Good morning and welcome to Vera's R&D Day. I'm Dr. Marshall Fordyce, Founder and CEO of Vera Therapeutics. It's great to be in New York, and thank you for your engagement and for being with us in person today. Before we get started, I want to remind you that our remarks contain forward-looking statements under the Safe Harbor Act, and as such, we present this disclaimer regarding at-risk statements. Just before I get started, I want to acknowledge the very significant events happening in the world today and appreciate everyone's attention today on what is truly an international and collaborative effort, which is the biomedical research project. We invest in basic science. We translate that into clinical achievements, and those clinical achievements move forward into the public health for the betterment of mankind. That's why all of us do what we do in this room, and I'm thrilled to be focused on what we're doing today. This morning, I'll provide a brief corporate overview, including Atacicept's best-in-class potential and key differentiation as a potentially foundational new treatment for patients with IgA nephropathy, and highlight its broad optionality in non-renal disease areas, and review key near-term catalysts for the company. It's my pleasure today to outline this vision for Vera's growth ahead. I'll then introduce Vera's Chief Medical Officer, Dr. Robert Brenner, who will share Vera's indication expansion strategy for atacicept and the new studies we plan to initiate in the very near term. I will then open the floor for questions, which can be addressed by me, Dr. Brenner, or our expert panel, which I'll introduce at that time. Our mission is to transform the standard of care for patients with immunologic diseases, and the Vera team and all of our collaborators have made great progress towards a potentially major advance in medicine. Our lead product candidate is atacicept, a potential best-in-class and first-in-class dual BAFF-APRIL inhibitor, representing a next generation of B-cell modulation. It's currently in phase three in patients with IgA nephropathy or IgAN, and with much broader potential to change how we treat a wide variety of autoimmune diseases. In IgA nephropathy, atacicept targets the source of the disease, and phase two data through one and a half years shows a reduction in immune complexes, resolution of glomerulonephritis, significant reduction in proteinuria, and most importantly, kidney function as measured by eGFR tracking with the normal population. These collective results suggest that chronic dosing with atacicept offers the potential promise of a functional cure. Atacicept is the only B-cell modulator in development for IgAN that will have two-year data from phase two, which, if approved, would enable a differentiated data set at commercial launch. Atacicept is the only investigational B-cell modulator in IgAN with at-home self-administration being studied in both phase two and in phase three, which at one and a half years has yielded over 90% retention rate, meaning patients continue to take this medicine at home in an open label phase. Since our R&D day in January, Atacicept has been granted breakthrough designation by FDA, and we've continued and completed enrollment of the primary endpoint cohort in our phase three trial, putting us on track to read out our phase three data in Q2 of next year with a potential PDUFA date in 2026. Atacicept indication expansion will be our focus today. With a favorable clinical profile evolving in phase two and hopefully in phase three, we believe Atacicept has the potential to transform the treatment of multiple other autoimmune diseases beyond IgAN. Different from steroids and B-cell or plasma cell ablation in which immunosuppression occurs, Atacicept's precise BAFF and APRIL inhibition appears to be amenable to chronic dosing over time, where a clinically meaningful reduction in autoantibodies is balanced by the retained ability to fight infection during treatment. Today, we'll share an update on the expansion of our clinical program for Atacicept as we move beyond the IgAN population in our pivotal trial and explore Atacicept's clinical utility in a broader population of patients with autoimmune kidney disease, where we project an opportunity to reach greater than 200,000 patients. Beyond our announced update today, it does not escape our notice that the ability to deliver a safe and tolerable reduction of disease-causing and disease-associated autoantibodies well beyond the nephrology space, and expansion in the future may include multiple indications in the rheumatology, hematology, neurology, and metabolic fields. Vera is well-resourced for a potential commercial launch in 2026. Regarding exclusivity, we expect biologics exclusivity protection through 2038 in the U.S., which represents 12 years from launch. Given the strength of our data set and our lead time to market and our near-term strategy to demonstrate leadership for IgAN patients and their physicians, Vera has already begun to execute on an IP strategy that may extend Atacicept LOE beyond 2038 and the broad optionality that we've created. We've initiated work on a next-generation program for PK/PD exploration with dosing frequency that will be detailed by Dr.Brenner. Among other benefits that may reset the patent and IRA clocks. Vera has $384 million in cash as of June 30, 2024, and our team is attracting fantastic talent, planning for success, and has been actively scaling the organization for potential commercial launch in 2026. This is an exciting moment for patients. Vera is leading a paradigm shift in how we treat autoimmune diseases, beginning with IgAN as Atacicept's clinical data support its potential to target the source of several autoimmune diseases. On a solid foundation, Vera has created broad optionality to expand our clinical investigation of Atacicept in IgAN, in non-IgAN autoimmune kidney diseases, and in a broader autoimmune disease population. Today, you'll hear from Dr. Robert Brenner about our strategy and current activities to expand Atacicept beyond phase three to a broader IgAN population, where prevalence in the U.S. is estimated to be 160,000 patients. You'll also hear about our plans and current clinical activities to expand into additional autoimmune kidney diseases beyond IgAN, where we see strong rationale to take advantage of Atacicept's emerging clinical profile. In the future, we may share additional clinical activities to study Atacicept in non-renal autoimmune disease and further plans for additional molecules. Atacicept is currently in phase 3, putting us on track for a BLA filing next year and commercialization in 2026. Atacicept's differentiation is based on disease-modifying mechanism of action, which we believe is best supported by the totality of clinical evidence presented and long-term normalization of kidney function, which is rarely, if ever, seen for new drugs in nephrology. Among the four B-cell modulators in phase 3 trials pictured here, Atacicept is one of two that inhibits BAFF and APRIL. The Atacicept program is the only program to study at-home self-administration, 1 mL subcu injection in a randomized double-blind placebo-controlled trial in phase two, and over one and a half years, greater than 90% of patients continue on the drug. We believe this approach in phase two potentially de-risks phase three results, and as the only program with two-year data from phase three, we're well-positioned with a robust data set at launch. Vera is in a strong financial position with $384 million, which funds operations through approval, and we have 54.8 million shares outstanding. Vera has multiple potential value-building catalysts in the near and midterm. Later this month at ASN, we'll share our full two-year results from our phase two trial in IgAN as a late-breaker oral presentation. Last month, we also announced our full enrollment of phase three primary endpoint cohort. And with today's announcement of our expansion into new trials, we'll be in a position to share additional clinical data from two new studies in 2025. Next, our Chief Medical Officer, Dr. Robert Brenner, will come to the podium to share our vision for expanding the potential of Atacicept and the rationale and plans for these additional studies. Rob. Thank you, Marshall, and good morning. It's really a privilege to be here with all of you today. The story that we have been working on at Vera is one that has not been generated in isolation. We're a team. We call ourselves Team Vera in a real way. And so, in many ways, I want to start by acknowledging the hard work of all my colleagues, some of whom are here today, but many of whom are participating virtually and listening in. It's because of all of their dedication and hard work we're in a position to be able to have this conversation with all of you, and so it's my honor to be able to do that. So why are we here? We're here because we have learned vast amounts in recent decades about the way that the immune system has evolved to support us all in the state of health, but importantly, how the immune system can also go awry and where the concept of autoimmunity drives a variety of different flavors of human disease. As it relates to Vera, we have a precision B-cell modulator, and we know that B-cells are the sources of autoantibodies that bind to autoantigens and fuel disease. Therefore, the B-cell itself becomes a target of interest, and that's where the construct of Atacicept and the ability to change the expression of immunoglobulins from B-cells is so powerful. There are two cytokines and only two cytokines that fuel the activity of B-cells. If you will, these are the tools similar to the way that we go to the wall and change the thermostat that control the activity of these cells that drive antibody production and, in the case of autoimmunity, drive autoantibody production. Therefore, it gives us an approach to think about autoimmunity in a much broader context than only thinking about the lead indication of IgA nephropathy. But let's start there. So IgAN is a disease of B-cell origin with kidney pathology. We know that B-cells produce both an autoantigen, galactose-deficient IgA1, and antibodies to galactose-deficient IgA1, which form in situ immune complexes. Those circulate, they can get deposited in the kidney, clog the glomerulus, the filtering apparatus of the kidney, much like coffee grounds in a coffee filter, where they drive local inflammation and chronic fibrosis and scarring, ultimately loss of kidney function in patients where the need for renal replacement or with dialysis or transplantation is required. So if we know that B-cells are the cell of origin of autoantibodies and autoantigen, and we know that there are two cytokines and only two cytokines that fuel the activity of these cells, what kind of reagent could we