Biogen Inc. ($BIIB)

Great. Thanks very much. This is going to 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 just you can each of you 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. So Diana, do you want to go first?

Sure. Thanks for having us, Paul. So my name is Diana Gallagher. I have several of the therapeutic areas of Biogen, so the Alzheimer's, the MS and the immunology portfolios, and I've been at Biogen almost 11 years this month, yes.

Awesome.

And Steph 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. So yes, so 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. So super, super interesting. I feel like the question though, that everyone has when they look at this target and think about the amyloid experience is the whole correlation first causation question. So 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? And again, what is out there that sort of suggests that you can actually modify the disease by reducing levels of tau in the brain?

Yes. Thanks for the question. I mean we feel quite confident that tau is an important target in Alzheimer's. It is 1 of the 2 pathological hallmarks of the disease. And the emergence of tau pathology really coincides even more closely than amyloid prevalence with the coincident cognitive decline. So 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 is out there and one which we're really interested by. It is, as you noted, a hypothesis that needs to be tested. And we think that the baby 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, have not been able -- they've really been targeting the extracellular tau, but we believe that the best way to fully test the hypothesis to really shut down all the isoforms and see what happens. And we've been able admittedly a small 1b to sort of show evidence that the ASO approach, the MAPT ASO can do that. We see it knockdown in the CSF. We see the signal on the tau PET. And now the CELIA trial is designed to say, okay, if we do that, we do it for a period of time over 18 months, what does that look like on clinical endpoints? So highly innovative space and hopefully begin to answer the questions about that relationship between clinical endpoints and manipulating tau.

Yes. Okay. Great. Maybe talk about like the safety of the approach, not just like 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 in tau describes it as like maybe one quote I found was an 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. So yes, I think that tau does perform critical functions related to structural integrity of neurons. And so 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 with really no gross neurological effects. So we feel like we've targeted a degree of knockdown, which is sufficient to test the hypothesis and manage safety. Of course, we acknowledge there's still questions there, which is why we're testing different doses and different dosing paradigms in that to really establish the safety and tolerability, that PK/PD relationship and then ultimately with efficacy. So we're definitely trying to explore lots of different elements in the CELIA study, including safety and tolerability for MAPT ASO...

Okay. But like right now, you feel fairly comfortable about the safety of like 60% knockdown, for example?

Yes, yes. I mean I think that's on the range of what we saw in the Ib study in the CSF. And so of course, we're continuously surveilling and monitoring how the patients are doing in the trial. And so we have not only the main trial, but a long-term open-label extension. And so yes, we continue as planned. And then, of course, it's ultimately that relationship between efficacy that we are waiting to read out.

Yes. Okay. As it relates to tau reduction and like how much reduction we need, I remember like intimately well, the analysis you guys laid out of the aducanumab Phase IIIs, right, and 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? And also, how do we know that maybe the tau lowering you're seeing with IT delivery is in the right areas of the brain. So 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. And so that has been something and was a big point of the Ib to -- which wasn't sort of designed to look at clinical efficacy, but really was designed to look at CSF and then examine on tau PET. And so we were able to see in the Ib 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. But 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, the second question, we don't know, and that's one of the things why this is such an exciting, interesting, but really still pioneering study to say, okay, now how hard, how much, how long and how does that translate into efficacy? And so that's something in this -- as we read out top line from CELIA will help us start to piece together.

Yes. Yes. 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?

Yes. So we think about this as a true proof-of-concept study that's going to 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 2 different dosing paradigms and their relationship to clinical endpoints. So it is out to 18 months with CDR sum of boxes, very -- as well as multiple other cognitive endpoints that we're studying. So we feel like we'll be able to understand those relationships that would allow us to decide how, when, if it makes sense to move to the next trial. But there definitely will need to be additional evidence. This is a proof-of-concept study. And so our expectation is we'll need to continue 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. Yes, of course. Maybe to clarify for people listening, like is the thought -- obviously, the thought would be you'd need another like big Phase III. But is the thought that 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 that allows us to determine how we want to move forward with the asset. It is not sort of intended to -- and it would be part of a submission and supportive, but it's not intended to be something that we can use in the absence of other confirmatory data. So we feel like to help us figure out key questions, safety, tolerability, dose dosing paradigm, it's positioned well for that. But again, as we said, we're trying to answer a lot of questions in a field that no one's ever sort of been able to engage the target this robustly. So we'll know more as we start to pull down the data and see.

