Thank you, everybody, for joining me at the next presentation in our Wedbush ASN Rewind. My name is Laura Chico. I'm one of the Senior Biotech Analysts here at Wedbush. Joining me for this next session, we have Uday Patel, who is the Head of the West Coast Hub at Biogen. Uday, thank you for joining us today. Very excited to have you here. Thanks, Laura. Great to be here. We're kicking off each of our panel discussions with a little bit of focus on the ASN meeting specifically. The first question I'd love to toss out to you is, what are your biggest takeaways coming out of the ASN event? I think, what was most surprising? What was a little familiar? Anything that you'd like to highlight here in the beginning? Absolutely. I think from the beginning, you know, the opening plenary with Prabir Roy-Chaudhury, the ASN President, with his history of working with Key, and his really focus on trying to help us usher a new era in nephrology that really focuses on cure, along with many other ASN Presidents. I think this year is the year it felt like a tipping point, right? We have not only a wave of new innovative therapies coming online, but there was really kind of a more clear focus of how cure is possible. That was reiterated by a number of plenary speakers. Also, you just walking around, you sensed a different level of enthusiasm about the promise of new therapies versus really just treating the complications of progression with renal replacement therapies. I think that certainly echoes a lot of the themes that we're hearing from other folks as well. You're finally getting closer to these toys actually coming to market and be able to fill up the toolbox or the toy chest with them. Let's pivot over to Biogen's efforts and, I guess, specifically with Felzartamab. I thought it might be helpful for those in the audience that might be a little less familiar. I wanted to give you a few minutes to maybe help us set the stage and talk a little bit more about Felza's origin story, but also the various pivotal studies going on today, because there are actually quite a few pivotal efforts already underway with Felza. Absolutely. The origin story probably starts with at least the creation of Human Immunology Biosciences, or HiBio, really a company founded by Travis Murdoch to focus on developing targeted therapies for severe immune diseases. There were a variety of different potential approaches, but one of the really most compelling opportunities for a targeted therapy that could have a real impact across a range of immune diseases was using anti-CD38, which is expressed on the professional antibody-producing cells in the body. They examined a number of different therapies in development and found one that they really had the conviction would potentially offer essentially a best-in-class opportunity for an anti-CD38 therapy, specifically for immune-mediated diseases. This was at MorphoSys. MorphoSys was a company more recently acquired by Novartis, developed wonderful antibodies. They had this program that they had launched years ago, had developed this molecule specifically for immune diseases, completed preclinical safety toxicity studies, which was not possible with other CD38s, did a reproductive safety toxicity study as well, and started development in a number of sort of indications, proof-of-concept studies that when we licensed Felzartamab from them, inherited. We inherited several live programs, which already sort of had a bit of a path in rare kidney, which was, I think, a fortuitous opportunity to make advances there. Okay. I think that's a great spot to start. Targeting CD38, I think it's a bit of a novel strategy within nephrology specifically. I'd love to start kind of the 30,000-foot view and drill down, but maybe talk about the indication selections that have been chosen initially to pursue with Felza. Just for our audience, we're talking about not only IgA nephropathy, but AMR, PMN, among others. Walk us through how you first got to these indications specifically, and then how perhaps that was triaged or narrowed over time. Absolutely. Maybe thinking about the sort of context here, there's been an explosion of autoimmune diseases, immune diseases worldwide, but most of them are actually the largest components of those are really antibody-driven diseases. Pathogenic antibodies that affect a variety of different organ systems, whether that's the kidney, the neurologic system, whether it's a hematologic manifestation, a dermatologic manifestation. A number of specific pathogenic autoantibodies have been identified. These pathogenic autoantibodies are produced by plasmablasts, plasma cells, which express CD38, which is why targeting them seems so promising. Essentially, the breadcrumb trail that I think people have been able to follow is that out of desperation, when people have tried using anti-CD20s, which CD20 is not expressed on these cells, whether this is ineffective for these severe patients with a variety of these autoimmune diseases, it's not worked. Off-label use of available marketed anti-CD38s has been effective. There's a number of case reports across various disease indications. I think that informed the MorphoSys team about some areas to try to start their early development. A quintessential autoimmune disease is primary membranous nephropathy, where for at least 80% of people, that pathogenic autoantibody is directed against PLA2R. PLA2R is expressed on podocytes. When these antibodies bind to the podocyte, it essentially causes kidney damage by forming these deposits, thickening the basement membrane, creating sort of very severe nephrotic syndrome for patients. The initial studies that MorphoSys ran were in primary membranous nephropathy. They had a few different studies underway, three different studies that we inherited. One was looking at a