generate in biotechnology to declare war on this cell? And in my mind, this is an important part of the narrative that Vera has and will continue to share with the external community. It's a big part of why I decided to join the company at the beginning of this year. So we live in an era of modern biotechnology where we have the capacity to create Fc fusion proteins. And it turns out that B-cells are stimulated by both BAFF and APRIL through a number of different receptors. But one of these B-cell surface receptors is called the TACI receptor, and it has nanomolar potency for both BAFF and APRIL. So from a biotechnology perspective, we can harness that knowledge and create a precision tool that uses the extracellular binding domain of TACI fused to Fc, which gives us a soluble receptor with a 35-day half-life that binds both BAFF and APRIL with nanomolar potency. This is a powerful tool. And in my mind, a real question is, if in one agent we have the ability to bind both BAFF and APRIL, what could be a more elegant way of trying to change the activity of a B-cell than this approach? And I think while there are other approaches in development using monoclonal antibodies, I think the prospect of binding both BAFF and APRIL with a tool that was rationally designed is the most elegant way to evaluate the opportunity to interrupt disease. So in IgAN, if we have this precision tool, what might we expect would be the goal of therapy if we would be able to use it in patients who have demonstrable disease? And what we shared back in January was that we believe that there's a quartet of findings that in aggregate define disease modification in this disease. It begins with prompt reduction in the autoantigen or galactose-deficient IgA1, resolution of the inflammation that's going on in the glomerulus as measured indirectly by hematuria or blood in the urine, reduction in proteinuria, which in the U.S. is the primary endpoint that has been used to drive accelerated approval for new agents in this disease, and most importantly, to try and achieve the asymptote of what we would like to do with our patients. And that is to modify their eGFR profile, the slope of their GFR from one where the natural history is to lose 4-10 mL per minute per year to one that looks more like the general population who's losing about 1 mL per minute per year. That is an aspirational goal. And back in January, we shared the results from our 72-week experience in the ORIGIN program that Dr. Lafayette presented, where we showed just that. We showed a prompt and sustained reduction in galactose-deficient IgA1, rather dramatic resolution in hematuria of about 75%-80%, a near 50% reduction in proteinuria, and importantly, a GFR profile that no longer looked like historic IgAN and also didn't look like the eGFR profile of patients who are being treated with an intervention for a chronic kidney disease, but now a GFR profile that looks more like that of someone who doesn't have a biopsy-proven kidney ailment at all. Importantly, these were the data that my colleagues at Vera and I used to approach the FDA and ultimately secure a breakthrough designation this past spring. So I want to talk a little bit about this concept of eGFR slope and an eGFR profile in IgA nephropathy and chronic kidney disease and what we've seen with Atacicept. So in nephrology, we have been thinking about contextualizing GFR, a measure of kidney function, by measuring the slope of GFR decline. At different times, we've had other ways of thinking about describing GFR and contextualizing it, but I would say in 2024, there is a lot of consistent embrace of using slope as a way of thinking about GFR across different programs, across different diseases. And the natural history of eGFR slope in IgA nephropathy is that patients are losing in that neighborhood of four to eight, maybe six mL per minute per year when they're unattended. If patients aren't identified as having IgA nephropathy until they've lost 40% or 45% of their endogenous kidney capacity, meaning they've got a GFR not of 100 mL per minute, but of 60, if they're losing 6 mL per minute, you can do the easy math of how long it will take for them to have a GFR that has been reduced about 15 mL per minute, at which time we usually start dialysis or provide a transplant. In contrast, patients who have healthy kidneys have an annual GFR loss of about 1 mL per minute. And so if we take that same cohort of patients who have biopsy-proven IgA nephropathy and have already lost 40% of their kidney function, if they only lose 1 mL per minute from that point on for the rest of their life, there's very good chance that they won't require dialysis or a transplant before their life is over. That's the goal for the nephrologist, is to try and avoid the need for replacement therapy. And importantly, the data we showed back in January through 72 weeks showed that the Atacicept profile was overlapping with the general population's rate of loss of about 1 mL per minute per year. This story is further emphasized by a classic publication now from Jonathan Barratt and his colleagues, where they looked at the association between different baseline levels of GFR loss and different ages and calculated the risk that they might need renal replacement or a transplant during their lifetime, and importantly, what we see is that with currently approved agents that have a very different mechanism of action and aren't disease-modifying, whether we're talking about endothelin receptor antagonists, SGLT2 inhibitors, or corticosteroids, we see that at the rates of loss that we've observed in the clinical programs, the lifetime risk for patients with IgA nephropathy who achieve those levels of GFR loss in the 3mL, 4mL, 5 mL per minute range is very high. That's why guideline authors have called for a target objective of therapy is to get to a GFR loss of less than one mL per minute per year, basically to achieve the profile that we see in healthy people. Because only at that level, given the amount of GFR that's already been lost by the time the diagnosis is made, this is the area where we have the greatest chance of obviating the need for renal replacement. Why is it so important to be focused on dialysis and transplantation? What is it? So it's an expensive $200,000-$300,000 a year burden on the system in the United States. But more importantly, patients who matriculate into the ESRD stage who are requiring chronic dialysis have a five-year mean survival that's overlapping with cancer. This is a really important point. And so the opportunity to achieve what has been very rare in the history of renal drug development, which is a GFR profile that looks like the healthy population, means that we are avoiding the possibility that these patients might ultimately succumb to kidney failure where their mortality rate looks very similar to lung cancer or colorectal cancer. Okay. So what's on deck for us in the near term? So later this month, the ORIGIN phase 2b long-term data will be revealed in a late-breaking oral presentation that will be given by Dr. Barratt. That will occur on the Saturday of ASN Kidney Week in San Diego. As Marshall shared, this will be the longest experience in phase 2 of a B-cell modulator. That means at the time that we achieve initial approval based on proteinuria, we will also have two years of eGFR data. That compares very favorably to the data packages that will be available in the future for other agents and has been the case for previous agents at the time that they received initial approval by FDA. Importantly, and we've talked about this, given the similarity in the design of ORIGIN 2 and ORIGIN 3, that is, the way our phase 2 program was designed and the way our phase 3 program has been designed and being executed, they're basically blueprints of each other from a clinical trial design perspective. We haven't changed the dosing administration. We haven't changed the general makeup of the patients. We haven't really changed the makeup of the sites and the study coordinators. It's basically an extension of the phase 2 program. From a drug development perspective, that instills great confidence in what we might be able to expect from the phase 3 results based on what we've observed in phase 2. Importantly, as Marshall shared, we announced last month that we've completed the enrollment of the first 200 participants in the ORIGIN 3 program. These first 200 participants drive the readout of the nine-month proteinuria data that fuels our ability to file the BLA for accelerated approval with FDA. That data readout will occur in the second quarter of next year, and that means we are on track to file our BLA in the second half of 2025. So let's talk about our expansion roadmap. Where are we going and why are we going there in this particular order? So as Marshall shared, there are about 160,000 prevalent patients with IgA nephropathy in the United States. The way that phase 2 and phase 3 programs have been executed in this disease is to focus on patients with a certain proteinuria profile, a certain duration of time of having IgA nephropathy, a certain concomitant medication use, which probably reflects about 50 or 55, maybe 60% of the overall population. But Atacicept is a drug that is a precision B-cell modulator that turns down the production of both autoantigen and autoantibody. And if someone has biopsy-proven evidence of IgA nephropathy, it's hard to imagine that based on a slight difference in their proteinuria or the fact that they haven't been on a stable dose of SGLT2 for 12 weeks, that they wouldn't benefit from therapy. Where we're going is to expand in IgAN because we have an internal strategy to win in this disease. We think we have the leading clinical profile. We think our program has set the standard for what you can accomplish, and we want to translate that into further data generation to show that the full breadth of the fingerprint of IgA-mediated disease is amenable to therapy with Atacicept. We're going to begin by long-term evaluation of all participants who've completed the ORIGIN 2 and ORIGIN 3 program. It's not enough to take patients who have been willing to be randomized into a clinical study, follow them for the two years of follow-up, and then thank them and let them go on their way. We believe we have a corporate moral obligation to provide this study drug to participants until it's approved in the region in which they reside. But by doing that, it provides a powerful research tool for us to gain additional experience with the drug over many years of follow-up. Importantly, because ORIGIN 2b is concluded, those participants who re-engage with us in this ORIGIN Extend program will have been on a drug holiday. This allows us to look for the first time at what happens to patients who've had a washout of atacicept, what happens to their