Yes, fair enough. Okay. You guys are evaluating every 3 months and every 6 months. Do you think every 6 months is going to 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 logistical challenges to uptake that IT administration could bring.

Right. Yes, it's a great question. And 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, the extent which you need to engage it to see clinical efficacy. And then that's even an additional question for what the durability of that sort of looks like. So this was really designed over 18 months with the sort of continuous dosing in these 2 paradigms to allow us to see, is there a difference? And we do have the open-label extension data as well, which can help us inform what continuous sort of looking at the target, knocking down the target looks like. And we'll have to start to see if there's differentiation, if there's separation between those doses, what that separation looks like from a PK/PD, but then is there any different clinical endpoints, I think will allow us to sort of determine what the rationale for dose selection would need to be in a future study.

Yes. 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, ones 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?

Yes, 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 amyloid and tau sort of burden. So 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 of interest being the brain, really characterizing that pharmacodynamic activity and understanding that pathology as best we can, neuropathology with imaging, what that looks like on clinical endpoints. And then it took a long time to get there with amyloid therapies, sort of understanding ultimately the relationship between centiloid reduction and clinical endpoints and how we're bridging that back to plasma-based biomarkers. I think we're still at the earlier part of that journey, but hopefully, we'll get there, but we really are relying on the CSF and the imaging. And then we'll continue to augment, of course, with the blood-based biomarkers.

Right. Okay. 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 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 II study is positive, like how ready to go is this asset?

Yes. I think just as you said, taking a step back, Chris articulated it, and I'll just reinforce that as a company, we're very focused on sort of answering these questions and improving the patient experience across our portfolio. So this is really exciting what we're doing and assessing here with BIIB080, 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, but it's definitely a big focus for us as we think about not just do we get the right target and bring it to the right patients, but are we doing it in a way that is the best modality and the most convenient and efficacious way for them.

Okay. Can you -- 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?

Yes. I think we'll share more data as we move it further in the pipeline. Yes.

Okay. Okay. All right. We'll have to wait and see. All right. Well, in the meantime, I want to 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 presymptomatic studies, and we'll get the TB3 readout likely before the AHEAD 3-45 readout. So I think one of the major questions of TB3 hopefully is positive, right, is sort of what is the implied read-through onto the lecanemab presymptomatic study. So maybe talk about the design of your trial, like the thought process behind patient selection. And when we get the data from Lilly, what -- how will you interpret the read-throughs on to the probability of success for your own trial?

Right. So we definitely are interested and see the potential for anti-amyloid therapies in presymptomatic 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. This collaboration with Eisai on this trial is really designed to study a broad spectrum of truly presymptomatic patients. So just to sort of walk through it, the AHEAD 3-45 is looking at patients with an amyloid burden greater than 40 centiloids and is trying to determine if LEQEMBI can prevent cognitive decline in these "low plaque level patients," right? So clinically don't have evidence of cognitive decline, but definitely have the presence of amyloid at this level. And it's using a validated endpoint, the PACC-5, which has demonstrated sensitivity to detect cognitive changes in patients like this. So different than CBR Sum of Boxes, and we're hopeful that we'll be able -- because detecting that treatment effect, even though we're going out 4 years, it is a more nuanced in early disease and with progression being slow, but still happening, we want to be able to detect that. So that allows us to look at that sort of low amyloid level. And then we have AHEAD 3-45, which is even lower, so 20 to 30 centiloids and looking at further accumulation of plaque. So really can we sort of attenuate accumulation. And then if we can attenuate accumulation in AHEAD 3-45, 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 what an anti-amyloid therapy can do in this presymptomatic group over 4 years. So it takes a lot of data to see what's possible here. So it's a big investment. I think TB3 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 presymptomatic or kind of right sort of at that tipping point, not quite as early as ours. So I think we'll be answering different questions. If it works, first of all, great for patients and families who feel like -- and Steph and I go to meetings all the time where people, particularly with familial forms are like, I want -- I know what's happening, like I want to get on a therapy. This is like a ticking time bomb. So I think this allows us -- that will be good, but it won't answer quite the scope and the breadth that TB3. So positive readout, I think, reads through. "negative" we have to examine and then also say, hey, we have a different data set, possibly different endpoints as well as different inclusion criteria. So we feel like that's a really robust study to answer the questions we've designed.

