be used to derive what is a clinically meaningful difference from natural history. So we believe they're going to be very important, if not the scales. So I think that where we are is we believe these have objective components that will be important for the endpoint. We think these could serve as endpoints. But of course, you know, we will be engaging with regulatory authorities to really make that call on what is the appropriate endpoint. But at this point, I think EEG, as well as the Bayley and the Vineland assessment and CGI change are all going to be important components, if not potentially individual scales that we would include in a pivotal trial. But we haven't come to that point yet. Okay. Okay. Great. Last question here before we switch to the Q&A and the kind of key sub-Q questions. Just on Angelman’s from a competitive perspective, you know, we've done our own analysis of comparing across programs, across mechanism, preclinical data. And at least our high-level conclusion between your molecule and the Ultragenyx molecule was that, you know, there are some key mechanistic differences in how they actually bind to the target. It looks like Ultragenyx's molecule may be more potent but may have a more narrow therapeutic index. I don't know what your reaction to kind of that at least view would be, if you agree or disagree. But do you want to at least talk a little bit about how your molecule is similar and how your molecule is different and, you know, I guess your level of confidence that it may be the best program here? Yes. So the BIIB121 ASO, it has a 2'-methoxyethyl structural backbone. This is similar to Spinraza. That is really how we have developed the—Ionis has developed the ASO. The Ultragenyx ASO has an LNA backbone, which is similar to rugonersen, which was discontinued by Roche last year, when they saw the efficacy from their phase 1. We have done internal studies, and we believe that there's a different response curve between the two backbones. And we think—and we believe—that the 2'-methoxyethyl structural backbone is the better, backbone to have in the ASO. So that's one point to note. And we have done internal studies. The second point I think here that's important is we have not seen safety signals with BIIB121. Thus far, patients are tolerating the highest dose in the current HALO trial, which differs in comparison to the Ultragenyx GTX-102, which did have adverse events at the higher doses. Ultimately, they have resumed after clinical hold at much lower doses. So we think there's several things. There's both potency. There's ability to go to the right dose. And there's also the dosing frequency. There again, our assessments have shown us internally that, you know, the way we dose BIIB121, which is, you know, for the first two months and then every three months, is important because this is based on our PKPD data that suggests that Q3 administration is required to see the clinical benefit in Angelman's. This is different from Roche's rugonersen, which also has the LNA backbone, where they did it every six months. So we think there are significant differences. I also want to say that when rugonersen, you know, was discontinued, the way we kind of practice internally is we see that as an external trigger for our own portfolio. We go back and we look at all our data and reconfirm or—or say that our assumptions don't hold anymore. So we believe that this is differentiated. It has the potential to deliver. So we wanted to see it through. So that's an important point as well. Okay. Great. We'll look forward to that data. Let's switch gears to the lecanemab. I think the key question here that, you know, you've probably been asked many times, but we're going to continue to get asked probably until the PDUFA is really whether or not we have enough safety data for the sub-Q to de-risk approval. What's your kind of latest on your level of conviction that, the sBLA filing here is de-risked and that you and Eisai are aligned with the FDA? Yeah. So just to clarify a couple of points. One is that the subcutaneous Eisai has communicated this will be a BLA, not an sBLA. That's one point to communicate. The second is that we also have an IV maintenance filing that's going in, and planning that is an sBLA. So there's two filings we're talking about. We're talking about a subcutaneous maintenance filing, and we're talking about an IV maintenance filing. There is a difference in one being a BLA and the other being an sBLA. Coming back to the subcutaneous data, I think when Eisai presented this data in C at CTAD, what was really, really important about that data was that the six-month data with the 720 milligrams in with subcutaneous substudy of Leqembi in Clarity AD phase 3 OLE showed comparable results across PKPD and safety compared to the IV formulation. We believe that this data supports bioequivalence with IV, and there is a potential viability of a subcutaneous formulation of Leqembi. Thereafter, there have been multiple engagements. Eisai has spoken about them with the