Gd-IgA1, to their hematuria, to their proteinuria, and what happens to their GFR, and then to see what happens when they're re-challenged with the drug and have the opportunity to benefit again. I think this will be an important data set to address questions the community rightly has, which is, when might you stop therapy and what happens when you do? If we've documented what happens, it may be that many patients will decide to stay on therapy chronically as we envision the paradigm of the drug really allows. Next, I want to talk a little bit about dosing. Atacicept has been used consistently in the IgAN program, administered as a 150 milligram dose, which is a 1 mL volume, administered as a subcutaneous injection at home by patients. That's the paradigm we use in phase 2, and it's the same paradigm we use in phase 3. If I think about dosing approaches on an absolute scale, I think this paradigm is at the far end of what is really easy for patients to assimilate into their weekly routine. IgAN patients are otherwise young and healthy. They've got young families. They have careers. For them to wake up on a Saturday morning, to take out their syringe, to spend the five minutes to give themselves an injection, and then get back to their family and their weekend plans is a really easy thing for them to accommodate. That's not to say that in certain situations, less frequent dosing wouldn't be a benefit. And remember, I shared that Atacicept has a half-life of 35 days. Therefore, I think the PK is entirely amenable to less frequent dosing. And so Vera will begin a dose range-finding study in 2025 to look at a variety of different monthly doses to inform us as to what the right dose is for patients at this dose interval in the future. But in the near term, our enthusiasm for and our commitment to the weekly dosing paradigm with a 1 mL at-home subcutaneous injection has not deviated, and I couldn't be more excited about the potential future launch with that paradigm to really meet the needs for patients in a broad way. Okay. One of the most exciting things that my colleagues at Vera and my academic colleagues have been working on in recent months is a new program we call PIONEER. This is a phase 2 basket study in expanded IgAN cohorts. Think of this as the clinical development translation of a winning IgAN strategy. The goal here is to study atacicept broadly in all flavors of IgA-mediated disease, not just in those patients that meet the phase 3 inclusion criteria. So we've listed now six cohorts of patients who all have IgA-mediated disease but are just in addition to what we've been studying in phase 2 and in phase 3. We begin with IgAN patients who've got low GFR in the 20-30 mL per minute range. They've been excluded thus far in our program. Patients with low proteinuria, below the threshold that's required to get into ORIGIN 3. Patients who infrequently have very high proteinuria, well above a nephrotic range of three, eclipsing five grams per day. Adolescents who have IgA Nephropathy, who are of adult size, who would have the same opportunity to benefit as someone who is a little bit older, why should we be excluding them? Patients who've had kidney failure and have required a transplant due to IgAN but now have a recurrence of their disease, why should they not have the opportunity to benefit from precision B-cell modulatory therapy? And importantly, patients who have concomitant vasculitis along with evidence of renal disease. And for those of you who recall our January R&D day, you know I talked about a case study from an individual from 1791 in Vienna. His name was Wolfgang Amadeus Mozart. It's believed by me and others that Mozart had what's called Henoch-Schönlein purpura, or IgA vasculitis with renal involvement. Therefore, if Mozart were alive today, he would be eligible to participate in this clinical trial. I'm really excited about this program, and in my mind, this is a new foot forward in drug development for IgA nephropathy. I think when I look at the landscape of clinical development that has come before by all sponsors, they've been laser-focused on phase 2 to phase 3 to approval, focusing on the high-risk population. But I'm not aware that any sponsor has said, "You know what? We have enough confidence in the data we've generated to date, and we have enough confidence in the congruity between our phase 2 design and our phase 3 program that we're willing to step up our investment today and generate data in all patients with IgA nephropathy and not wait till after approval. So at the time that we launch, we'll have experience in all of these different flavors of IgA-mediated disease. One of the other things I love about this program is the efficiency that we're gaining by prosecuting in this direction. So because the inclusion criteria for this protocol are completely non-overlapping with ORIGIN 3, we can bring this study to the same sites that are still actively enrolling in our phase 3 program. So now when the coordinators and the investigators are going through the process of screening potential participants, if they screen into our phase 3 study, great, they can be randomized. But if they screen fail, they can be captured in the PIONEER program. That is a great incentive for the people who are doing the work at the sites and for the participants who are willing to think about being randomized or enter a clinical trial. There's great efficiency. But not only is there great operational efficiency, but from a corporate optics perspective, there's also great capital efficiency because this is a very efficient way for us to move forward, given the machine that's already up and running, for us to generate new data in complementary populations that right now are not being studied. So there are many reasons why I think the PIONEER program is a boon for patients. I also think it's a great approach and a logical approach for Vera to proceed with as the next step in our clinical activities. But we don't want to only think about IgA-mediated disease. So on the one hand, we want to maximize the opportunity there and go after all 160,000 prevalent U.S. patients over time. But we also want to talk about other flavors of autoimmune kidney disease that are not related to anti-Gd-IgA1 antibodies. And we think there are three other histologic diagnoses that are right in the wheelhouse for Atacicept for the next stage of our investigation. That includes membranous nephropathy, focal segmental glomerulosclerosis, and its sister histologic diagnosis, minimal change disease. In aggregate, these new diseases that all the populations of those diseases that have an autoimmune component, we think represents another 70,000 patients, which means in totality, the clinical development program for atacicept now is poised to potentially cover 230,000 patients in the United States. So let's talk a little bit about autoimmune glomerular disease and a cell of interest for thinking about this. So the ultrastructure of the filtering apparatus of the kidney within the glomerulus includes one epithelial cell subtype that is really important, and that's called the podocyte. The podocyte is a cell where its biophysical makeup is essential for its ability to contribute to the physical barrier that keeps large macromolecules from being filtered from the glomerular capillaries into Bowman's space, which is the beginning of the formation of urine. These epithelial cells have a structural makeup that includes a number of foot processes that help to form this barrier to filtration of macromolecules. And in certain settings, the protein makeup within this cell is disrupted and dysregulated. Proteins like Rho and Rac are involved in this. And when there's disruption, you get change in the biophysical makeup of the cell. These foot processes are effaced, and this natural barrier to macromolecule release from the bloodstream into the urine is removed, and that drives clinical proteinuria. So we will talk about some of these diseases as being "podocytopathies." They're disorders that involve this particular cell, the podocyte. One of the interesting things about this is there can be an immune-mediated component to the effacement of foot processes in podocytes. And that's where I think we have a great opportunity with atacicept. So let's begin with the first of these diseases, membranous nephropathy. Just like in IgAN, we've talked about anti-Gd-IgA1 antibodies that are produced by B cells. Here, we can talk about anti-PLA2R antibodies that are produced by B cells that are binding to a glomerular antigen called PLA2R. This is expressed by podocytes. And when anti-PLA2R binds to PLA2R, it can drive this disruption of podocyte integrity, dysregulation of the cytoskeletal makeup, effacement of foot processes, and overt proteinuria, larger proteinuria than we often see in IgA nephropathy, exceeding what we would say is a nephrotic range of three grams per day. So because this is the generation of anti-PLA2R antibodies is driven by B cells, this is a very similar opportunity from a mechanistic perspective, as we've been talking about for some time with IgA nephropathy. We're just talking about a different autoantibody that we want to declare war on, so we can think about inclusion of a cohort of patients who've got biopsy-proven membranous nephropathy and have demonstrable high titers of Anti-PLA2R antibodies, just like we think about patients who've got biopsy-proven IgAN, and importantly, because patients with membranous nephropathy are treated in the same clinics that are involved in ORIGIN 3 and are treated in the same clinics that now will be involved in PIONEER, we can add a cohort into this program that's not only focused on IgAN now, but that can include patients with MN who've got Anti-PLA2R antibodies, and over time, we can look at the reduction in Anti-PLA2R antibodies as an indicator of the signal that we've had the impact on the disease that we will hope. I expect that we'll see a prompt reduction in anti-PLA2R if the drug is working as we expect in this disease. Then over time, we'll see a reduction in proteinuria that will deepen over time. That's the hypothesis. Because we've already engineered the Pioneer program, the ability to augment it with an MN cohort means a very efficient way of moving forward with both the winning IgAN strategy, but also a way of getting new signal detection in a complementary disease. Wait, there's more. We can move beyond an anti-PLA2R story, and we can think about another autoantibody-mediated autoimmune disease, and that is FSGS and minimal change disease. FSGS and MCD are histologic diagnoses. We often think about them as sister diagnoses, and they have a heterogeneous etiology. What do I mean by that? There are a number of different things that can drive a histologic readout that results in declaring a patient as having FSGS