Yes. Okay. That's great. So we saw a 30% disease slowing about in the early MCI population for lecanemab and donanemab. And obviously, that varies a little bit based on the cut. But how are you thinking about what a realistic effect size might be in presymptomatic? Like what's the evidence for this to be a bigger effect? And have you powered the study assuming a bigger effect? Like what's your confidence level there?

Yes. You're right in the sense that supported by Phase III data from a low and no tau group, which suggests like the earlier you go in disease, you might see a bigger treatment effect. And of course, no one's ever designed it exactly like we've designed AHEAD 3-45. So you have different burdens of amyloid and it's going to be impossible to make it -- we literally can't compare like sort of presymptomatic and symptomatic of what's going to happen. We have to run the trial. But we do see in the low and no tau subgroups, so in the populations that we feel like are earlier in disease progression in the long-term extension, 70% of patients have had no cognitive decline and 50% of patients have shown even some improvement at the -- versus baseline at 4 years with continuous lecanemab. So again, we'll have to test it in the 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 could be to see a more dramatic attenuation or even holy grail. So we'll see it when we see prevention of cognitive decline. So we can only extrapolate from that existing data and look at the slightly earlier groups, but they're not -- I don't want to say they're comparable to how early AHEAD 3-45 is.

Yes. Okay. Okay. I guess with TB3 is being set up as being event-driven, it's maybe like more intuitive that they could make a claim around like a relative risk reduction on the proportion of patients that progress to like a more clinical Alzheimer's phenotype. Would you -- if the AHEAD 3-45 is positive, would you be able to make the same type of claim or the same types of like data cuts that would be obviously helpful from like a marketing and digestibility perspective?

Yes. I think it's a great question. It's -- we'll obviously look at all the data that they generate, and we are also collecting a really extensive amount of both biomarker as well as clinical data. So I think -- and we will have different subsets of patients in all the way from the sort of above 40 and then down to that 20 to 30. So I think that that's possible. And we will have 4 years of data, which will be a pretty robust set of analysis to look at. So I don't want to 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. Okay. And that data is 2028, correct?

Yes.

Okay. Okay. Maybe last question on Alzheimer's, but just from like a logistical and treatment capacity perspective, I think the cynical view on presymptomatic is something like 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 presymptomatic 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?

Yes, it's a great question. And I think what's exciting is the world is changing, and we're seeing it happen like even in real time. So there are key enablers that are going to need to be implemented for that to happen. And 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, it still takes time for patients to sort of move through the funnel. And so the majority of neurologists are using blood tests now to at least -- they're starting to get comfortable with them and then go to confirmatory imaging studies. And we start to see like how comfortable people will get with that? Can they get comfortable with blood-based biomarkers alone as a move, we're starting to imagine a scenario where that could happen. There may even be a scenario where it starts to amyloid testing at or after a certain age will become part of a panel, right? You start to look at what's your accumulation over time look like in conjunction with other potential risk factors that you have and sort of monitoring you for that. And the more data we collect and understand in natural history studies, the more comfort we will gain around time to intervention. So 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 imaging, you reduce by 50% the screen fill rate. So it is feasible. And then the subcu would be the other part that a route of administration for at-home use will also be. And sort of -- I think those are factors that may allow primary care doctors to play a bigger role because we can't load this all on to 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. But I appreciate you joining. So yes, I mean, obviously, a topical time for your group as well with salanersen and high-dose SPINRAZA. Do you want to maybe just kind of 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?

Absolutely. So 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 to target optimization of efficacy, but doing so with once yearly dosing, which is obviously a huge advancement for the field if successful. And we were able to present data from our Phase Ib study. I get a lot of questions about why did we design this Phase Ib study the way that we did. Obviously, designing a Phase I study for an investigational therapy in a landscape that's relatively crowded and has effective therapies available, we had to make choices. So 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 for their investigator. And so there was clear clinical evidence for 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. And so the study enrolled 2 age groups, 6-month to 2-year olds and a 2- to 12-year-old cohort, and we looked at 2 different doses. So we looked at both a 40-milligram and an 80-milligram dose. And so really a number of different cohorts there and the total end was 24. And 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. And so 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 both plausible for moving forward into Phase III. Of course, we were looking again at pharmacokinetics across those doses. But interestingly, we've 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. So 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. And so again, consistent with sort of the active neurodegeneration that we'd be expecting in this population. And 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. And 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 really wouldn't be expecting to see continued improvement or attainment of novel new WHO milestones because in some cases, they had been, for example, 5 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. And so 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 III studies, it really has informed the design of these Phase III 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?

