Great. Thanks very much. This is gonna be an interesting 45-minute discussion on a number of topics within the Biogen pipeline. With me is Diana Gallagher, Head of Clinical Development, and Stephanie Fradette, Head of the Neuromuscular Development Unit. Maybe you can each just sort of briefly introduce yourselves, how long you've been at Biogen, and then we can get right into it. I think I wanted to start with maybe talking about tau, but we can cover a lot of stuff. Diana, do you wanna go first? Sure. Thanks for having us, Paul. My name is Diana Gallagher. I have several of the therapeutic areas at Biogen, the Alzheimer's, the MS, and the immunology portfolios, and I've been at Biogen almost 11 years this month. Yeah. Awesome. Hi, Stephanie Fradette. Again, thank you. Thank you for having us. I lead our Neuromuscular Development Unit, and I've essentially been at Biogen for the last 16 years, believe it or not, and really focused on our neuromuscular efforts for over the past decade. Okay, awesome. All right. Well, great to talk to you, both of you, and thank you both for taking the time. I'm super interested in this tau readout. I have followed this space for a while. We were always somewhat skeptical on the antibody approach, and it feels like the oligo approach is super interesting, not just because you can knock it down at the source, but also because your PET data shows there may be actually like a clearance mechanism for existing tau. Super, super interesting. I feel like the question, though, that, you know, everyone has when they look at this target and think about the amyloid experience is the whole correlation versus causation question. Maybe just to, like, walk through the evidence for why tau is a disease driver and not just a correlate. What do we know about tau's role in the disease process? Again, what is out there that sort of suggests that you can actually modify the disease by reducing levels of tau in the brain? Yeah. Thanks for the question. I mean, we feel, you know, quite confident that tau is an important target in Alzheimer's. It is one of the two pathological hallmarks of the disease, and the emergence of tau pathology really coincides even more closely than amyloid prevalence with the coincident cognitive decline. You know, there are lots of theories about how this works, but the idea that the amyloid comes in and deposits and then the tau is being sort of uncaged and moving through the brain, very coincident with cognitive decline, and they're sort of working in parallel is a hypothesis that, you know, is out there and one which we're really interested by. It is, as you noted, you know, a hypothesis that needs to be tested, and we think that the BIIB is a really interesting way to test that hypothesis, to establish for the first time proof of concept, right? Because the antibodies, as you mentioned, you know, have not been. You know, they've really been targeting the extracellular tau, but we believe that, you know, the best way to fully test the hypothesis is to really shut down all the isoforms and see what happens. We've been able, you know, admittedly in a small 1b to sort of show evidence that, you know, the ASO approach, the BIIB080 can do that. We see it knocked down in the CSF, we see the signal on the tau PET, and now, you know, the CELIA trial is designed to say, "Okay, if we do that, and we do it for a period of time over 18 months, what does that look like on clinical endpoint?" Highly innovative space and hopefully, you know, begin to answer the questions about that, you know, relationship between clinical endpoints and manipulating tau. Yeah. Yep. Okay, great. Maybe talk about, like, the safety of the approach. Not just the data you've seen so far obviously, like, I think is the most important, but on a theoretical level, like, what do we know about the role of tau in adult brains? Like, I think a lot of the literature on tau describes it as like maybe one quote I found was a integral cytoskeletal protein. Like, is it critical in the brain? Like, do we know that? What have you seen so far, and, like, what are the theoretical risks, if any? Right. Yeah, I think that tau does perform critical functions you know, related to structural integrity of neurons. It's never been our sort of idea that we would knock it out completely. Genomic data, however, suggests that up to 50% reduction in tau may be associated, you know, with really no gross neurological effects. We feel like we've targeted a degree of knockdown, which is sufficient to test the hypothesis and manage safety. Of course, you know, we acknowledge there's still, you know, questions here, which is why we're testing different doses and different dosing paradigms in that to really establish, you know, the safety and tolerability, that PK/PD relationship, and then ultimately with efficacy. We're definitely trying to explore lots of different elements in the CELIA study, including safety and tolerability for a BIIB080. Okay. Like, right now you feel fairly comfortable that the safety is, like, 60%. Yeah knockdown, for example? Yeah, yeah. I mean, I think that's on the range of what we saw in the one B study, you know, in the CSF. Of course, we're continuously surveilling and monitoring, you know, how the patients are doing in the trial. We have not only, you