or MCD. They can have non-immunologic-based chronic kidney disease. Classic model is renal ablation, where you remove a certain amount of kidney tissue. But there are other flavors of non-immunologic disease that drive this histology. But importantly, there is a component of this disease that is directly being driven by an autoimmune component. And in recent years, we've identified the protein nephrin also expressed by podocytes. And when anti-nephrin autoantibodies bind to nephrin, you get a very similar mechanistic story as you get with anti-PLA2R binding to PLA2R. You get disruption of the podocyte cytoskeleton, effacement of podocyte foot processes, and nephrotic-range proteinuria. So we can come back to Pioneer, and we can say we've got our winning IgAN cohorts. We've got our membranous nephropathy cohort with demonstrable levels of anti-PLA2R antibodies, and now we can look at biopsy-proven FSGS or minimal change disease and patients who've got demonstrable levels of anti-nephrin antibodies. Another cohort to add to this study in a very efficient executional way to give us readout that we can reduce anti-nephrin antibody levels initially, and then also to measure proteinuria and GFR over time, so one program that has the ability to allow us to go much deeper and broader in IgA nephropathy to study anti-PLA2R podocytopathy and anti-nephrin podocytopathy, so this story, in my mind, allows us to think a little bit more broadly, and it's not lost on me that we're in New York City, about half a mile to the northwest of the Lasker Foundation. In 1960, the Basic Science Award that was given by the Lasker Foundation went to Watson and Crick for the discovery of double-stranded DNA. If you go back to the original Nature paper from 1953, you'll see that Watson and Crick talked about this new structure of DNA, but they also said, "You know, it's not lost on us that we can think more broadly about just the structure, and we can think about a replication mechanism that's invited by what we've learned." I think this same general concept of having a near-term plan and thinking about the mechanism of this particular drug, but then taking a step back and thinking about the broader long-term opportunity, which we're not solving today, but we can ask a question today, and we can say it's not lost on us that this is possible. And that is antibodies associated with other autoimmune kidney diseases. So what do I mean by that? So let's look at the timeline of how we've learned about different autoantibodies in autoimmune diseases that involve the kidney. So if we start on the left, it was in the late 1990s that we identified Gd-IgA1 and anti-Gd-IgA1 autoantibodies. Ten years later, we learned about PLA2R and anti-PLA2R antibodies. And now we've got a commercial assay that we can use to assess that. More recently, we learned about nephrin and anti-nephrin antibodies. But undoubtedly, there are other constructs of autoantibody, autoantigen combinations that are fueling the same phenotype of proteinuric or, in some cases, nephritic kidney diseases. But we've got a drug now, a drug candidate that's a precision B cell modulator. So it's great that we know about Gd-IgA1 and anti-Gd-IgA1. It's great we know about PLA2R and anti-PLA2R, and it's great that we know about nephrin and anti-nephrin antibodies, but what about the things that we haven't yet characterized? Well, Atacicept is a drug that has potentially been an incredible therapeutic, but I also think it's interesting to think about it as a potential diagnostic. What if we had a patient who presented with nephrotic-range proteinuria who we suspected might have an autoimmune component, but they didn't have high titers of anti-PLA2R, and the anti-nephrin antibody isn't available commercially today? It will be in the future, but we don't have it today. We could give that patient a trial of the drug for eight or 10 or 12 weeks and look at reduction in proteinuria, and if they had that, they would be able to be categorized as a patient who has a B cell modulatory responsive autoimmune kidney disease. And if we didn't know what their autoantibody was, we could do some proteomics and try and figure out what's circulating in that patient that's driving this phenotype. And it also allows us to think about a clinical trial. We could take patients, identify that they're an early responder, and now randomize them to therapy or no therapy and lead to a really efficient way of progressing to an approval. So it's a very interesting concept for the future. I think only by having a tool like Atacicept can we even ask the question, might we be in a position one day not only to categorize patients by their histology, but can we think about defining patients based on the fact that they have an autoimmune disease and they're responsive to B cell modulation as a way of categorizing them as a cohort of patients, irrespective of if they got the same or a different histology from a biopsy? In aggregate, the story that I've shared with you about winning in IgAN, about venturing into membranous and moving forward into FSGS and minimal change disease, focusing on those groups that have an autoimmune component, means a prevalent population in the U.S. of about 230,000 patients. As Marshall said, that's not lost on us at Vera that the opportunity for Atacicept is much broader than these focused definitions of autoimmune glomerular disease that we're going to attack in the near term with PIONEER. There are many other places that we can and intend to go. We also want to be prudent in terms of how we are moving forward. These are things that we'll talk about in the future. In the near term, we're focused on starting ORIGIN Extend, starting PIONEER, and moving forward to generating those data for the ultimate benefit of patients. To build on what Marshall shared earlier, this is the way we think about the new modern view of the projected catalyst for the company over the next 18 months or so. We've got the activities that we previously shared that include the 2b 96-week data that we'll reveal in a number of weeks, phase three top line results in the second quarter of next year, BLA submission for accelerated approval in IgAN in the second half of next year, and a projected U.S. launch in 2026. This is now met with new activities from the Extend program and from Pioneer. Extend will begin this year, and that means we'll have data readout for the first time from a portion of that cohort in 2025. The Pioneer program will begin enrolling in 2025, and we'll have initial data readout from that protocol next year as well. So in aggregate, a large advancement of the things that we're looking forward to over the next 18 months. With that, I want to thank you all for your attention and turn it back to Marshall. Thanks so much, Rob. Fantastic to get your perspectives on this. At this point, I'd like to introduce our expert panel and have them come up to our director's chairs here. Hopefully, they're not too tall. It's my real pleasure to welcome three expert clinicians, researchers, and respected leaders in the field: Dr. Jonathan Barratt, who's Professor of Renal Medicine at the University of Leicester, Dr. Richard Lafayette, Professor of Medicine and Nephrology at Stanford University Medical Center and Director of the Stanford Glomerular Disease Center, and Dr. Brad Rovin, Lee A. Herbert Professor of Nephrology at Ohio State University Wexner Medical Center. So, thanks so much for joining us, and we have the ability to ask questions from the floor live. I did get a few already, so I'm going to begin with a few that I've already received by text, and then we'll open up the floor to questions. So questions can be directed to any of our experts today or to Rob or myself or Sean. So first question is to Dr. Barratt. I need glasses. First question is to Dr. Barratt. Do you think that the nephrology community is aware of the importance of targeting an eGFR of minus one mL per minute per year slope? And do you think this target is achievable today or with the availability of a new drug candidate in the next one to two years? I think there is a lot of interest in the RaDaR data. But of course, that's a U.K. population. But we are seeing data coming out from the U.S. So John Sim has some really interesting data from the Kaiser Permanente group in California that really reflects the outcomes from RaDaR. We have data that's going to be published shortly in Sweden that reflects again that severity. And there'll be a paper coming out from China shortly that also reflects the severity of the disease and what we hope to achieve. And we already have data that the GFR at time of presentation is already significantly impaired in the majority of patients. And as Rob said, it's very simple to do the math. If you're 30 years old and you present with a GFR of 55, it doesn't take much to work out what your rate of loss of kidney function needs to be to avoid dialysis in your lifetime. And we know in the United States, actually, patients present much more closer to CKD4 than in other parts of the world. So they present later. They're young people, late presentation. We've got to work very, very quickly to give them treatments to prevent kidney failure in their lifetime. And that has been an aspiration for all of us for most of our careers, to be quite honest, because all the treatments we've seen that manage CKD slow but do not stop that rate of progression. Again, nowhere near as you showed that one mL per minute. But we're starting to see data and the data that you presented today that means this could be possible to actually impact on the rate of loss of kidney function to the extent we need to prevent kidney failure in the lifetime of our patients. John, just to follow up on that, can you give us just it was mentioned briefly by Dr. Brenner around the KDIGO guidelines? Maybe a little bit of context for the crowd today about the KDIGO guidelines, where they stand today, and where we expect them to go in the near term. So the update has been out for public review, which closed on Monday. So those public comments will be taken on board, and the draft will then be updated with the idea that we will have a fast turnaround for publication early in 2025. So you can access those on the KDIGO website. And it's very clear that in the guideline, what we are putting forward is a sense of urgency to make the diagnosis, a sense of urgency to treat, and a sense of what our target should be. Now, our target, we state, is to get kidney function rate of loss less than one mL per minute per year. But of course, that's something we can only look back on over time. And what is the immediate thing that we can measure in clinical practice is proteinuria as a surrogate for that rate of loss. We are really asking clinicians to drive that proteinuria as low as possible with the