Yes. And 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. And so while I can't say anything definitively, we haven't run 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. So we're really trying to maximize efficacy while also spreading out that dosing interval with this program. So we have more to learn in the Phase III setting, but I think the early signals tell us that it's doing something unique and time will tell.

Okay. Do you want to talk about the design of that Phase III study? And I guess the SMA -- the world has really changed a lot since the SPINRAZA pivotal studies were conducted. So 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 going to be able to answer the question around similar or better efficacy than the standard of care?

Yes. So there are 3 Phase III studies that we've announced and provided detail on over the last week. The heart of all of this is the pivotal. So it's the STELLAR-1 study. This is a trial that we're conducting in treatment-naive presymptomatic infants with 2 or 3 SMN2 copies. And what we're basically looking at is are they able to achieve key milestones, so sitting in the 2 copy population and walking in the 3 copy population within normal development time lines. And so we're really trying to -- this is a study that we will look to, to establish salanersen's sort of effectiveness as a monotherapy. We are also running a supportive STELLAR-2 study, and this study will enroll individuals that received gene therapy pre-symptomatically. And 6 months later, they're randomized to either receive salanersen or sham controlled. And so again, here, it's different than what we did in Phase I, where these patients had over evidence of suboptimal clinical status here irrespective of that. we're going to be able to look to see if you are initiating salanersen in that population, what's happening. And putting those 2 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. So this is really important as we think about the future sort of future treatment decisions for the incident population in particular. And 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 enroll 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. And so that will help us understand, again, the other -- 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.

Yes. Okay. Okay. Got it. Makes sense. So then maybe in the context of this, do you want to 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?

Yes. So I would say that we're lucky with SPINRAZA because it's the only therapy that has the opportunity to optimize -- that we have the opportunity to optimize, I should say. And so 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. And while treating an infant pre-symptomatically may allow that infant to walk, which is -- was completely unheard of 10 years ago when we were having conversations, their gate may not be and in many cases, is not normal. And so 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 achieve better outcomes tomorrow and high-dose SPINRAZA is a huge part of that. And so we're working to try to get high-dose SPINRAZA to people living with SMA around the world. And then ultimately, we would anticipate that many of those individuals would choose to transition over to salanersen if and when it is approved and available.

Yes. Okay. Great. All right. Well, maybe in the last 10 minutes or here, we can just cover the litifilimab readout and maybe a quick other question on on DAPI and Felza. But starting with the litifilimab data, which is coming soon, Diana. So maybe I'll just -- I'll ask you like a total weighted question and hear your response. So I think on the investor community, there's like people have become just inured with how challenging lupus can be and how you can have these Phase II data sets that look promising and then the Phase III doesn't replicate. And I think in the context of that, when I get questions from investors on liifatelimab, it's like it looks like the drug is active, but the p-values are not 0.01, they're kind of closer and then the endpoint in the Phase III has changed. And so just in like the backdrop of that, maybe help us make sense of the Phase II data and like how confident can we be going into this Phase III study? Like is this the kind of study you feel like this is fairly derisked 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 works as well as we hope?

Sure. Great questions. And I think it kind of falls into 2 different pieces, like asset and then sort of lupus drug development and execution. So maybe I'll sort of start from the asset standpoint. We know that manipulating -- BDCA2 is a better target. 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 of this mechanism and manipulating that PDC biology, all the way from a skin study, 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 the back-to-back papers in New England. And there, we were really -- and it's been methodical all along the way, right? And there, we're really showing on the SLE side, what impact does this formerly BIIB059 or now litifilimab, what does litifilimab do on skin and joint effects in patients with lupus and so you saw that their reduction in tender swollen joints as well as improvement on multiple skin metrics as well as SRI-4. So that was a proof-of-concept study. It was not designed or powered to be as big as what you'll need to do for a Phase III study, but it gave us the confidence to move into a Phase III study. And remember, we're doing 2 Phase III studies. So we're going from that proof-of-concept study to then power 2, 540 patients each on SLE trials. So definitely the ability to answer the question with the replicate SLE studies powered for SRI-4 I think we feel good about. It did require and as it should to go from POC to Phase III, really expanding that. And then as you say, people have POC and they go to Phase III, what do you do differently? And I think, first of all, right target, which we feel like we have. Second, right patients. 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. And so really...