few different doses of Felzartamab, as well as repeat dosing. Another was looking at sort of this nine-dose regimen that they had arrived at for a one-year period. That is the one that allowed us to see that this could really have a real benefit in patients who either were very high risk upfront or had relapsed or never responded to CD20s. The other really insightful observation they had was that in IgA nephropathy, this disease was not responsive to CD20s at all. It was another example where targeting the antibody-producing cells directly, selectively depleting them, could have an outsized effect. For IgA nephropathy, it was a nice phase II where essentially in a single study, although it was small, there were five arms, placebo against two doses versus five doses versus nine doses. There was a Japanese subcohort for one year. It was a two-year study where people were dosed and then followed up to two years. What we saw was tremendous efficacy that was extended well beyond the dosing interval. For example, after five months of dosing with nine doses, essentially there was durable treatment effects out to two years. AMR was also, again, insight from case reports of off-label use where patients seemed to respond to anti-CD38 in the context of AMR. This was a very thoughtful investigator-initiated study by two sites in Europe, University of Vienna, Georg Böhmig, and at Charité in Berlin, Dr. Klemens Budde. They conducted this study, 22-person study, randomized, double-blinded, with biopsies for inclusion at six months and one year, saw tremendous efficacy, 80% resolution by histology. The key pathologic score there, microvascular inflammation, went down to zero for the majority of people who were treated. This had never been seen before. These two investigators have been part of multiple other phase II proof-of-concept studies as well as phase III that went on to be unsuccessful. This was sort of transformative efficacy that was observed in AMR. Those were the foundational indications that we sort of adopted and carried forward as we had positive results into phase III. At the same time, once we had Felza, the first new study we launched was a signal-seeking study in lupus nephritis. People who had not been fully responsive to prior therapies, really a small open-label signal-seeking study. That is currently underway still. Okay. Helpful. I think kind of coming out of ASN, obviously a lot of buzz around IgA nephropathy. Maybe that makes a logical starting point as well. You mentioned the durability piece of the early data for Felza, which certainly stood out to us, particularly against the backdrop of a changing therapeutic landscape. We've gone from having no therapies to, in a few months, we're likely to have a couple or at least one targeted therapy on the market. I'd love to get your perspective on how you see Felza fitting into the evolving treatment landscape. I assume your base case assumes the approval of the April biopsy as well. Maybe that would be a good starting point. Where does Felza best fit into IgA nephropathy? Yeah. So first of all, it's never a good time to be patient, but how wonderful is it that we now have multiple, multiple therapies showing efficacy, not only sort of foundational therapies like SGLT-2 inhibitors, endothelin receptor antagonists, which will help with the overall CKD preservation of kidney function, but also targeted therapies that focus on inflammation that might be driven by complement. To your point, I think there's a class of potential disease-modifying therapies that includes therapies that will modulate the B cells that are producing these autoantibodies that drive disease. These antibody-producing cells produce Gd-IgA1, galactose-deficient IgA1, and then the autoantibodies against those. That can be addressed by inhibiting APRIL and/or BAFF. To your point, there's a number of different therapies that have been evaluated. We've got interim readouts on multiple, and we're expecting a final FDA decision on one of them here, hopefully within the month. That's fantastic. Those therapies look like they're reducing proteinuria, stabilizing GFR, and having a real effect on the drivers of disease. Long-term could be incredibly powerful for preventing progression to kidney failure. That's wonderful. I think the opportunity that CD38 offers on top of that is also disease-modifying, but selectively depleting these cells so that you no longer have to continue dosing. What we know from the APRIL/BAFF inhibitors is three to four months after stopping dosing that proteinuria returns and progression may return as well. Although they're effective, they're essentially modulating the B cells, and so they require ongoing dosing, whereas targeted selective depletion with anti-CD38 seems to provide a durable response that certainly appears to be as long as up to two years and potentially longer. I guess, could there be a scenario then for APRIL therapies? You just kind of alluded to it. I have a hard time imagining APRIL, APRIL BAFFs being dosed on a pulsed or periodic basis, but remission is one of the intriguing aspects of the Felza dosing. I guess as you're thinking forward, could a Felza-cycled approach be what advances in the marketplace within IgA nephropathy? Yeah. I think as we think about these options for patients, we step back and say, let's think about the lens through which patients and providers are going to make some decisions. Obviously, safety. We still need to see that in all of these studies. So far, many of the reports have been relatively small and/or the durations of therapy have not been long. We do need to have a better understanding of long-term safety. We do not know the effects for any of these therapies for chronic administration over long periods of time. Efficacy, I think the bars are set pretty clearly to