know, the main trial but, you know, a long-term open label extension. Yes, we continue as planned, and then, of course, it's ultimately the, you know, relationship between efficacy that we, you know, are waiting to read out. Yeah. Okay. As it relates to tau reduction and, like, how much reduction we need, I remember, like, intimately well, you know, the analysis you guys laid out of the aducanumab Phase 3s, right? How getting to that much bigger amyloid reduction was really the difference between having meaningful efficacy or not. In the context of that, like, do we think that this level of tau lowering is enough? Like, is there anything we can point to? Also, how do we know that maybe the tau lowering you're seeing with IT delivery is in the right areas in the brain? Maybe you could sort of speak to both of those points. Sure. I'll take the second one first, which is, are we hitting in the right regions? That has been something and was a big point of the 1B, you know, to, you know, which wasn't sort of designed to look at clinical efficacy, but really was designed to look at CSF and then, you know, examine on tau PET. We were able to see, in the 1B, reductions in tau PET across multiple areas of the brain that we believe are relevant, and that's in the public domain. Happy to send it back over if folks are interested. We do feel like we're having nice engagement there, both in the CSF and on the tau PET studies. Again, the question becomes, to your point, you know, the second question, we don't know, and that's one of the things, why this is such an exciting, interesting, you know, but really still pioneering study to say, "Okay, now how hard, you know, how much, how long, and how does that translate into efficacy?" That's something, you know, in this, as we read out top line from CELIA will help us, start to, piece together. Yeah. Yep. Okay. Makes sense. Maybe talk a little bit about the study itself, and do you feel like this study is well powered to elucidate an efficacy signal? Like, what would be the hurdle for success? Yeah. We think about this as a true proof of concept study that's gonna allow us to sort of, as you said, understand the safety and the tolerability, look at the target engagement both in the CSF and on the imaging studies, and then look at the two different dosing paradigms, and their relationship to clinical endpoints. It is out to 18 months with CDR Sum of Boxes, you know, very, as well as multiple other cognitive endpoints that we're studying. You know, we feel like we'll be able to understand those relationships that would allow us to decide, you know, how, when, if it makes sense to move to the next, the next trial. But, you know, there definitely will need to be additional evidence. This is a true proof of concept study. You know, our expectation is we'll need to continue, you know, to study this to further frame out that relationship between dose and clinical effect, as well as an expanded safety database and all the things you need to do for a registrational novel entity in a disease like this. Of course. Yeah, of course. Maybe to clarify for people listening, like, is the thought, obviously, you'd need another, like, big phase 3. But is the thought that, you know, this is a robust study where, like, the decision you make is going to be a p-value driven decision, or is it more of a qualitative whole picture decision? Does that make sense? It does make sense, and I think we really are thinking about this as a proof of concept study for internal decision-making, you know, that allows us to determine how we wanna move forward with the asset. It is not sort of intended to. It would be part of a, you know, a submission and supportive, but it's not intended to be, you know, something that we can use in the absence, you know, of other confirmatory data. We feel like to help us figure out key questions, safety, tolerability, dose, dosing paradigm, you know, it's positioned well for that. Again, as we said, we're trying to answer a lot of questions, in a field that, you know, no one's ever sort of been able to engage the target this robustly. Again, we'll know more. Right. As we start to pull down the data and see. Yeah, fair enough. Okay. You guys are evaluating every 3 months and every 6 months. Do you think every 6 months is gonna be enough to get there? Maybe talk about, like, the modeling work you've done or any data you have that I guess you have some durability data that supports this dose. I feel like that's obviously super important given the, you know, logistical challenges the uptake that IT administration could bring. Right. Yeah. It's a great question. You know, just again, coming back to it, as you sort of alluded to, we're first trying to understand this relationship between how much you need to engage the target, you know, the extent which you need to engage it to see clinical efficacy. Then that's even an additional question, for, you know, what the durability of that sort of looks like. This was really designed, you know, over 18 months with the sort of continuous, you know, dosing in these two paradigms to allow us to see is there a difference. We do have the open label extension, you know, data as well, which can help us inform what continuous sort of, you know, looking at the target, you know, knocking down