treatments that we have available, because that's the best way on a day-to-day basis that we can estimate that we are getting closer to that one mL per minute per year. The KDIGO is very, very clear. It is a complete change from the previous guideline from 2021. Diagnose early, hit hard early with a much higher target for reducing proteinuria and slowing rate of loss of kidney function. Great. Thanks so much. The next question is for Dr. Lafayette. How does the ORIGIN Extend and PIONEER programs compared to other development programs in IgAN and autoimmune kidney disease? And do you think these studies will have an impact? Yeah. So good morning, everybody. It's great to be here. And I do think that these programs are extremely important to look at longer-term safety, first and foremost. It's really important. It's very nice to be in the Atacicept programs because there is a past history with the drug, and there's been many, many patients treated for moderate term, and the drug's looking extremely safe. I think it's really important still to have further experience. I think the differentiation for origin two to have two years of experience to show that safety, but not only that, but to show an ability to have a good, solid, prolonged effect on proteinuria, as Dr. Barratt mentioned, which is our main surrogate outcome of what's going to happen to kidney function, but also to be able to look at the kidney function itself and say that's remaining stable, stable, stable. Because even though we use proteinuria across disease, we've seen in different programs that even if we control proteinuria, we're still seeing substantial loss of kidney function, better than it would be without antiproteinuric therapy. But these types of therapy that get to the root of the disease may be more effective at preserving kidney function, seem to be so far. So I think extending that experience is going to be critically important to make sure it stays true, that our assumptions are holding, that the agents are safe. Again, extending this to other populations is going to be very, very helpful because that's what we need to do in our clinical practices themselves. And then finally, compared to other programs, again, the data's certainly the most mature, certainly the most promising, the most de-risked, as Dr. Brenner would say, and others are trying to follow. I think we'll see certainly extension data, longer-term data, and entering other programs. But this certainly gives Vera the chance to be the leader. Great. Thanks, Dr. Lafayette. I have to make the comment that beyond the ORIGIN three protocol, extending Atacicept clinical exploration into adjacent populations is something that we're leading in, we will lead in. And it makes me think of particular patients I've met at the IgAN Foundation who I now look forward to seeing next year at the IgAN Foundation meeting and saying, now we have a trial for you. It's not comfortable being a physician CEO saying no to a patient when they see the promise of the molecule. You explain what you're doing, and you have to say no. So this is a really, first on a personal level, an exciting step for the company. But also from a corporate perspective, this is what we mean when we say we're going to have important clinical information on these patients. So excited for that next step. Dr. Rovin, a question for you. Could you comment on the strategy to potentially define autoimmune kidney disease not only based on histology, but also by the presence of autoantibodies and glomerular antigens, and perhaps even based on response as a diagnostic tool? Dr. Brenner's last comment. Yeah. It's pretty exciting to think about the different possibilities. We've been stuck for a long time basing almost everything we do on histology. And the problem with histology is the kidney has a defined, limited set of responses to histology no matter what the disease is. And so that can become very confusing as you move forward in trying to understand what various things like proteinuria actually mean. Now, if we start moving towards an immunologic/physiologic response, this idea that Dr. Brenner posited just a few minutes ago is very intriguing, which is the idea, can we simply start to target what we believe or what we can show is the disease pathogenesis instead of just the histologic findings? Then going backwards, if we don't have a diagnosis, which is what he was saying, but we use a short course of a drug like Atacicept and then we get a very good response, can we then go backwards in that patient population and identify a potential immunologic cause, i.e., an autoantibody? So for me, who investigates the molecular pathogenesis by dissecting kidney biopsies and looking at transcriptomics and proteomics, this is the next generation of where we need to be. This is where cancer already is. We, as a community in nephrology, have not done that to date, but we're rapidly catching up, I think. Great. Thank you, Dr. Rovin. Such an opportunity to have everyone here. I'm going to stop looking at my phone and open the floor to questions, and I'll give some precedence to our analysts. I just want to, again, thank the analysts who've been following this story for some time. How about I begin with you, Ritu? We should have a mic for you. Thanks, Marshall. Ritu Baral, TD Cowen. Thanks for taking the question. This is for, I guess, all of the doctors. Insofar as we look at Gd-IgA1 reduction for IgAN, is there a threshold for pathological antibody reduction, anti-nephrin, anti-PLA2R for membranous nephropathy and/or FSGS that has been identified? And then for those indications, could proteinuria prove to be a key accelerated approval? Is it as meaningful for these indications to drive a potential accelerated approval like with IgAN? Great. Great question. Maybe I'd start with Dr. Brenner, just a few comments, or yeah, and then hand it to whoever you'd like. That's right. It's a great question, and in many ways, we're going to learn. I think Pioneer provides an opportunity for us to look at this with open eyes. I'll let the others comment. I don't think there is a tried-and-true set of definitions that exist today. I think we're going to learn, right? We'll see what is the percentage reduction that we achieve with anti-PLA2R and anti-nephrin antibodies. What's the correlation between that and reduction in proteinuria? My personal view is that proteinuria reduction in these diseases is as important as it is in IgA nephropathy. Therefore, I think if the regulators have embraced using proteinuria to drive an initial approval, I would see no reason why that wouldn't be cogent in these diseases, but we'll have to see. Anybody want to comment? Yeah. So if we just deal with IgA nephropathy first, we've never had drugs that have been capable of reducing Gd-IgA1. So we've never had the ability to track that change with outcomes. And the way I think I would look, and I'm going to advocate here, the two-year data that will be presented at the ASN, our goal is to reduce the rate of loss of kidney function to normal physiological aging. So if I look at that population and I work backwards, how much Gd-IgA1 did I need to reduce at three or six months to achieve that two-year outcome? Because clearly it was enough, because any more would have not added, would have not made the kidney function any better, because we're not presuming the kidney function is ever going to get better than physiological aging. So whatever that is with Atacicept at three months, at six months, it was clearly enough to generate the response, which is most important to me in patients, which is their GFR. So we're going to learn that as we have more longer-term data. So I think that's where we're going to look back and understand that amount of Gd-IgA1 reduction. And it may well be different with different mechanisms of action. We don't know whether achieving that level of Gd-IgA1 reduction with a BAFF and APRIL is the same as achieving it with an APRIL only or with a CD20 depleter. We're going to need to work that through over time. In terms of FSGS minimal change, particularly FSGS in terms of outcomes, there is a project called the PARASOL project, which is where you need to look, which is where the regulators and the worldwide academic community are looking at outcomes for drug approval in that disease, and this is something that is a work that's evolving, which is going to come up with some conclusions by the end of the year, so the FDA is involved, the EMA is involved, and really, the global data for FSGS is being shared to do the analyses to tell us what is a good outcome in terms of measurable outcome to give a drug approval, and there it looks like it's going to be proteinuria, but that hasn't been confirmed, and then I'll probably hand over to Brad about membranous, because I know he's been involved. Thanks, John. And just for the audience, we're meeting next Monday to discuss the interim look at the PARASOL data that hopefully will be presented at the ASN. So this project is right on track to look at proteinuria and GFR in FSGS. Membranous is a little bit trickier. And there'll be a sort of an editorial coming out in Kidney International that was the result of an FCUR meeting. But one of the things that we've postulated with membranous nephropathy, at least PLA2R, which is the most common form of membranous nephropathy, is that we want the autoantibody to go to zero. In other words, we want immunologic remission, and then the change in proteinuria will follow. And we know that the change in proteinuria in membranous is delayed when you start to give immunosuppressive agents. Your idea of the threshold is still important because the ELISA defines PLA2R as normal, which probably isn't the right word, less than 14 units, but in fact, we all have patients who have active membranous with the ELISA having less PLA2R, and some folks think that this has to go to zero, and of course, it depends on the ELISA and the sensitivity of the ELISA, et cetera, and this is all going to get better over time. We have the one ELISA that's approved already. The idea of proteinuria and membranous is really a tricky situation because the delay in proteinuria response in terms of getting immunologic control can be several months, and so it's pretty significant, so what we advocate in the paper is a PARASOL-like approach for membranous nephropathy, asking the renal community to come together and provide data on their own cohorts. We would love to use an antibody for accelerated approval and then follow it up like we're doing with the paradigm of IgA now and FSGS trials, following it up with a GFR over time. This has been a challenge, I'll just admit, with the FDA, and I'm not entirely sure they buy into this entire concept, but they are co-authors on the editorial, so you might have a chance to read the paper was just