So how do you do that to try to homogenize the population?

Yes. I think it's about looking at ensuring patients who have active disease activity despite standard of care, right? So you really don't want the mildest form like early 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. And then it's diligent, diligent execution. I mean running global -- 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 that it's required, the level of training at multiple sites to help ensure that we're sort of enrolling the right patients and then collecting the data really judiciously. So I would just say we feel the Phase II results were in both SLE and CLE quite robust, allowing us to make this decision to go forward in CLE. So just let me say one thing about SLE. I wouldn't -- 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 and that is the primary in the replicate Phase IIIs. And in CLE, it's that CLASI endpoint, and that's something we worked incredibly hard on looking at those effect sizes. You see it in the New England paper, and we're about to share new data on the Phase II portion of the AMETHYST CLE trial. So we're also in that Phase II/III for CLE as a late breaker at AAD at the end of this month. So again, this idea, are we manipulating the biology with litifilimab, we feel like we are. And so we're excited to hopefully get registrational data at the end of this year on SLE and followed by CLE. So, I hope that helps.

Okay. Great. No, that was awesome. Okay. Fantastic. I'm going to go quick...

DAPI, I can jump to that quickly. I mean their first Phase III, one of like only the third positive Phase IIIs that we've seen in SLE. I think there's a lot of -- we didn't see the dose response in an -- like the way the dose response in the Phase II, but we learned from that DAPI Phase II adjusted in Phase III, executed against Phase III, hit the primary endpoint as well as have multiple evidence of supporting data of what matters to patients beyond BICLA or SRI-4, which are these composite endpoints, but we saw meaningful tapering of steroids. We saw reduction in flares. We saw fatigue, improvements in fatigue, which really, really is important to patients. They deal with a lot in lupus, but if you ask them what are -- like what's one of the most debilitating symptoms, they say this just absolutely profound fatigue. So seeing that consolidated effect by manipulating CD40 biology suggests to us we're really having significant multisystem impact in lupus with the CD40 pathway.

Yes. Okay. Great. And 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 going to run into this?

Yes. So you're right. Historically, the first generation of the CD40 ligand molecules were the -- they had an Fc Fab fragment that was believed to be the causal for platelet activation and aggregation, which led to clots and thrombosis and negative events. So this -- our DAPI is designed specifically and engineered with an Fc free Fab fragment. And so 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. And so we engineered that completely out. And so it's a heavily PEGylated molecule that allows us with the Fc-free Fab fragment. And based on the safety and tolerability that we've seen so far, here is quite differentiated from first gen, in terms of any risks of that clotting above and beyond what is endogenous to the disease.

Okay. Okay. Great. I still have a list of a few other things I wanted to ask, but I'll just kick one last one, Felza. 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 probability of having like a truly differentiated product in an area of unmet need?

Yes. So I think you're right. One fun thing about Felza with and immunology in general when you go after is a pipeline and a product. And so 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 go through, have renal failure, then end up getting a transplant, then have their transplant rejecting, sometimes pretty within 6 months. And so that proof-of-concept data that we generated where you basically initiate the therapy and you can see this profound -- you're already an antibody-mediated rejection and we can resolve that is really pretty exciting. And that's an opportunity that's probably underappreciated, 11,000 patients in the U.S. who have AMR 6 months after a transplant, and we saw 80% resolution at 6 months in the Phase II. So obviously, we're in the Phase III. We need to sort of replicate that, but that's quite exciting. And then in terms of other drivers, you're right, the opportunity in IgAN 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. Patients always want as much medicine as they need and no more. Sort of fix me and then can I get a break. And so 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. And then, of course, membranous is another really debilitating condition. So if we can bring something, particularly if people after first line need to go to another one, I think it's exciting. So it's all 3, each for different reasons. But I would say that having 3 Phase IIIs with this asset positions us really nicely to move forward.

Yes. Okay. Great. Well, I know we could have talked about a lot more, but I really appreciate you all taking the time, and we got through a lot of topics and interesting details. So thank you so much, and thanks, everyone, for dialing in and listening.

Thank you, Paul.

Thanks, Paul, for having us.

Great.