FDA on the data. So that's one piece to kind of keep in mind. A big focus of the subcutaneous substudy data was plaque removal. So what we were looking at for bioequivalence on PD was plaque removal. We saw this. We saw this in the treatment naive individuals, the cohort of 72. But I do keep reminding audiences that we also collected data in Clarity AD in more than 300 patients in who received IV Leqembi and then switched during the study and then switched to subcutaneous formulation after six months of IV treatment. This is important. We're continuing to collect data across both these cohorts. On the regulatory front, Eisai has announced recently that the regulatory filings for subcutaneous would be split into two separate filings. So Eisai first aims to submit the filing for maintenance subcutaneous with an autoinjector following—that is, following 18 months of bi-weekly IV treatment. A separate filing is being planned for the subcutaneous autoinjector induction phase, which is the first part before the plaque clearance, 18 months. We believe that the potential here is for a lower dose of subcutaneous AI in the induction phase, which has the potential to optimize the patient experience and potentially may also have an impact on a—on a slightly different rate of ARIA. But really, the focus here is to optimize the dose for induction based on the 6-month data that we had at CTAD, where we saw, you know, that we met bioequivalence because that was really the first hurdle. Can a subcutaneous dose actually remove plaque? That's a checkbox at six months. The question is, what's the dose for, you know, what is the right dose for induction? And there's a potential that could reduce it. So we are in discussions. This is requiring additional engagement, and we're continuing to do that. And Eisai has also provided some dates externally, very recently that the IV maintenance they expect in the second half of the fiscal year of 2024, which is their Japanese fiscal year. So it's October 2024 to March 2025. And then for the autoinjector induction, they expect that by fiscal year 2025, which is March by March 2026. So overall, there's been a number of discussions, a number of meetings with the FDA as the data have emerged to really discuss the design of a potential, you know, what is the right dosing strategy? What should be filed first? What should be filed second? Eisai is, of course, the regulatory lead here. They lead these engagements. But Biogen has a seat at the table, in all of it, and we review all the documents. So it's, you know, going to be tough to speculate on what regulators will ultimately decide. But when I look at the data that we generated at six months and the patient's unmet need, and the importance of, this formulation, you know, I—I think we are going to see progress as we—as we continue to move forward. Thank you, Priya. Two quick follow-up questions. So why why is it its own BLA? And are there any is there anything implicit there on the leverageability or lack of leverageability of the data from the IV? And then as it relates to induction, you know, given this kind of ongoing discussion around the right dose, are you comfortable that you have the clinical data to answer that question and that you're not going to need to generate more clinical data? Sure. So the first thing is that it's a BLA because it's considered by FDA as a combination product. That it's as simple as that. It is important that it be filed as a BLA because it's not really supplemental. Second question about the clinical data, we believe that amyloid reduction is the right PD endpoint. So we don't believe we need a clinical study. You know, there may be, like, PKPD and all of these types of things that need to be done, but certainly not a clinical outcome study. Okay. But does that mean you don't think you'll need to treat any more patients with different dose levels, even just, like, monthly? We may need to for the induction piece. For the maintenance, we believe we have the package. Right. You know, we're working towards submitting that. That's the SC autoinjector maintenance filing. For the SC autoinjector induction, we will have to generate some data, which is why they've communicated the fiscal year 2025 as when they think that that'll be possible. But we're not talking about a phase III study here. We're talking about. Biogen. You're talking about Biogen. Yeah. Okay. No, it makes a lot of sense. Okay. You know, in your view, or I guess look, look at Phase, right? The ARIA rate for sub-Q is nominally higher than it was reported for IV. In your view, is the ARIA rate actually higher for the sub-Q, or is this noise? And would you expect the monitoring requirements for sub-Q to be different or more burdensome than the IV? Yeah. In my personal view, I think it's very similar, very similar. I have said this before. We have a very small sample size that was Leqembi-naïve. It was 72 subjects. It was considered adequate for PKPD, but of course, it's not the size of a large trial. But what we saw, importantly—so