the target looks like. We'll have to start to see if there's differentiation, if you know, if there's separation between those doses, what that separation looks like from a PK/PD, but then is it any different on clinical endpoints. I think will allow us to sort of determine what the rationale for dose selection would need to be, if in a future study. Yeah. Okay. Can I ask a question just like, maybe this is a little bit of like a naive question, but when you think about, like, tau PET and what tau PET is telling you about happening in the brain versus, like, the p-tau assays we have, like, 181 and 217, obviously one's in the plasma. But, like, are those getting at the same change in the underlying subtypes of tau, or could they be telling us, like, sort of different things about what's happening in the brain? Yeah, I think it's a great question, and I think we're still sort of understanding the relationship between the peripheral biomarkers and how much they're reflecting, you know, amyloid and tau sort of burden. We feel like the reason we're looking at the CSF, and we're looking at the tau PET, is to really see in the organ, you know, of interest being the brain, you know, really characterizing that pharmacodynamic activity, and understanding that pathology as best we can, neuropathology with imaging, what that looks like on clinical endpoints. It took a long time to get there with, you know, amyloid therapies, sort of understanding ultimately the relationship between, you know, central amyloid reduction, you know, and clinical endpoints and how we're, you know, bridging that back to plasma-based biomarkers. I think we're still at the, you know, earlier part of that journey, but hopefully we'll get there, but we're really relying on the CSF and the imaging. We'll continue to augment, of course, with the blood-based biomarkers. Okay. Chris Viehbacher has talked about Biogen having a backup non-IT administered tau pipeline asset. At a session I hosted with him and some investors, he talked about, like, that being a super important part of the strategy here and sort of making sure that that was lined up ahead of this data readout, you know, in this chance that this is positive that you can move forward with something like that. What else can you say about this candidate you guys have in your pipeline? And if this Phase 2 study is positive, like, how ready to go is this asset? Yeah. I think just as you said, taking a step back, Chris articulated it, and I'll just reinforce, you know, that as a company, we're very focused on sort of answering these questions and, you know, improving the patient experience across our portfolio. This is really exciting what we're doing, you know, and assessing here with the data, but we are also working on next gen platforms across different tissue types, including the CNS, and they are preclinical programs, so we're not able to say too much more at this point, but hopefully can share more in the future. It's definitely a big focus for us as we think about not just do we get the right target, you know, and we're bringing it to the right patients, but, you know, are we doing it in a way that is the best modality and the most convenient and efficacious way for them. Okay. Are you able to answer if this would be something like that's with the same ASO, but like a conjugate, or if it would be like a different candidate entirely? Yeah. I think we'll share more data, you know, as we move it further in the pipeline. Yeah. Okay. All right. We'll have to wait and see. All right. Well, in the meantime, I wanna talk about one more Alzheimer's topic, and then maybe we can ask you, Steph, some questions on the muscle side. But on Alzheimer's, right, there's obviously also a ton of anticipation around the pre-symptomatic studies. And we'll get the TB-3 readout likely before the AHEAD 3-45 readout. I think, you know, one of the major questions if TB-3, you know, hopefully is positive, right, is sort of what is the implied read-through onto the lecanemab pre-symptomatic study. Maybe talk about the design of your trial, like the thought process behind patient selection. And, you know, when we get the data from Lilly, what, how will you interpret the read-throughs onto the probability of success for your own trial? Right. We definitely, you know, are interested and see the potential for anti-amyloid therapies in pre-symptomatic Alzheimer's as a significant opportunity and feel like the AHEAD 3-45 study is really well-positioned to answer the question on early intervention. You know, this collaboration with Eisai, you know, on this trial is really designed to study a broad spectrum of truly pre-symptomatic patients. Just to sort of walk through it, the A45 is looking at patients with an amyloid burden, you know, greater than 40 centiloids and is trying to determine if Leqembi can prevent cognitive decline in these, quote, low plaque level patients, right? Clinically, you know, don't have evidence, you know, of cognitive decline, but definitely have the presence of amyloid at this level. It's using a validated endpoint, the PACC5, which has demonstrated sensitivity to detect cognitive changes, you know, in patients like this. Different than CDR Sum of Boxes and, you know, we're hopeful that we'll be able to detect that treatment effect, even