Hey, good morning, everyone. Welcome to Day Two at the 37th Annual Piper Sandler Healthcare Conference. This is David Amsalem from the Piper Biopharma Research Team. We're delighted to have Biogen with us. We have Dr. Uptal Patel, who's the head of Biogen's West Coast Hub, and we're going to have what I think is a really timely discussion focused on Biogen's immunology pipeline. There's a lot in advanced development. There's some big data readouts over the next few years. So I think this will be a really interesting and certainly timely discussion. So thank you, Dr. Patel, for joining us, and wanted to dive right into felzartamab, your CD38-directed treatment here. So I know you and the team hosted a webinar earlier this year highlighting the clinical program. You talked not just about autoimmune diseases impacting renal function, but also other autoimmune disease settings with this molecule in mind. So given that backdrop, can you talk more broadly about the CD38 target and why you see it as particularly interesting? Yeah, first, thanks for having us, and thanks for having an opportunity to share some of our experience with felzartamab. I think, you know, the story for CD38 really begins with recognizing that antibody-producing B cells that express CD38 have been implicated in a number of autoimmune diseases, particularly those with pathogenic antibodies driving the diseases. And so that context is important in recognizing for a number of different antibody-driven diseases, available therapies just have not been effective. And so having a more plasma cell, plasma blast targeted therapy, which are the antibody-producing cells that drive these diseases, was something that was very appealing from a therapeutic perspective, allowing more targeted therapies, allowing the earlier B cell populations to remain intact, while you then address these important pathogenic antibody-producing cells. Sure. So more specifically, looking into the role of CD38 in a range of autoimmune diseases impacting renal function, why is renal disease your top clinical priority? Yeah. Well, prior to Biogen, felzartamab came to HI-Bio via a company called MorphoSys that developed felzartamab. And they were, you know, acquired by Novartis since then, but had a history of producing very good antibodies. And what they saw was this opportunity to target CD38 for autoimmune diseases versus the currently marketed anti-CD38s that have been used for multiple myeloma. So out of desperation, clinicians around the world have used available anti-CD38s off-label to treat their more difficult-to-control patients and have published these experiences over the past two decades. And what you see is a breadcrumb trail of spaces where essentially targeted CD38 therapy could be effective in these autoimmune diseases. And so kidney diseases are in that group. What's nice about them, I think, is that there's been an evolution in the endpoints that allow essentially trials that could be done on a sort of more feasible timeframe in a number of different rare indications where available therapies haven't been effective. As an example, for IgA, anti-CD20 therapy does not work, yet it's an autoantibody-driven disease. So that, I think, provided the foundation for a number of different rare kidney disease opportunities for them to start in that we've been, you know, fortunate to pick up. Yep. So I think your most advanced program is in late antibody-mediated rejection in renal transplantation patients. So before we go into the existing body of data, I wanted to level set the underlying unmet medical need here, the size of the population, and essentially what is the target population here. Yeah. Maybe I'll start with a couple high-level thoughts. Sure. Target population is roughly about 11,000 people. And that's a subset of the, you know, three or four hundred thousand people who are alive with a kidney transplant. And this subset is those with late antibody-mediated rejection, which is the first area we're starting in. But there's a lot of other adjacent opportunities in this population. And so if you think about the context here, patients who've received a kidney transplant essentially have been given this opportunity to have the preferred treatment for kidney failure versus dialysis. And this is the number one cause of late graft loss that there are no effective therapies for. That is devastating for patients. And so having something that could reverse that course and preserve these precious societal resources of kidney transplants longer is a really important problem to address. So let's talk about your phase 2 data here. It's published and, you know, it was highlighted in the webinar, but I think it'd be good to review the body of data in late antibody-mediated rejection. Yes. So this was a small phase two study, 22 participants, randomized one-to-one, felzartamab to placebo. The felzartamab dose regimen was nine doses over five months. And this population was exclusively DSA-positive late antibody-mediated rejection. So people well past six months after transplant, generally though, about eight years into their transplant course. And what we saw was inclusion biopsies were required for entry, and then the primary endpoint was safety. But what we had was two efficacy time points at six months and 12 months. So the six-month time point was shortly after the course of felzartamab