I'll walk you through the incidences, you know, the incidences with IV in Clarity AD, where the N was 898. It was a large N, right? Was 12.6% for ARIA-E, 17.3% for ARIA-H, and, you know, 8.9% for isolated ARIA-H. In the SC substudy, where we—the 72 patients—we saw 16.7%, 22.2%, and 8.3%. So we don't believe these are significantly different. That's number one. Number two, with ARIA, we have collected a lot of data across so many trials. We really understand how ARIA is characterized, not only in terms of incidence but in terms of, you know, frequency in ApoE4, non-ApoE4, severity, you know, need to discontinue, need to change the clinical dosing, all of that. And from that perspective, the characterization remains the same. The monitoring protocol, the characterization, all of it remains the same. So we don't believe that it is significantly different. That said, if there's a very significantly different dose in the induction phase as we're currently evaluating, it is possible it could be different, you know, but it—I don't expect it to be characterized differently. I think it will fall in a similar pattern because that is what we've seen with ARIA. Yeah. Okay. Okay. Fair enough. Last Leqembi question. And, you know, we have, I think, another 12 minutes. So I want to touch upon the lupus programs, the anti-tau program, which is super interesting. But just on—just on Leqembi, look, I—I'm saying this as a Leqembi optimist. I think, you know, I've been really surprised by the pace of the launch. I think other people have been surprised too. We knew about, you know, all the logistical impediments, but, like, it's Alzheimer's, right? Like, I—I—I thought there would just be more of a push in the neurology community to figure out these things faster. I guess, when you think about sub-Q, where would you rank order, you know, the burden of biweekly IV administration on the impediments to Leqembi uptake? Do you think sub-Q, you know, moves the needle modestly, moderately, or, you know, really significantly when we think about a launch inflection? I think that the biggest hurdle we are seeing so far across Eisai and Biogen and all the, all the, you know, discussions and efforts we are undertaking is really access to a neurologist and getting a patient on the treatment pathway. It's not really the, the Q2, you know, Q biweekly IV. That said, I think if we had the option—we have already always embarked upon subcutaneous as a convenience option for patients. I think it's going to be important. So it's going to be important, but is it going to change the inflection of uptake? Maybe modestly because really, the problem that we're seeing right now, the bottleneck, is getting access to a neurologist. Once you get access to a neurologist and once they're committed and—and agree on treatment, you know, the—the rest can fall into place. We know that there's, elasticity on the infusion centers. While they can be difficult in the beginning, we've seen several centers, several individual neurologists overcome that hurdle. So we don't see it as a major stumbling block. Where we, Eisai and Biogen believe subcutaneous could be really important is in the potential preclinical or presymptomatic space. And this is an important inflection because we, as you know, we have the AHEAD 3-45 study where we are looking at presymptomatic patients. And in that population, you know, you can imagine that subcutaneous dosing could be important. So establishing it now and continuing to build on the foundation, hopefully, we will see success and optimism at the end of the AHEAD 3-45 trials. That would be a very good place to land for subcutaneous formulation because that's a population that can easily self-administer because they really do not have the cognitive, unfortunate, impairment, right, that patients with early AD do. If you step back, that's where we think, and that's why we continue to believe this is going to be important, and also to define the dose for the induction phase. Yeah. Okay. All right. Makes sense. Thank you. Appreciate it. So let's, let's talk about the two lupus programs you have in phase III. And I guess, is it litifilimab and dapirolizumab? Did I say those right? Okay. Yes. You got it. I didn't even have to practice. That's great. You know, how do you look at the strength of the data for each of these? Is there one that you think has a slightly higher POS than the other? And maybe just kind of give us a scope of this program and, you know, where you are excited, where we should be a little bit cautious, maybe. Yeah. So overall, we are excited about these programs. We believe that they deserve to have progressed to phase III, and we think that, you know, this is going to be very important data. SLE is a very heterogeneous disease. And, you know, there are many ways to assess progress and improvement. So I want to first talk about litifilimab because this is really an important Biogen program. As you know, it was born at Biogen. And the phase II LILAC study, which is really an important