though we're going out four years, you know, it is a more nuanced, you know, in early disease and with progression being slow, but still happening, we wanna be able to detect that. That allows us to look at that sort of, you know, low amyloid level. We have AHEAD 3, which is even lower, so 20-30 Centiloids, and looking at further accumulation of plaque. Really, can we sort of attenuate accumulation? If we can attenuate accumulation in AHEAD 3, then we start to say, "Hey, we're looking at both amyloid accumulation at low levels as well as preventing cognitive decline." It's a pretty powerful data set to bring to bear about you know, what an anti-amyloid therapy can do in this pre-symptomatic group over 4 years. It takes a lot of data, you know, to see what's possible here. It's a big investment. I think TRAILBLAZER-ALZ 3 is designed differently, but also really interesting. It has, based on what we can see in the public domain, a little bit more of a skew towards sort of pre-symptomatic, you know, or kind of right sort of at that tipping point, not quite as early as ours. I think we'll be answering different questions. If it works, first of all, great for patients and families who, you know, feel like. Steph and I go to meetings all the time where people, particularly with familial, you know, forms, are like, "I want. I know what's happening. Like, I wanna get on a therapy." This is like a ticking time bomb. I think that will be good, but it won't answer quite the scope, you know, and the breadth at TRAILBLAZER-ALZ 3. Positive readout, I think, reads through. A quote-unquote negative we'd have to examine and then also say, "Hey, we have a different data set," you know, possibly different endpoints, as well as different inclusion criteria. We feel like that's a really robust study to answer the questions we've designed. Yeah. Yep. Okay. That's great. We saw a 30% disease slowing in the early MCI population for lecanemab and donanemab, and obviously that varies a little bit based on the cut. You know, how are you thinking about what a realistic effect size might be in pre-symptomatic? Like, what's the evidence for this to be a bigger effect and, you know, have you powered the study assuming a bigger effect? Like, what's your confidence level there? Yeah. You know, you're right in the sense that supported by phase 3 data from a low and no tau group, which suggests like the earlier you go, you know, in disease, you might see a bigger treatment effect. Of course, no one's ever designed it exactly like we've designed AHEAD 3-45. You have different burdens of amyloid, and it's gonna be impossible to make. We literally can't compare like sort of pre-symptomatic and symptomatic of what's gonna happen. We have to run the trial. We do see in the low and no tau subgroup, so in the populations that, you know, we feel like are earlier in disease progression, in the long-term extension, you know, 70% of patients, you know, have had no cognitive decline, and 50% of patients have shown even some improvement versus baseline at 4 years with continuous lecanemab. So again, we'll have to test it in AHEAD 3-45, but it's this idea coming from the open label extensions and other supportive data that the earlier you go, the more likely, you know, you could be to see a more dramatic attenuation or even holy grail. So we'll see it when we see it, you know, prevention of cognitive decline. We can only extrapolate, you know, from that existing data and look at the slightly earlier groups, but they're not. I don't wanna say they're comparable to how early, you know, AHEAD 3-45 is. Yeah. Okay. Okay. I guess with TRAILBLAZER-ALZ 3, it being set up as being event-driven, it's maybe like more intuitive that they could make a claim around like, you know, a relative risk reduction on the proportion of patients that progress to like a more clinical Alzheimer's phenotype. Would you, if AHEAD 3-45 is positive, be able to make the same type of claim or the same types of, like, data cuts that would be, you know, obviously helpful from like a marketing and digestibility perspective? Yeah, I think it's a great question. We'll, you know, obviously look at all the data that they generate, and we're also collecting a really extensive amount of both biomarker as well as, you know, clinical data. I think we will have different subsets of patients all the way from the sort of above 40, you know, and then down to that 20 to 30. I think that's possible. We will have 4 years of data, which will be a pretty robust, you know, set of analysis to look at. I don't wanna, you know, speculate before we see anything, but I think we're very happy with the way we've designed it, which allows us to characterize the treatment effect. Okay. That date is 2028, correct? Yes. Okay, maybe last question on Alzheimer's, but just from like a logistical and treatment capacity perspective, you know, I think the cynical view on pre-symptomatic is something like, you know, it's been super challenging to even get to a high treatment rate of the symptomatic population, right? Like, is the world even ready to start trying to treat pre-symptomatic patients from both a bandwidth perspective, a diagnosis perspective, like an insurance perspective? Like, what would you say to that? Like, how do you think about this as sort of an