was provided or placebo. And then the 12-month endpoint was off therapy for the last six months. And what we saw was remarkable. So the primary pathologic component that defines antibody-mediated rejection is a score looking at the inflammation of the microvasculature in the kidney. The microvascular inflammation score is generally what drives the histologic classification. The medians were moderate AMR, moderate to severe AMR, matched in placebo and felzartamab. Two-thirds of the people in the felzartamab arm achieved MVI scores of zero at six months. This is unprecedented. None of the other therapies that have been tried in phase 2, multiple different phase 2s targeting a variety of different mechanisms have ever achieved that. Essentially we had about 80% reversal of microvascular inflammation at that six-month time point. The scores got low enough such that you could be classified as not having active AMR. By 12 months off therapy, we saw a reversal of some of that, suggesting that, you know, perhaps ongoing dosing would be required. That's what we've taken into the phase three study. Regarding the phase three, can you just walk through the design and primary outcome measures? Yeah. So it's designed very similarly. It's a one-year study, and we'll have essentially people randomized to felzartamab or placebo. And at six months, because of the overwhelming efficacy that we saw, we didn't think that it would be reasonable to keep people on placebo. And essentially all the placebo participants will cross over to active treatment. And those originally assigned to felzartamab will continue on some version of maintenance therapy. So we'll have assessments at six months, just like we did in phase two, as well as 12 months. The difference will be that 12 months will include a felzartamab arm that has received maintenance therapy. Okay, and what will the initial top-line data look like? Or in other words, what will we get in that top-line read? I believe that's a 26 event, if I'm not mistaken. 2027. 2027, sorry. But what will the top-line contain? Yeah. So this is an important space for which there are no prior comparators, just for context. The last phase 3 in this space was an IL-6 antibody that was looking at a five-year overall graft survival primary endpoint with a two-year accelerated endpoint looking at kidney function. So what we've designed is very different because of the compelling phase 2 study results we saw. And so we'll be looking at reversal of AMR by histology. So what defines the disease once it's reversed, essentially the lack of disease is the primary endpoint. There's a number of important supportive data that will support that. The first is when in our phase two, we also saw that a biomarker that reflects graft injury, so donor-derived cell-free DNA, which is specific to graft injury, also dropped, you know, very aggressively with treatment starting within the first few weeks, stayed down with treatment, and then as disease activity picked up, that also picked up, so that's a very early marker of disease control that we'll have data on in the phase three, and then we'll also have exploratory data of, you know, looking at molecular markers that also corroborate sort of this resolution of AMR, and then the overall function, you know, with kidney function, we'll have larger numbers in this phase three to also look at that, and that's something that we saw again in the small phase two, suggestive evidence of not only preservation, but perhaps some improvement in kidney function. And that will be, you know, better powered in the phase three. So just to be clear, just to clarify, in 2027, the first pulling back of the curtain, so to speak, will be that 12-month data. That's line. That's up. That's up. Okay. Got it. In terms of IgA nephropathy, just moving on to that program. So as I understand it, bigger market, but a lot of drug development here. So you have the April target, you have the BAFF targets. I mean, so these are, you know, there's a lot of excitement here, but a lot of competition. So with all that in mind, you know, where do you see the fit for felzartamab, just putting the body of clinical data aside and just knowing what we know, you know, how do you see the fit mechanistically with, you know, with all these other agents that, you know, are targeting, that have other targets? Yeah. So in IgA, lots of progress. Every month there's new announcements, which is great for patients. And we're excited to see all of that. I think where felzartamab really has an opportunity to sort of stand out is that we think it'll be the only option that will allow durable disease control off treatment. And so why do we believe that? Hearkening back to this mechanism, again, CD20s don't work. So depleting earlier B cell population isn't effective in controlling disease. And we know that the plasma cells and plasma blasts that drive the disease are what need to be addressed. And so by directly depleting them, essentially remove the disease-causing cells. And in our phase two study, that's probably what accounted for the really, you know, impressive durable effects that we saw. So after a nine-dose regimen, five months of dosing, out to two years, we saw ongoing reduction of proteinuria as well as total IgA that suggests that it's really got this, you know, important disease-modifying mechanism. So how will that fit into