point here, met its primary endpoint in both Part A, which was SLE, and Part B, which was CLE. The other—I mean, I don't know how much time you want to spend, but I think what's really important is that, you know, it's a very exciting program because we saw, you know, really statistically significant differences in Part A and Part B. And we are using the SRI-4 in our phase III program. But in the LILAC study, we saw that this was also different. It's because of the lack of multiplicity control and, you know, consistent with standards that—and it was a secondary endpoint. So we didn't say it was statistically significant, but we saw a very important difference there. So this is important because it's a first-in-class humanized IgG1 monoclonal antibody. And it works through the BDCA2 pathway, which we believe is expressed on plasmacytoid dendritic cells. And that is what reduces the type I interferon. And type I interferon, clinical significance path—you know, kind of working through that pathway has been established in SLE. But we believe that this is going to be an important approach to drug this pathway. So we think it's a very important candidate. We also think that CLE is a really important opportunity. No, treatments in 70 years. In SLE, there continues to be a high unmet need. So we remain very focused on our TOPAZ studies, two phase III TOPAZ studies, and our CLE AMETHYST phase II/III study. On Dapi, it's another mechanism. It's an anti-CD40L or ligand pegylated Fab. And this is in collaboration with UCB. It's a very important inflection point for us this year. We'll be reading out on the phase III, on one phase III. The underlying assumption is that we would need a second phase III if it's positive. But we are being very clear about how we proceed with it. So rather than having two, we have one. And here also in the phase IIb study, you know, the primary endpoint was a dose response in Dapi with Dapi in SLE patients at week 24 but using the BICLA and prespecified dose response models. Although this endpoint wasn't met, we saw that Dapi was very generally well-tolerated and demonstrated significant separation versus placebo on multiple clinical and immunological parameters. So higher proportion of patients with BICLA responders, higher proportions of patients with anti-dsDNA titers lowering, as well as complement level lowering as early as week 8. So we think this is going to be important. And, you know, we're waiting for the readout. Now, I guess to that point, right, given you're doing one study now, you may need another one. There was also another CD40 ligand strategy here that I think in a slightly different indication was it lupus nephritis that didn't work. Like, is it safe to say that this is the higher risk of the pro of the two programs and, and as a result, you're proceeding more cautiously, or is that not a fair depiction? Yeah. You know, I think it's a different approach. I think the risk here isn't really about the pathway. We think the pathway is really important causally, but it didn't meet its primary endpoint in phase II. And we believe that that's because of the prespecified dose response. So that's our assessment of the data. Yeah. But it didn't meet it versus litifilimab that had, you know, met its primary endpoint in both CLE and SLE. So I think that is a distinction. And so we are being very objective in how we invest in Phase III programs. And that's what you're seeing come to life here, how are we investing in a Phase III program. But it does not reduce my enthusiasm for the pathway and for our belief that, yes, if we can design the right trial and have the right patients, we—we can actually see an impact of the pathway. With regards to the BI failure for CD40L, we think it's distinct. It was lupus nephritis. You know, it's a very common, as you know, it's a very, lupus overall is a very complex and heterogeneous disease. So, you know, ultimately, we'll be looking for a meaningful change on primary endpoint and key secondary endpoints. I wanted to say that it's not about right now, our understanding of a registration of packages we will require two studies. But we're still being deliberate. We're doing some planning, but we're not going overboard and starting a phase III. So that's how we're thinking about this. And we think BICLA is a very sensitive and clinically meaningful composite measure that will require modification and improvement across multiple body systems with a moderate or severe baseline, you know, and without the need for escalation to background medication. So we've designed the trial to give us an answer in that population. And, you know, we saw encouraging results in that population. So what we've taken is our belief from phase II, translated it to the right design for phase III. And in that, we feel we will get a very clear answer. But we are excited about the pathway. Okay. Okay. Great, Priya. Thank you. So, you know, as you saw from what I sent you, right, there were probably five more programs that I wanted to ask about. But I