addressable commercial opportunity from a pragmatic perspective? Yeah, it's a great question. I think what's exciting is the world, you know, is changing, and we're seeing it happen like even in real-time. There are key enablers that are gonna need to be implemented, you know, for that, you know, to happen. I think you're starting to see what would they be. Blood-based biomarkers, diagnostics will be important, right, to make a diagnosis. Even in regions where there's a lot of access to neurologists as well as imaging studies, you know, it still takes time for patients to sort of, you know, move through the funnel. The majority of neurologists are using blood tests now to at least, you know, they're starting to get comfortable with them and then go to confirmatory imaging studies. We start to see like how comfortable people will get with that. Can they get comfortable with blood-based biomarkers alone? You know, as we move, we're starting to imagine a scenario where, you know, that could happen. There may even be a scenario where amyloid testing at or after a certain age will become part of a panel, right? Yeah. People will start to look at what's your accumulation over time look like and in conjunction with other potential risk factors that you have and sort of monitoring you for that. The more data we collect and understand in natural history studies, the more comfort we'll gain around, you know, time to intervention. I think that diagnostic piece is really huge. We know even in the AHEAD 3-45 study by implementing blood-based biomarkers as a screening event before confirmatory, you know, imaging, you reduce by 50% the screen fail rate. It is feasible. Then the sub-Q would be the other part that, you know, a route of administration for at home use will also be. Sort of, I think those are factors that may allow primary care doctors to play a bigger role 'cause we can't load this all onto the neurology community. We need an easier way to sort of make the path easier for PCPs too. Right. Okay. All makes sense. Great. All right, Steph, thanks for being patient here. I appreciate you joining. Yeah, I mean, obviously a topical time for your group as well with salanersen and high-dose Spinraza. Do you wanna maybe just kinda level set and talk about some of the MDA presentations for salanersen, and then we can talk more about sort of positioning and next steps there? Sure. Absolutely. Just to take a quick step back, salanersen is an investigational ASO. It was designed with novel ASO chemistry that's really designed to increase potency, and that allows us, you know, to target optimization of efficacy, but doing so with once-yearly dosing, which is obviously a huge advancement for the field if successful. We were able to present data from our phase 1b study. I get a lot of questions about why did we design this phase 1b study the way that we did? Obviously, designing a phase 1 study for an investigational therapy in a landscape that's relatively crowded and has effective therapies available, we had to make choices. This particular study was designed or run in individuals that had received gene therapy, and they had received that gene therapy at least 6 months prior to enrollment in the trial, and they were perceived to have suboptimal clinical status per their investigator. There was clear clinical evidence for, you know, unmet need, the potential for additional efficacy. This, of course, wasn't a powered efficacy study. We really were focused on looking at safety, pharmacokinetics, and then looking at both biomarker and clinical outcomes in a more of an exploratory way. The study enrolled two age groups, 6-month- to 2-year-olds and a 2- to 12-year-old cohort, and we looked at two different doses. We looked at both a 40 mg and an 80 mg dose. Really a number of different cohorts there, and the total N was 24. Sort of the new news that we presented last week was that we now had at least a year of follow-up in all 24 of those participants. We were able to sort of take away a couple of different things. First and foremost, both the 40 and 80 milligram doses were considered generally well-tolerated, and you know, both plausible for moving forward into phase 3. Of course, we were looking again at pharmacokinetics across those doses. But interestingly, we learned quite a bit, perhaps more than we even expected, with regards to the biomarker and clinical outcome data. We saw that consistent with the fact that these individuals had suboptimal clinical status, they also had elevated neurofilament levels. In the good majority of these patients, they came in with levels of Neurofilament that exceeded what we would expect, both in an untreated and treated population of SMA. Again, consistent with sort of the active neurodegeneration that we'd be expecting in this population. Once we were able to initiate salanersen, we were able to bring those levels down rapidly and sustain those reduced levels of Neurofilament over time. Then on the clinical outcome side, again, we're It's a heterogeneous population, but what we're seeing is in many of these cases, these infants and children, I should say, we literally wouldn't be expecting to see continued improvement or attainment of novel new developmental milestones because in some cases, they had been, for example, five years out