preventing progression. Patient preference is important. To your point, could there be sequential or combination therapies that allow optimal patient preference to come in? This could also include what happens to be covered for them, right? That is the second part of all of this for the entire community: how do we get these therapies to patients? That is a complex journey of all of the HTA assessments and pricing reimbursement access issues. Those could be patient-specific as well, depending on where you live and how you are covered. I think the part about if we sort of start with the theme we started with, with potential cure, I think that is what patients want. Therapies that might allow us to get closer to that could be really, really important to facilitate. Getting rid of the cells that produce the pathogenic autoantibodies that drive the disease is compelling. We do not know what happens for possible return of disease activity. Will it happen in the majority of patients or just a fraction? Are there ways we can identify who might be more susceptible to reactivation of disease? Could, to your point, maintenance therapy with some other approach be helpful in minimizing that? It's not clear. I think one of the things that we're looking forward to is in conjunction with our phase III study, we'll have a long-term extension study where we'll be able to understand the sort of time course of this durability and the need for retreatment with at least a CD38 or other therapies. Okay. Maybe that brings me to my next question around kind of the bar for success within the phase III setting. It's kind of a twofold question because there's a regulatory hurdle that needs to be met. Certainly, there's clear precedence, I would say, for FDA to approve above that 30% proteinuria reduction mark. Obviously, the evolving landscape might impose a different competitive bar. I'm kind of curious, how do you think about a successful phase III Felza readout in IgA nephropathy? What does that look like, perhaps? I think the bar for now hasn't changed, but I think the coming year or two, we could see it evolve. So far, we haven't had disease-modifying therapies fully approved, but that's about to change. Moving forward, studies that start one, two, three years from now may have trouble having placebo-controlled trials. That's issue number one. The second is the bar with which all of these are going to be compared will evolve as well as new therapies enter the market because some of these patients may not fully respond. Some of them may have been treated with some of these newer therapies, but still have active disease and end up in new studies. We'll have a different, perhaps, background therapy, perhaps population of patients who might be more incident rather than prevalent over time. I think some of those nuances will need to be considered. There is probably going to be some geographic polarization here that occurs because of access differences in where the disease is well-controlled versus not well-controlled. I think all of that will need to be considered as people look at the data that are being used to provide the evidence for not only registration, but then for patient and physician decision-making. Okay. Very helpful. It would be interesting to see how everything changes over the coming 18, 24 months even. I'd like to pivot over a little bit towards AMR, if that's okay. I think the readout in the phase III AMR study is likely one of the first pivotal data points that we will get for Felza. If I recall correctly, I think you're anticipating data in the 2027 time period for this study. This is also one where you have some de-risking data with Daratumumab. You mentioned kind of these other studies with off-label use demonstrating it could reverse AMR. I'd love for you to walk through a little bit in more detail some of that phase II data, but also maybe help us put that into context for what it means in the phase III setting, if that makes sense. Yeah, I think so. Late AMR is a really important indication for us. It is the leading cause of kidney transplant loss. We know that essentially the pathology is driven by microvascular inflammation and in some cases, persistent donor-specific antibodies. The diagnosis is essentially made through surveillance or indication biopsies. It is diagnosed pathologically. The current standard of care is really not adequate. There are not any approved therapies, and most patients do go on to progress. In fact, over 75% of transplant loss appears to be related to this if you have been identified as having late AMR. Most people have a median graft survival after diagnosis of about two years. Really high unmet need. We think there is a significant opportunity to change this given the very compelling data from our phase II, but it was a small study. We do need to replicate that. What we saw was, like I said, reversal of AMR by biopsy. What was important was that even though it was small, everything was consistent across different assessments. Not only pathology, but molecular scores, as well as we were able to measure biomarkers of graft injury that are very specific to the graft, and those essentially normalized with treatment. We were able to see, again, small numbers, not statistically significant, nor powered to do that, but saw differences in preservation of kidney function that directionally were supportive. I think all of this is important in designing the phase III. What we also saw, though, was that in the phase II trial, people received treatment for five months. This nine-dose regimen over five months, they had a six-month biopsy that showed resolution. By 12 months, with no additional therapy, there was evidence of recurrent AMR activity. That showed up as increases in the molecular scores, increases in the pathologic scores, the MVI