accepted last week. You'll have a chance to read it shortly. Great. Thanks, Brad. Lisa. Hi there. Liisa Bayko at Evercore ISI. Two questions, actually. The first one, just in the context of Parasol and the topic of variability, can you talk about the variability of eGFR in the IgAN population? You kind of showed it as pretty linear, but there's still a wide range of 4-10 mL. Does it change over time? What does the pattern look like? And then question number two is, what is the latest thinking on any ethnicity differences for IgA Nephropathy in different populations? I know the Asian population has been called out quite a bit. I'm curious about the latest thinking there. Thank you. Yeah. So those are wonderful questions. Again, clinically, we're only starting to see really great databases about stability of GFR change in patients with IgA nephropathy. I think very fortunately, the world's really been revolutionized. So patients are now going to be subjected to much better therapeutic paradigms. So we'll see. But historically, we could look at patients over three years, five years, or 10 years, get their progression rates, and see that for an individual, it was very predictive. If you were progressing at a certain rate of, let's say, three ml per minute per year for a few years, that was likely what you were going to do. And it was going to be relatively stable. Individual patients sort of have peaks and valleys of progression over time and intercurrent illnesses. But still, for populations, they get to be pretty linear. This is something that can be followed better in populations than in individuals, but still very predictive. You can still find high-risk and lower-risk populations based on their progression rate. Again, the higher the proteinuria, the lower the GFR, the more likely they're going to have more rapid progression and need more immediate therapy. Again, with this paradigm, we want to treat everybody with effective therapy. Not only that they can stave off rapid progression to dialysis, but ever progression to dialysis as well. To your other point, yes, race and ethnicity really does have an impact in this disease, both to the genetic issues, environmental issues, access to medications. So I think we have to be very cautious in our approach to the trials. And the phase 3 trials have been very laudatory in that there's a good mix of male-female patients of different races and ethnicities, and especially trying to represent the fact that this is worldwide an Asian-dominant disease followed by Caucasians, fortunately mostly rare, and people of African heritage. So sort of following that paradigm, and so far, at least coming back to atacicept, it looks like it's well-balanced, that it works across populations. And we'll learn that better from the phase 3 data. Other comments? Great. Vamil? Thanks. Vamil Divan from Guggenheim. So two questions, if I could. So one, we've touched on this a little bit, but this sort of 96-week data that's coming up at ASN, a lot of investor focus there, but also with all these other programs that are reading out. Can you just talk maybe for the KOLs just your range on what you'd like to see at two years, given the natural history that we see in terms of eGFR decline, whether it's for Atacicept or the others? Kind of what's clinically meaningful from a slope at two-year endpoint? And then my second question, more for the company. A lot of interesting programs you're talking about here. I think another question we commonly get is your ability to advance all this on your own. Is there any thoughts of partnering any of this or working with other companies to accelerate this work where you'll get out faster than what maybe Vera could do on their own? I'll just answer the last one first, and we'll come back to the slope question, but there's clearly interest. Vera is announcing this expansion today because we're capable of doing it on our own, and we're doing it on our own. I think we're creating a lot of value quite quickly. Currently, we do not have plans for partnership. The question to GFR slope, Richard? Yeah. So I think you saw the 72-week data. And Dr. Brenner presented that very nicely, saying it really met all the aspirations. So we had a really beautiful, stable impact on galactose-deficient IgA, on proteinuria, and on hematuria as well, and then real beautiful stabilization of GFR. So the 96-week data would be hoped to show stability, that again, the galactose-deficient IgA is steady, that proteinuria stays stably down in a lower-risk range, and that GFR achieves what the guidelines are suggesting, that it stays at less than one ml per minute per year progression rate. I think that would be considered super. Again, scientifically, we would want to, again, maybe look at that data even more, look for other biomarkers of success versus not success among subpopulations who do exceptionally well versus less well. So there'll be more work to do. But upfront, we just want to see that that 72-week data is holding true at two years. And that would be really exciting. Yeah. Sorry. I'm just going to comment on the partnering thing. To be honest, I have patients. Now, I know in the UK, we would have enough patients to recruit to all of those IgA substrata, because this is what patients are asking for. We are screen-failing people. We're not even bothering to bring them up because of their GFR, because of their proteinuria. So those patients actually exist, and they've been ignored by every single phase three trial since phase three trials started. So there's a massive pool of these patients. The worry is going to be being a site that gets opened early, because we're going to just recruit these patients really fast. And the commonest thing I get called about is recurrent disease in kidney transplants. And I'll let these guys comment. I could fill that study with 10 patients. I could give you the names now. That's how important this subset are. And the same for IgA vasculitis. So there is going to be absolutely no problem recruiting these patients. The problem's going to be disappointing lots of sites that the numbers have already been chewed up. So what you can guarantee us three will be doing will be twisting Rob and Marshall's arms behind their back to increase the numbers, because there is such a massive unmet need in those populations. So I don't know. I've never been in a meeting like this. I don't know if there's any levity allowed, but. Seemingly so. Okay. Good. Good. So yesterday, we have our pathology conference, and they presented a young guy who's got recurrent IgA that's rapidly progressive, and so we discussed this, and I said, well, I would love to get Atacicept to treat this patient, because I have nothing else to give him other than cyclophosphamide. Plus, you understand he's transplant, so he's on a bunch of other immunosuppressives that he just burst right through, and so the idea was, could I, at dinner tonight, after the company has had plenty to drink, induce them to let me use the drug on a compassionate basis? But seriously, I think that this plan of going forward in these populations is absolutely critical, at least in the United States, where I have access to a lot of these drugs that have been approved. I have not been using Filspari very much for IgA nephropathy, but I use it off-label for FSGS, for example. I am using the Calliditas product. I'm not saying anything bad, right? Everybody here knows all the field. I've been using the Calliditas for patients with low GFRs and with no proteinuria who have active urine sediment. So all of these things, I believe, can be addressed by the drugs that are actually looking at the pathogenic mechanism of generation of IgA. And so I'm very excited about actually getting to do it in a trial. And as John said, I think all three of us have wanted this sort of thing, and we've not got it yet. And the other thing is extending it down to kids. We tend to ignore kids because they're harder. I realize adolescents are not particularly kids, but at least it's a step in the right direction, and nobody else is moving in that direction yet, so I think we have to acknowledge Vera for doing that. Thank you, Brad. And levity is allowed, especially when the pipeline means you want access to atacicept. Rami. Thanks for taking my questions, guys. Rami Katkhuda, LifeSci Capital. I guess first, can we touch on the current treatment paradigm in membranous? What portion of patients are moderate to high-risk and require treatment? What portion of patients kind of don't achieve remission with rituximab currently? And then secondly, for the company, it sounds like you'll have early proof of concept next year with Pioneer. How quickly do you envision Atacicept coming to market for these newer indications if all goes well? So I'll start with the membranous treatment paradigm. So again, we risk assess our patients. About half of them will be moderate to high-risk and need therapy right away. Depending on where you are regionally, at least in the U.S. and most parts of the world, people will reach for Rituximab most commonly now. But there are still places that really like this, Cyclophosphamide and Prednisone alternate month regimen, because still historically that has a slightly higher response rate and lower relapse rate. So it's certainly reasonable. But these are older patients who get this disease, and there's certainly concerns of the risk of that regimen, even though the risks haven't been differentiated in clinical studies. There's still folks who still go to calcineurin inhibitors because they're very easy to prescribe. They're highly effective, but there's a tremendously high relapse rate. So overall, again, half of patients need to be treated right away. About another 10%-15% need to be treated in a delayed fashion. So people do come to therapy and don't reliably come to spontaneous supportive care remissions. And still, after all of that, at least a third of the patients are left either unresponsive or recurrently relapsing. So there will still be quite a significant unmet need. And again, the therapies are still, in the case of cyclophosphamide and substantial doses and exposure to prednisone, can have nasty side effects and a risk for adverse events. In the case of rituximab, still some concern for irreversible immunosuppression. So I think there's huge opportunity for new therapies and definitely would like to see them come forward. I work on the KDIGO guidelines, so I don't necessarily agree with everything that all the work groups write. Thought for launching. What's that? Thought for launching. Yeah, of course. So let me just say, from a historical perspective, we have really sat back and watched membranous nephropathy evolve, because the only therapy we had was cyclophosphamide. And many of my colleagues, not the folks sitting here, are reluctant