from receiving gene therapy, and once salanersen was initiated in these children, in many cases, they were able to actually achieve a new milestone. You know, taking a step back, this gives us confidence that salanersen has the potential to be a differentiated therapy in the SMA landscape and gives us a lot of confidence in moving ahead with these Phase 3 studies. It really has informed the design of these Phase 3 trials, and we're looking forward to getting them off the ground. Okay. Great. At this point, do you think salanersen is clearly more effective than Spinraza or even high-dose Spinraza, or is that, is the jury still out there? Like, obviously, once annual is a huge advantage unto itself, but how are you thinking about the other piece of the puzzle? Yeah. To that point, the goal of salanersen, of course, less frequent dosing is important, but we can't sacrifice efficacy. Efficacy is front and center in the minds of clinicians and families in the SMA world right now. While I can't say anything definitively, we haven't run, you know, a direct head-to-head experiment, what I will say is it's designed to achieve concentrations and efficacy consistent with the high-dose Spinraza. We're really trying to maximize efficacy while also spreading out that dosing interval with this program. We have, you know, more to learn in the Phase 3 setting, but I think the early signals tell us that it's doing something unique and time will tell. Okay. Do you wanna talk about the design of that Phase 3 study? I guess the SMA, you know, the world has really changed a lot since the Spinraza pivotal studies were conducted. I guess maybe talk about the design, and then, like, when that study reads out, like, is it going to be clearly comparable, where we're gonna be able to answer the question around similar or better efficacy to the standard of care? Yeah. There are three Phase 3 studies that we've announced and provided detail on over the last week. The heart of all of this is the pivotal STELLAR-1 study. This is a trial that we're conducting in treatment-naive presymptomatic infants with two or three SMN2 copies. What we're basically looking at is, are they able to achieve key milestones, sitting in the two-copy population and walking in the three-copy population within normal development timelines. You know, this is a study that we will look to establish salanersen's effectiveness as a monotherapy. We are also running a supportive STELLAR-2 study, and this study will enroll individuals that received gene therapy presymptomatically. Six months later, they're randomized to either receive salanersen or sham control. Again here, it's different than what we did in phase one, where these patients had overt evidence of suboptimal clinical status. Here, irrespective of that, we're going to be able to look to see if you are, you know, initiating salanersen in that population, what's happening. Putting those two studies together, we'll be able to look at monotherapy salanersen relative to monotherapy gene therapy, relative to the initiation of gene therapy followed by salanersen in a presymptomatic population. This is really important as we think about the future sort of future treatment decisions for the infant population in particular. Then on the other side of the coin, we have a study called SOLAR that's going to be conducted in teens and adults, and this is a study that will involve both treatment naive and risdiplam-treated individuals. 60 treatment naive, 30 that are switching over from risdiplam. Though I will say after spending the week with the SMA community both at MDA and SMA Europe last week, we're getting a lot of push to increase the size of that risdiplam-treated cohort. There's a lot of excitement about understanding that specific population. That will help us understand again, you know, the broad spectrum of SMA individuals, both treated, untreated, and across the different age groups and phenotypes to really help us understand the positioning of salanersen in the future landscape. Yeah. Okay. Got it. Makes sense. Maybe in the context of this, do you wanna talk about the high-dose Spinraza program and just in general, like how does that fit into the not just the treatment paradigm in kind of the near to midterm, but like the overall portfolio that you're building over the long term in SMA? Yeah. I would say that, we're lucky with Spinraza because it's the only therapy that has the opportunity to optimize, you know, that we have the opportunity to optimize, I should say. We started the development of this high-dose regimen several years ago, and really this is our step into a next era of treatment in SMA. I think we're just now as a field coming around to the fact that while the first generation of therapies has done a tremendous amount, it's completely changed the trajectory of SMA. There's still a great deal of unmet need. While, you know, treating an infant presymptomatically may allow that infant to walk, which is, you know, was completely unheard of 10 years ago when we were having conversations, their gait may not be, and in many cases is not normal. We know that there's clear unmet need. We know that there's an urgency to treat. We hear a lot of clinicians say, "I don't want to look back 10 years from now and wish that I had done something different." We