think of all those in our last few minutes here, I really want to talk about the tau program. And, you know, maybe I'll give a quick preamble of our perspective, and this will help hone in our conversation. From our perspective, right, tau is an excellent target in Alzheimer's. It's a challenging target for monoclonal antibodies because it's largely intracellular. And your anti-tau ASO has shown, you know, really interesting data on tau lowering that I don't think anyone else has seen before. So that all looks great. I think the two main questions that we have here are really, one, will knocking down tau at the source be safe? So maybe you could talk about that. And two, you know, you're embarking on this kind of larger phase IIB study. You know, when we think about, you know, the scope of this program, right, is that at this point, do we just kind of have to wait, you know, two or three more years to get a real answer, or is there any sort of upside to that? Yeah. So I think overall, thanks for raising this. I think it's an underappreciated asset in our pipeline. We are very excited. It's really the hallmark, second hallmark beyond amyloid. And the preclinical data are the most direct evidence for target engagement for BIIB080, our anti-tau ASO. So we've looked at, I'm going to speak first to really what gives us confidence that knocking down tau won't be toxic. So just the current understanding of the biology of tau is that there are redundancies in the biological processes that tau participates in such that knockdown has an important impact on pathologic gain of function but not on the physiologic function. This has been published, even more recently by Chang in 2021. In mice, complete knockout of tau is tolerated, and animals are viable. To date, five different tau knockout mouse lines have been generated and phenotypically characterized. In all five lines, no overt phenotype has been reported in adult mice. But age-related older mice, or cognitive deficits have been reported in some models, suggesting that complete tau knockout on motor and cognitive function in animals is inconsistent and inconclusive. Now, moving on from that, we have access to the UK Biobank, and our translational sciences team has done extensive amounts of work on this particular question: genomic assessment of the loss of function tolerance of tau. So basically, when we look at experiments of nature that are analogous to tau knockdown, it suggests that if you have heterozygous loss of function of tau in humans, it's likely to be tolerated. And, we've seen that pharmacological downregulation of tau in an adult may not have the same effect on a potential safety trait as a long, lifelong genetic loss of function of tau. Right. In our study, in our phase 1B study, we saw about 50%, you know, 50%-60%. But we also saw a convergence, as you'll remember, of the fluid biomarkers that are representative of tau many weeks after the last dose, 16 weeks after the last dose, continuing to be sustained. We also saw reductions from all areas of the brain. And we saw an emerging clinical profile that looks like it's having an effect. So we believe, and we haven't really seen, I mean, obviously, it's been a very small study. So we haven't really seen clinical data beyond what we've shown you, you know, at CTAD and previously at, at other congresses in 2023. But we are very encouraged with where we are. Do we have to wait it out? Yes, because I think from a tau perspective, what we see internally has helped, you know, we believe this is the program to invest to lead here, invest to win, invest to lead. So it's a real priority. We are recruiting for the CELIA trial. It's a large trial. And what we really need to isolate is what's the right dose and what's the right dosing paradigm because this is intrathecally delivered. So we're looking at quarterly as well as biannually. And this is based on our understanding from the phase 1b trial. And we're looking at 3 different doses. So this is important. The primary endpoint is CDR sum of boxes at 18 months, but we'll have a lot of other secondary endpoints. And, you know, we always have, the provision for an interim. But in this case, you know, we may need to really be very deliberate to get those results and build on them. So we're looking at all the options, and we continue to evaluate it, constantly, especially in light of the emerging clinical data we saw from phase I. But I think it is going to be important to stay the course for a couple of years for sure. All right. Well, thank you very much. I appreciate all the perspective and for giving us a few extra minutes of your time, Priya. So thank you again for doing the panel this morning. And thanks, everyone, for listening. It looks like we had awesome attendance on here. And I appreciate those who sent me questions. Sorry, I didn't get to everything. But I hope you stick with us for our next broader neurology panel with Steve Paul. So thank you again, Priya. I appreciate it. And hope to see you soon. Thank you, Paul. Bye-bye.