to use cyclophosphamide, and with good reason, but it can be done safely, certainly, if you know how to use it. And so we would let membranous nephropathy languish, trying to get the proteinuria under control with RAS inhibition. And years ago, when I first started at Ohio State, which is a long time ago, I said, "I would want to be treated. I don't want an autoimmune disease occurring in my kidneys for any length of time, even though a third of the patients are said to spontaneously remit." And so everyone told me, "You're crazy. Why would you put a patient on?" And I didn't put him on Cyclophosphamide. I followed the rules, but it really bothered me. The advent of getting drugs with less toxicity makes me want to treat all the patients as soon as possible. Now, if you give me a patient that has a very low PLA2R and not much proteinuria, I'm okay to sort of wait and see if those are going to spontaneously remit. And of course, to what I'm saying, A, it's my own opinion, and B, there's an exception to every rule. Patients who have high PLA2R levels and a lot of proteinuria, they're not going to remit, and they need to be treated. And the fact that we have drugs now, Rituximab is one, that is relatively safe compared to other drugs, then there's no, it should be a knee-jerk that we start to treat these folks. Now, what was left, I think Rich is exactly right, 40% of the people are not getting into remission with rituximab. And the ones that are getting into remission, there's an overwhelming number of partial remissions instead of complete remissions. So that's the other thing. I want to go into complete remission if that's possible. I don't want to have proteinuria, because I believe proteinuria is toxic to the parenchymal cells of the kidney. So I think that rituximab is a good step forward in allowing us to broaden our treatment and change, hopefully, our philosophy over time on how we treat membranous and approach it. What I really like about the BAFF/APRIL inhibitor is that we're targeting B cells, and we're targeting plasma cells, because we hit BCMA on the plasma cell. We know from the FELSA data that we published earlier this year in KIR that we can get a nice decline in PLA2R antibodies targeting the plasma cell, but that's short-lived, because a lot of those patients popped up again. The idea of simultaneously hitting and modulating the B cell that will eventually become the plasma cell that's making the autoantibodies is extraordinarily appealing. If Atacicept can bring the same degree of safety to the membranous population, and I have no reason why it wouldn't, to the membranous population as it does to the IgA population, then you have a very nice combination of a drug that will give the B cell depleters, i.e., the anti-CD19 or CD20s, a run for their money. Let's be 100% clear here. Obinutuzumab is finishing up a membranous trial. And it works way better than rituximab, in my experience, in most of the diseases I treat, again, off-label with the drug, because it isn't available for most of our diseases yet. So I think this is going to be sort of where we end up. We're going to have a B cell paradigm for membranous. We're going to start to treat early. And Atacicept might be actually a perfect one to initiate that treatment. And I think a big difference for all the diseases we're talking about is if you take a depletion strategy, you have no control over when those B cells come back. And it varies from patient to patient. And we all know there is absolutely no point vaccinating anyone once they've had Rituximab, because they're not going to generate antibody responses. The beauty of this approach, with the half-life that you have, is if a patient becomes sick or there's a pandemic, for instance, and people need to be vaccinated, you can stop this therapy, give the drug holiday, allow for those vaccinations to happen, or if that person's sick, allow that treatment to be treated, and then restart without that worry that actually you've given the drug, it's in the system, and you're going to have to wait six, eight, 12 months before their B cell replete and actually have a functional humoral immune system. So I think it's really important that you can switch on, switch off quickly, particularly for membranous, where it's a disease of much older people. In a 30-year-old with IgA nephropathy, they're almost indestructible. But in a 60-year-old or 70-year-old who might have diabetes, coronary artery disease, et cetera, et cetera, we need to be that much more cautious about how we manage their immune system. Also, John and Rich, I mean, one of the things that I've found remarkable looking at the IgA data is you do see a depletion in the immunoglobulins, but it's really right now the biggest depletion is in IgA. And you still maintain a pretty healthy IgG level with the B cell modifiers, which goes along with what John's saying. I mean, I'm talking ideal world, no pandemic, nothing else. We have to be very careful about being cavalier with these drugs. We do get infections sometimes. And so if we can maintain the humoral immune system or the cellular immune system, whatever you want, we have an advantage in treating. Yeah, that's an important point, and maybe, Rob, you could describe what we saw, because we did run ORIGIN-2 during the COVID-19 pandemic. It's a randomized control trial. At the time, I was visiting sites and making sure that we could recruit during the pandemic, and one might imagine taking a B cell modulator raised some concern around infection, and what we saw was actual balance in infections generally, as well as COVID-19 specifically, positivity rates, no difference in severity and no deaths due to COVID in patients taking active chronic administration of atacicept. John, that's something you've commented on before, maybe just your view of that data to date. Yeah, I mean, I think that's really reassuring. We in the UK had very numerous bad experiences of people who had received Rituximab, and then the pandemic hit and didn't respond to their vaccines, didn't respond to an infection, so that they were then at risk of recurrent infections in an elderly population, because that's who we use Rituximab in. It's ANCA vasculitis. It's membranous at the moment. And I think what we would have really very much liked is to have been able to interrupt therapy, get the patient properly vaccinated, and then reinstitute therapy to stop disease relapse. But of course, we didn't have that opportunity, because we have no control over when those patients replete their B cells. So that was a real challenge for us. Of course, we need to make sure before we give Rituximab, for instance, that we are making sure they have all their vaccinations up to date. Of course, you can never guarantee what's going to happen in the future, and people will replete at different times. Great, great, great discussion. Keep going here. Pete, please. So a couple of questions. Pete Stavropoulos from Cantor Fitzgerald. With the current understanding of PMN and sort of extrapolating from the kinetics of IgA reduction from the ORIGIN study, considering the half-life of IgG, what's your expectations in terms of time to seeing a sufficient reduction in the antibody response, PLA2R, and may translate to basically reductions in proteinuria? Is 36 weeks sufficient time? That's one question. And then to the KOLs, you did mention recurring IgA nephropathy in patients that have transplants. So can you just talk a little bit about how much of an unmet need that is right there? Can you also discuss if there's any data out there that suggests that inhibiting APRIL or BAFF is safe in these patients that are on other immunosuppressants and the possibility of actually reducing AMR? Maybe we start with Rob on the kinetics of PK. I'll just make a comment first. There is already a trial of BAFF inhibition in membranous nephropathy that's published. And that was done in the UK. And you can very clearly see just targeting BAFF without the additional efficacy of APRIL results in reductions in PLA2R. Now, I can't remember the exact timeline, but that's published in NDT. So you can see there the tracking of PLA2R, the tracking of proteinuria with this kind of approach. But of course, that doesn't add the added value of targeting APRIL as well. Yeah. Yeah, this is a signal detection study, so we're going to define it for the first time. We want to have a larger number of subjects than have been reported to date with MN that get treated with a dual BAFF APRIL inhibitor, and we'll characterize what happens to changes in anti-PLA2R and what's the correlation with reduction in proteinuria. We're looking forward to going through the process. I've forgotten the second question already. No, those were the questions about the kinetics and the ability to, but again, I think, yeah, so I'll move to the recurrent IgA then, so it is an issue. Again, our standard textbooks will really say that about 50% of patients who had IgA nephropathy who get a transplant will recur. A lot of times that's by biopsy, so it's probably a segment of that, which is about 10% or 15% that get clinically meaningful disease, because we know that when we look about the first 10 years after transplant, only a couple% of IgA patients lose their kidneys, but when that happens, those often happen violently and aggressively, and that's despite good immunosuppression for the transplant, so it's really important to have a pathway forward, and you accumulate a good number of these patients worldwide over multiple centers, so it's really important. In terms of the safety, we do treat these patients very aggressively with additional immunosuppression beyond their core therapy of a calcineurin inhibitor and a Mycophenolate drug, frequently with things like Rituximab, Obinutuzumab, other agents for things like you mentioned both antibody-mediated and cell-mediated rejection. So I do think it'll be tolerable. These patients, again, are very closely supervised. They're often on antimicrobial prophylaxis. So it's always going to be a concern about infections. But this profile, again, looks good compared to some of the other things that we'll do to these patients already. And then just very quickly to the idea about antibody-mediated rejection, that's certainly another B-cell-mediated disease. And there would be interest in studying that as well. Sorry. Just to say, in RaDaR, we have now close to 5,000 patients. And we have all their transplant data. And there's studies, there's work going on that will describe the natural history of recurrent disease in transplantation. And we'll talk about outcomes, because I think just like we've underestimated the risk of loss of graft function or loss of kidney function with IgA, I think we underestimate the loss of graft function in an IgA nephropathy population. Of course, within RaDaR, we