know we only get one pool of motor neurons for life, and we're sort of consolidating all of the tools that we have that tell us about the health of those motor neurons so that we can act today to try to, you know, achieve better outcomes tomorrow, and high-dose Spinraza is a huge part of that. We're working to try to get high-dose Spinraza, you know, to people living with SMA around the world. Ultimately we would anticipate that many of those individuals would choose to transition over to salanersen if and when it is approved and available. Yeah. Yep. Okay. Great. All right. Well, maybe in the last 10 minutes you're here, we can just cover, you know, the litifilimab readout and maybe a quick other question on DAPI and Celsa. You know, starting with the litifilimab data, which is coming soon, Diana. Maybe I'll ask you like a totally loaded question and hear your response. Like I think on the investor community, there's like people have become just enamored with how challenging lupus can be and how you can have these Phase 2 datasets that look promising, and then the Phase 3 doesn't replicate. I think in the context of that, when I get questions from investors on litifilimab, it's like it looks like the drug's active, but the P values are not point oh one. They're kind of closer, and then the endpoint in the Phase 3 is changed. Just in like the backdrop of that, maybe help us make sense of the phase 2 data and like how confident can we be going into this Phase 3 study? Like is this the kind of study you feel like this is fairly de-risked, and like we understand it's overpowered, or are we still in that gray zone where we're trying to fully prove out that this drug, you know, works as well as we hope? Sure. Great questions. I think it kind of falls into two different pieces, like asset and then sort of lupus drug development and execution. Maybe I'll sort of start from the asset standpoint. You know, we know that manipulating BDCA2 has been a target. You know, it's a homegrown molecule. We've been very interested in it for a long time. Like it's been. We have a deep understanding, you know, of this mechanism and manipulating that PDC biology all the way from a skin study. You know, 1B, really beautiful, heavy biomarker, 1B study that we did. Then that gave us the confidence to move into the proof of concept studies, which are, you know, the back-to-back papers in New England. There we were really. It's been methodical all along the way, right? There we're really showing on the SLE side what impact, you know, does this formerly BIIB059 or now litifilimab, what does litifilimab do on skin and joint effects in patients with lupus? You saw that there, you know, reduction, you know, in tender, swollen joints as well as improvement on multiple skin metrics as well as SRI-4. That was a proof of concept study. It was not designed or powered to be as big, you know, as what you'll need to do for a Phase 3 study, but it gave us the confidence to move into a Phase 3 study. Remember, we're doing 2 Phase 3 studies. We're going from that proof of concept study to then power 2,540 patients each SLE trials. Definitely the ability to answer the question, you know, with the replicate SLE studies powered for SRI-4, I think, you know, we feel good about. It did require, and as it should, to go from POC to phase three, you know, really expanding that. Then, as you say, people have POC, and they go to phase three. What do you do differently? I think, first of all, right target, which we feel like we have. Second, right patients. You know, you really have to rigorously look at those inclusion/exclusion criteria and make sure you're putting the right patients in. Lupus is a complicated, really heterogeneous disease. Right really ensuring that. How do you do that to try to homogenize the population? Yeah. I think it's about looking at, you know, ensuring patients who have active disease activity despite standard of care, right? You really don't want the mildest, you know, form, like the early. Okay You know, tiny bit of rash. Are we really sure they have lupus to begin with? We really have worked very hard to get the right patient population in there. It's diligent execution. I mean. You know, we've learned a lot in the past decade ourselves as well as the field, what it takes to run global trials, the level of adjudication, you know, that it's required, the level of training at multiple sites to help ensure, you know, that we're, you know, sort of enrolling the right patients and then collecting the data really, you know, judiciously. You know, I would just say, you know, we feel, you know, the Phase 2 results were in both SLE and CLE, you know, quite robust, allowing us to make this decision to go forward in CLE. Just let me say one thing about SLE. I don't think of it as changing the endpoint because the POC wasn't powered or designed to hit on SRI-4, but we collected SRI-4. Right The primary in the replicate Phase 3s. In CLE, you know, it's that CLASI endpoint, and that's something we've worked, you know, incredibly, you know, hard on looking at those effect sizes. You know, you see it in the New England paper, you know, and we're about to share new data on the phase 2 portion of the AMETHYST CLE trial. We're also in that Phase 2, 3 for CLE as a late breaker at AAD at