the other therapies? So I think what's evolving is that there'll be some foundational therapies, you know, building on ACE inhibitors and SGLT2s. The new ERAs will certainly provide a, you know, potentially non-disease-modifying foundational CKD progression prevention set of therapies. The next class that, you know, will be important to some patients are those that address really inflammatory manifestations of IgA. So like, for example, the complement inhibitors will have a role for some patients. And then the APRIL BAFFs are a really important advance for patients. What we see there is that, you know, these agents modulate B cell maturation and viability of plasma cells, plasma blasts. But in all of these studies, you know, when they include the off-drug components at the end of their studies, you see that within three or four months, proteinuria returns back to the high levels at the beginning and eGFR progression continues. So they work, but they require ongoing dosing. And so what we also don't know is the long-term, you know, effects of requiring this B cell modulation on, you know, other important safety parameters. So I guess one point of differentiation is potentially the absence of the need for ongoing dosing. Does that appear right there? Absolutely. Yeah. So in our assessments, you know, with patients' providers, that's a really compelling opportunity. So we think all of these options will be important for patients, but also choice for something that could be, you know, could provide more durable long-term treatment-free efficacy. One question I had about the pivotal study here is that how do we think about pace of enrollment here? I mean, you're competing for patients and there's a lot going on in the space. So how do you think about that? Yeah. You know, first, I think what's important is that these therapies have helped increase the awareness of IgA nephropathy. So more patients are being tested, which is a good thing. And more patients are being identified. We're somewhat fortunate in that many of these phase 3s have been fully enrolled. And so it's also a good time to come online with a new program. Many of these therapies that are getting accelerated or full approval still aren't available in a variety of places, and uptake has been low. So it still provides, I think, an opportunity for, you know, clinical trials to provide a new therapeutic option for patients while we evaluate the efficacy and safety. So I wanted to, in the interest of time, toggle over to the PMN program. So as I understand it, lots of rituximab usage here. So I guess with that in mind, can you talk to the different subgroups of PMN patients where you envision a fit for felzartamab? Yeah, absolutely. So PMN, also some growing interest in the therapeutic development space, which is fantastic for patients. Clearly, a long history of anti-CD20 use, again, off-label. There's no approved therapies for PMN. But what the literature suggests is that for high-risk patients who start off with, for example, in the PLA2R-positive patients, if they start off with very high autoantibody levels, they tend to not be as responsive to anti-CD20 therapy. So we think that's a direct opportunity for targeted plasma cell, plasma blast depletion, where we've seen very rapid reductions in PLA2R in high-risk patients. The other is that unlike IgA nephropathy, you know, there is a sizable proportion of patients who respond to CD20. There's also a sizable proportion of people who either don't respond initially because they've got these plasma cells, plasma blasts, and niches that can't be reached. And these cells don't express CD20. And so you see lack of response initially or relapse because essentially the CD20 therapy is not depleting these cells that are producing these pathogenic autoantibodies. So I think there's two big populations. The first is, you know, upfront in high-risk patients and as well as perhaps second line in patients who don't respond or relapse after CD20. Okay. What's the size of the population that don't respond or relapse after CD20? Yeah. So that's anywhere from, you know, 30%-50% of patients. You know, it depends on how long you follow up. But it's a sizable proportion of patients. Now, with the better CD20s, that could be slightly smaller. But even with a more potent CD20, the biology isn't going to be different. Those cells still don't express, you know, the plasma cells, plasma blasts don't express CD20. And they do express CD38. So it provides this opportunity for targeted therapy even after CD20 therapy. One more question about felzartamab, just briefly. Just talk about your potential clinical development plans for the drug beyond late AMR and IgAN and PMN. What other trials could come next? I think you talked about lupus nephritis, if I'm not mistaken, but I know there's others. Just help us give a roadmap of what comes next. Yeah. So So the short-term roadmap, we do have an active phase 1b signal-seeking study in lupus nephritis. This is an open-label study with up to 20 participants. And we'll look forward to sharing some data on that in the coming year. The second study that we're just about to kick off is a related subset of that AMR population I described being quite large. So currently, the current phase 3 is in DSA positive antibody-mediated rejection. There's also, you know, from the work we've done, a recognition that