score, and then some of the other supportive biomarkers as well. What does that mean? That means that with this disease where you have a foreign body in the recipient, the immune system has recognized this, and the immune activation is severe enough that there probably needs to be ongoing suppression of these antibody-producing cells and NK cells, which is the other part of the story that I do not think people expected, but we showed in a nice Nature Medicine paper that it probably was the NK cells and NK cell depletion that drove a lot of the improvement in microvascular inflammation. That's sort of a more newly recognized part of the pathophysiology that essentially not all of antibody-mediated rejection is driven by antibodies, that there are donor-specific antibody-independent mechanisms that may be mediated by NK cells. Depletion of the antibody-producing cells and NK cells together appears to be what may have driven the results we saw. That requires ongoing suppression. The biggest difference between the phase II and phase III is that people will receive ongoing dosing in that second six months. The other part is that because we have evidence of potential really transformative efficacy, the participants who are randomized to placebo initially will cross over to active treatment at six months. Okay. That was going to be my next question. The key differences. Continuous dosing the second six months. Kind of similar question as we asked earlier, but what does Transcend need to demonstrate then in terms of a success bar? Is it just, I am wondering how eGFR improvement kind of fits into this as well. Yeah. So I think the primary is really resolution by histology of AMR. We want to see reversal of that. The BAMP-22 classification for pathology scoring is what we're using in the phase III. The 2019 version was used in the phase II, but that's evolved. There are no major differences that are sort of applicable here other than a separate category called isolated microvascular inflammation, which we can talk about separately. For AMR, resolution by histology adjudicated by a panel of pathologists is our primary endpoint. What we're also looking at is the durability of that to 12 months, so between 6 months and 12 months. Also, what we want to see is consistency across all of those other mechanisms that we described that gave us confidence that there was a real treatment effect here. Looking at the reduction in the markers of injury, the donor-derived cell-free DNA, and then to your point, stabilization of GFRs is also important. That will also allow us to then look at what the changes overall could predict for the graft. There is now a score, the IBOX score, that has been qualified in the EU as a potential secondary endpoint supportive for kidney transplant trials that essentially is a mathematical model using a variety of clinical and patient characteristics, but including these pathology scores and GFRs to essentially predict longer-term graft survival from these parameters. In a small exploratory analysis of the phase II data, we show that we do change the IBOX risk prediction of future graft loss with treatment with Felza. We will be using that as well. That is currently under review at the FDA as a potential surrogate endpoint. Okay. I'm just kind of thinking ahead here, but what type of AMR patients then would be most likely to benefit from Felza? I guess as you're thinking about kind of a marketing strategy, is there a certain segment that would be pointed towards for Felza? Yeah. If we sort of zoom out of what's happening in the transplant space, there's about 250 transplant centers in the US. 50 to 100 manage the majority of patients. Although some community nephrologists have patients who've graduated from those centers and are now under their care, patients are routinely followed for graft function. If there's any changes, usually that triggers an indication biopsy to explore possible causes. The diagnosis is made by, again, a biopsy. The patients who are included in this trial are those who've had a kidney transplant for at least six months, and that qualifies as sort of antibody-mediated rejection showing up late versus more perioperatively in the first six months. Generally, that aligns with having De Novo donor-specific antibodies versus preformed that relate to sort of a different context around transplant with mismatches and desensitization needs. Okay. I'd be remiss not to kind of pivot over towards membranous for a little bit only because there are multiple things going on with Felza, but certainly looking forward to the Transcend data, but less investor attention on PMN, Primary membranous nephropathy at this point. However, I do think this is an area that we start to see increasing interest in as we're going forward here. I think with that, you've observed varying types of varying degrees of relapse rates with different therapies in PMN. How do you approach this in terms of a patient population? Again, kind of similar question as in AMR, but where does it make the most sense to focus on within PMN for Felza? Yeah. So again, also good for patients that there's been a really tremendous evolution of therapies for PMN. Our observation in starting all of this was that CD20 does work in a good number of patients, but it also doesn't work in a large number. That provided a real sort of motivation to sort of think about how selective depletion of the antibody-producing cells could help with controlling this disease. For our phase I two studies that we generated data on, PLA2R autoantibody levels were an inclusion, and specifically high levels were what we were looking at. Higher risk patients with high PLA2R autoantibody titers, but also people who were explicitly refractory to multiple courses of prior therapies. Those generally included anti-CD20s