the end of this month. This idea, are we, you know, manipulating the biology with levofilimab? We feel like we are. We're excited to hopefully get registrational data, you know, at the end of this year on SLE followed by CLE. Hope that helped. Okay. Okay, great. No, that was awesome. Okay, fantastic. For DAPI. All right. I'm gonna go quick. DAPI, I can jump to that quickly. I mean, their first phase three, one of only the third positive phase threes, you know, that we've seen in SLE. I think there's a lot of. We didn't see the dose response, you know, in an MCP-Mod. Like, you know the way the dose response in the phase two, but we learned from that DAPI phase two, you know, adjusted in phase three, executed against phase three, hit the primary endpoint, as well as have multiple, you know, evidence of supporting data of what matters to patients beyond BICLA or SRI-4, which are these composite endpoints. We saw meaningful tapering of steroids. We saw reduction in flares. We saw fatigue improvements in fatigue, which really is important to patients. They deal with a lot in lupus, but if you ask them, you know, like, what's one of the most debilitating, you know, symptoms, they say this just absolutely profound fatigue. Seeing that, you know, consolidated effect by manipulating CD40 biology, you know, suggests to us we're really having significant, you know, multisystem impact in lupus with the CD40 pathway. Yep. Yep. Okay, great. For CD40, like, can you talk a little bit about there's this sort of safety history here, with, I believe, a subtly different approach. Remind me if it's either receptor or ligand, but, like, what's the context there, and what's your level of confidence that the TI for DAPI is wide and you're not gonna run into this? You're right. Historically, the first generation of the CD40 ligand, you know, molecules were. They had an Fc Fab fragment that was believed to be the causative for platelet activation and aggregation, which led to clots and thromboses and negative events. Our DAPI is designed specifically and engineered with an Fc-silent Fab fragment. That was always top of mind for us, particularly because lupus patients do have increased risk of clotting just as part of their underlying disease biology. We engineered that completely out, and so it's a heavily pegylated molecule that allows us, you know, with a Fc-silent Fab fragment. Based on the safety, you know, and tolerability that we've seen so far, appears quite differentiated from first gen, in terms of any risks of that clotting above and beyond what is endogenous to the disease. Yeah. Okay. Okay, great. You know, I still have a list of a few other things I wanted to ask, but I'll kick one last one. Felza. Okay. Three indications, right, that you talked about AMR, IgAN, PMN. How would you rank order where you're most enthusiastic, not just in terms of probability of success, but, you know, probability of having, like, a truly differentiated product in an area of unmet need? Yeah. I think you're right. One, a fun thing about Felza within immunology in general when you go after is multiple, you know, a pipeline and a product. I think we're excited about multiple aspects. As you said, we see that antibody-mediated rejection as a really exciting and interesting sort of sea change for patients who are immediately, you know, go through, have renal failure, then end up getting a transplant, then have their transplant rejecting, sometimes pretty, you know, within 6 months. That proof of concept data that we generated where you basically, you know, initiate the therapy, and you can see this profound. You know, you're already in antibody-mediated rejection, and we can resolve that is really pretty exciting. That's an opportunity that's probably underappreciated. 11,000 patients in the U.S. who, you know, have AMR six months after, you know, a transplant, and we saw 80% resolution, you know, at six months in the Phase 2. Obviously we, you know, we're in the Phase 3. We need to sort of replicate that, but that's quite exciting. Then in terms of other drivers, you're right. The, the opportunity in IgAN, you know, is also, I think, really exciting. We have the potential to bring a differentiated approach where you sort of come upfront with this therapy, and then you potentially have these holidays, which again is really meaningful for patients, to have these opportunity. You know, patients always want as much medicine as they need and no more. Sort of fix me, and then, you know- Right Can I get a break? That's a really interesting paradigm shift there for IgAN. We know it's a crowded space, but there's a lot of unmet need. Then, of course, membranous nephritis, you know, is another really debilitating condition. If we can bring something, particularly if people after first line need to, you know, go to another one, I think it's exciting. It's all three, each for different reasons, but I would say that having three Phase 3s with this asset, it positions us really nicely to move forward. Yep. Yep. Okay. Great. Well, I know we could have talked about a lot more, but I really appreciate you both taking the time, and we got through a lot of topics and interesting details. Thank you so much, and thanks everyone for dialing in and listening. Thank you, Paul. Thanks, Paul, for having us. Great