DSA negative AMR is an important population. And so in the past year, what's become clear is that the epidemiology of that population has become more clear. It's about half the size of the DSA positive AMR population. And their outcomes are almost as bad. Essentially a very, you know, important complication that can lead to kidney failure almost as much as the DSA positive population. We're kicking off a phase two study any day now that will allow us to examine the efficacy of felzartamab in this isolated microvascular inflammation population. The nomenclature here is an evolution because previously the dogma was that these DSAs, donor-specific antibodies, drove the disease. But some of our work has identified that there's also DSA independent mechanisms that drive this microvascular inflammation, particularly driven by NK cells that also express CD38 that we also deplete with felzartamab. Okay. That's very helpful. No, no, sorry, and then the last set of indications is really kind of alludes back to that idea that there are a number of autoantibody-driven diseases that essentially have been implicated, you know, the plasma cells, the plasma blasts have been implicated in, and we see those as tremendous opportunities and we'll be starting a few new proof of concept studies in the coming year as well. Okay. So I wanted to spend the rest of our time talking about lupus, which is obviously a very important part of the immunology R&D portfolio. So I guess why prioritize SLE and other manifestations of lupus? I mean, particularly given that it's been historically so challenging in terms of drug development. So lupus is very heterogeneous. So I think this was summarized nicely by a patient in one of our recent focus seminars that, you know, patients with lupus will say, "My lupus isn't your lupus." And that heterogeneity has probably also been part of the challenge in identifying effective therapy. So far, there's only two approved therapies. We think the penetration is really only up to about 20% of the population that could benefit from therapies. And so this has been an active effort for Biogen for many years. We've got, I think, some really exciting data across two different mechanisms. And so with litufilamab, essentially targeting, you know, BDCA2, you're able to deplete the type I interferon signals through plasmacytoid dendritic cells that drive the disease. And with very compelling data from two phase 2s that suggest a pretty strong clinical effect, we're excited and looking forward to the readouts from those phase 3s in the coming year. And then the CD40L therapy with dapirolizumab pegol, again, already one positive phase 3. And that's really only the third mechanism that's been proven in a large phase 3 to be effective. And so we're running a second phase 3 and look forward to readouts following the others. So I wanted to take a step back. So there's disease heterogeneity. There's also heterogeneity on trial endpoints. So litufilamab, your endpoint here is the SLE Responder Index four. Dapirolizumab, I think it's BICLA response. So just help us understand the rationale behind the different endpoints here. And I know that these are validated endpoints, but I wanted to just get your thoughts on why different primary outcome measures for these different studies. And do you have buy-in from the FDA? Yeah. So the teams that have worked on that have, you know, built off of the proof of concept studies that we've got. And this is a space that's in evolution. And, you know, I think what we've found is that targeting the right endpoint with the right subpopulation is important. And we've been very, very grateful for strong partnership with FDA to find alignment across all of our programs. Litufilamab is also in development in CLE. My understanding is there's nothing approved in CLE. Can you talk to the Amethyst study in CLE for litufilamab? I mean, why a 24-week endpoint in part B of that study? It's a shorter duration relative to the SLE study endpoints. But I just want to understand what the rationale is there. I think one of the challenges for lupus, for those who've been in the space, is that there's a number of different, you know, multiple composite sort of endpoints that capture different aspects of the manifestations of lupus. What's nice about CLE is that you've got more objective data with these skin findings, right? What that allows is, I think, in some ways, a cleaner assessment that can happen more quickly if your therapy is working quickly. I think that's sort of that design reflects that opportunity in this subpopulation of lupus patients. Sure. And then I think I have time for one more question. I'll just fit in. So also a CLE study question. Just remind us to the extent that the Amethyst study is successful, can you file on it given the absence of approved therapies in CLE? I mean, is it designed as a registration quality study, I should say? Yeah. So I think if it were in isolation, that might be challenging. But it's not because we've got the broader lupus program. So I think, you know, that's sort of the opportunity here is that we'll, you know, that's sort of helpful on multiple fronts, the efficacy assessment more broadly across lupus, but also then, you know, a more robust safety database. All right. Terrific. Well, we're out of time. Thanks, Dr. Patel. Thanks to everyone in the audience. Great. Thank you.