and/or cyclophosphamide. What we saw was efficacy in a setting where people hadn't fully responded to other therapies. That gave us, I think, the motivation that there was an opportunity here for there's a role for CD38 therapy to provide essentially another therapy for patients who either aren't responding upfront, so could be high risk and less likely to respond to CD20s or relapsing from them. With that, our study is a pretty standard design. It's essentially open label because we're comparing a therapy that's IV to tacrolimus that's an oral therapy. We just wanted to make it a somewhat reasonable study for participants and not have them have blinded therapy of both. The two-year assessment of complete remission is also pretty standard. There have been a number of phase III that have followed this path. Essentially, getting proteinuria down below 0.3, 0.5 grams is sort of the bar with stable GFR as a corollary. Maybe taking a step back now because we've gone through each of the programs. I guess for PMN, would the phase III study support a registrational filing on its face? The reason I ask is maybe taking a bigger step back, what is the overall filing strategy for Felza? Is it a first indication, maybe an AMR, and then leveraging out as data rolls in? I'd love to kind of understand a little bit more on kind of how does Felza reach the market first and what has to happen for the subsequent indications? Yeah. Like you described, we're expecting data for AMR in 2027. Expect filing and approval in 2028. That will be the first indication. I mentioned isolated microvascular inflammation, and that is a new indication that essentially was identified from the 2022 Banff classification of AMR. This was a category that was sort of considered not rejection, but with additional study, very sound epidemiologic studies of large registries, it's clear that the people who have this essentially do not have DSAs. We can talk about a few reasons why they may not have DSAs measured, but they have the pathology of AMR that manifests as very severe microvascular inflammation. Their outcomes are almost as bad as those with full-blown AMR with the donor-specific antibodies. We're launching a study there. We're hoping that that could be something that we are able to also include. I again will follow a few years later followed by PMN. Okay. I think maybe one other question that we've previously gotten from investors is the formulation strategy around Felza. I guess any other commentary you could share around plans to adopt maybe a subcutaneous dosing formulation? Yeah. So the other CD38 you mentioned is daratumumab, obviously very impactful therapy for patients with multiple myeloma. They went to a subq formulation, and that improved, I think, the access for patients and the tolerability of administration. We, as HiBio, didn't have the resources to do that and have been thrilled that Biogen, we now have the full capabilities of a remarkable company and are working to develop subq options for Felza. Okay. Interesting. That'll be interesting to see the development there. I know we only have a couple of minutes left. The standard way we've been winding down each of the panels has been we started off with taking away key takeaways from ASN. I'd love to kind of wrap up, though, coming out of the meeting, what you're most excited about for Biogen and Felza specifically as you're heading into 2026. Yeah. I think what's exciting is the momentum that we have in deepening our understanding of the diseases we're studying. Across AMR, IgA, PMN, we have conceptual models of how the diseases actually are caused. With new therapies, we get to probe that biology in different ways and try to actually pressure test that. What we're finding is some of our insights about those disease mechanisms actually aren't correct. We're also using our current phase II data to look back at what are the insights that might help us understand these diseases through a new lens. As an example, the role of the NK cell in AMR. That was sort of paradigm-changing and really important because otherwise, without recognizing that, we weren't advancing therapies. As an example, plasmapheresis was the mainstay of therapy, physically removing these antibodies, but that didn't lead to efficacy. Now we have maybe potentially an explanation why that could be. Across IgA nephropathy, we talk about Gd-IgA, galactose-deficient IgA being the driver, but there is a dislocation between reduction in Gd-IgA, proteinuria reduction, and stabilization of GFR. Why is that? There are probably some other things happening. All of us have galactose-deficient IgA, but it is not pathogenic. What is the difference and what might be happening here? For PMN, similarly, there is clearly a complex part of memory cells and plasma cells producing these pathogenic antibodies. We are looking at ways that we can have a deeper understanding of that to sort of get to more optimal therapies for patients. Disease mechanisms is really important. I think also very important is completing enrollment for our active trials. Also thinking about the opportunities for Felza. There's a number of different indications where it could be helpful as a therapy. We know that from, again, what I described, the off-label use of currently available CD38s demonstrating efficacy where current therapies are falling short. Looking forward to sharing more about that in the future as well. It is an exciting time for nephrology. I'm excited that Biogen is advancing Felza here in a number of different indications. Looking forward to all the future data cards turning over. With that, I think our time is up. Uptal, I really want to thank you for joining us today. I appreciate all the insights and look forward to following the progress here. Yeah. Great. Thanks for having us, Laura.