have multiple different rare disease groups where we can compare outcomes in the IgA patients with the transplant compared to other rare diseases, perhaps non-immunological like PKD. So I think we're going to get that data. I wouldn't be surprised if it's a lot worse and has a greater impact on graft survival than we are thinking at the moment, because this will be the largest global study ever, because these people are young. We much more commonly transplant these young people than leave them on dialysis, because they're fit and they're able to have a kidney transplant. In the U.K., for certain, the vast majority of people with kidney failure who have IgA nephropathy actually have a kidney transplant rather than are living on dialysis. I'll just add a couple points, because Rich and John covered a lot. When you look at the felzartamab data, which is a plasma cell drug for membranous nephropathy, the declines in PLA2R were very rapid, like within the first month. And I think that that is really much quicker than we expect with rituximab or that we see with rituximab. So it's entirely possible that we'll see the same sort of rapidity with a drug that can hit the plasma cells like an APRIL BAFF inhibitor. So I think that's an important thing. The other thing you brought up was the safety issue. I have some experience with that, because we did have an atacicept in a lupus trial early on, a lupus nephritis trial, which was added to pretty significant background therapy. And we did see a lot of infections that caused the cessation of that particular trial. And in talking with Vera, as you saw in the very broad plans of going forward in looking at B cell-mediated, antibody-mediated diseases, I think you saw lupus up there, which I'm particularly partial to, because that's what I've spent most of my life studying. And I think that there's a lot of us in the lupus community who wanted an atacicept back. We just had to learn how to use it correctly. And so I think, as Rich said, in the transplant population in particular is a good example of where we have a lot of background immunosuppression that we would have to modulate, undoubtedly, if we added a BAFF APRIL inhibitor. But I actually think it's doable now. And Amit challenged me to give some ideas about lupus, how we could approach that with an atacicept. I think we can do that by just changing what we do with background immunosuppression. The other thing is we're married to weird background immunosuppressions that kill everything in a disease like lupus, simply because that's what we're used to. But we know now there's several new drugs approved for lupus that we could attach an Atacicept to, and I think would be much less immunosuppressive. So I'm pretty excited that we can go forward in diseases that traditionally have a lot of immunosuppression on board and actually relieve the immunosuppression burden to the patient significantly using a drug like this. Great, great comments. Ryan Deschner? Ryan Deschner, Raymond James. Maybe for the KOLs, I'm curious how your thinking on the dual inhibition mechanism, including BAFF, has evolved over the last 12 months with the new data sets in IgA nephropathy, but equally in the new indications that are being proposed here, PMN, FSGS, and minimal change. And I have a follow-up question. I'm sorry. I just want to clarify. You're talking about dual mechanism as opposed to APRIL alone? Just as in the advantage of adding on BAFF on top of. Yeah, so I think this is really nicely derived from basic science, and Rob really tried to highlight that, that if you can safely use two approaches to stop this pathologic approach of the B cells making harmful antibodies, that that just seems more of a winner idea. Again, there's animal models that suggest it's more effective. We know biology tries to find a way that if you only block one mechanism, the other mechanism may restore that sort of balance and allow the immune system to function more effectively, and in this case, we want to modulate the immune system and keep it at bay, so I think it's exciting to have a dual mechanism that appears to be safe and efficacious. Again, right now, we only have the most advanced timeline for IgA nephropathy, so we can go rah-rah. It's best so far, because we have the most advanced data for atacicept compared to APRIL alone. They may catch up. So I think time's going to tell. Just biologically, it's attractive, especially in light of this being the best-studied agent in terms of safety so far with more than thousands of patients treated to date. But we're going to have to stay tuned and see. And in terms of these other diseases, again, some of them are more immunologically active, less immunologically active. So we may see further differentiation in diseases that may require slightly deeper immunomodulation to get a prolonged and good effect. But time's going to tell. I think if you look at the genetic data, one of the genetic risk alleles that's been identified is the TACI receptor. And that signals through both BAFF and APRIL signal through both that. I think the genetic data would support the fact we ought to be targeting both of these cytokines. I come to the added value of BAFF, and I'm going to turn over to Brad here, because there's experience of what an anti-BAFF approach adds in lupus nephritis in terms of longevity of response and relapses. That may be where we might start to see differentiation over a more longer-term timeline in diseases where you're targeting both. I don't know, Brad, whether you want to comment on the Benlysta. Yeah. So one of the surprising outcomes, which I did not absolutely at all anticipate with the BAFF inhibitor in lupus nephritis, was that we stabilized GFR much better than background therapy. And now there are some data looking at BAFF inhibition in scleroderma and things that are more fibrotic, suggesting that we may have an effect. And remember, the BLISS-LN trial was two years long, so plenty of time to start fibrosing for the placebo group. So I'm wondering if by inhibiting BAFF, whether it's through the B cell or an off-target effect on fibrosis. So I'm pretty excited about that. And the other thing that was well known from the non-renal belimumab studies was that severe flares were prevented in extrarenal lupus with belimumab. And then last year, we published a post-hoc analysis of the BLISS-LN trial. And renal flares were also significantly fewer in the belimumab-treated group. Many of these diseases, if not every single one of our diseases, is generally a recurring disease. And every time, at least in a very aggressive immunologic picture like lupus, every time you have a flare, you initiate damage that's to date irreversible. So the more flares you have, the more predisposition you have to develop chronic kidney disease. And then that would progress on to potentially end-stage kidney disease. So I think that having the dual inhibition is really going to be very interesting in differentiating this drug, maybe not for IgA. I don't know. But certainly for the other diseases that we're thinking about targeting here that have different mechanisms and different sort of kinetics of autoantibody production and resolution. So I think we have to think about that. And I think it's also something we really don't understand is we're measuring immune complex formation. We're measuring autoantibodies. And we're assuming that's the sole way these drugs work. And I completely disagree with that. I think these receptors for BAFF and APRIL are found on other tissues. They're found in the kidney. And there actually might well be that stabilization of GFR you're seeing, just as Brad was talking about, is one, treating the disease at source, but potentially also treating some downstream consequences of kidney damage within the tubular interstitium and in the glomerulus by targeting those cytokines that are driving injury. And as you mentioned, scleroderma is a disease you would not think of in relation to kidney disease in terms of a fibrotic skin disease. Blocking BAFF signaling is effective. That's by blocking the ability of B cells to alter the microenvironment by all the cytokines and growth factors that they secrete. Nothing to do with antibody production there. So I think there's a real opportunity to try and delve down into what these drugs are doing in the kidney tissue itself, because that may be a mechanism of action that we haven't really thought about, but is really contributing to the long-term efficacy of these drugs in potentially all forms of B cell-driven kidney diseases. One to add to that. And I wasn't aware of this until I joined Vera and started snooping around the literature, which is always dangerous. But it turns out that that same concept is true as it relates to type 1 diabetes and islet cells. So there's a lot that we're still going to learn about in terms of what cells have receptors for these cytokines and what are they doing aside from stimulating B cell activity and antibody production. Ryan, yeah, just to be simplistic about it, the opportunity set for dual BAFF APRIL inhibitor appears to be broader than an APRIL alone. Hopefully, that came through from these comments. Did you have a follow-up question? Yeah, quick follow-up just on how you're expecting maybe optimal dose level to vary across these new indications and the likelihood of this being a chronic treatment across these diseases as well? Thanks. In terms of dosing, we're going to interrogate these diseases with the same 150 mg dose administered as a 1 cc self-administered concept for patients at home. We believe, based on what we've seen in IgAN, that that's the right dose to take into the signal detection work in these new opportunities. So that's the plan. Great. I'm going to try to go to folks who haven't asked a question yet. So Farzan? Hi, this is Farzan from Jefferies. So, question for Dr. Barratt, I guess. So, with the KDIGO guidelines setting the treatment goal at less than one ml, so how much was that potentially influenced by the Vera data or other B cell modulators? And then, in real-world practice, what combinations is it implying? Like, you have to use combo, which could be prohibitive, I guess, by payers. But then, which combos would potentially get you to that target level? So the one ml per minute here comes from observational registry data. So that is really, you know, and it is very, very simple math. So if you go, every time I do a talk anywhere in the United States, I just ask the fellows to go and look at the GFR at the day the patient was diagnosed, the day a nephrologist gets the opportunity to intervene, how old they are, and just mathematically calculate what the rate of GFR loss has to be for the rest of that patient's life. So that's very simple math based on real data, looking at GFR on the day we diagnose a patient, and therefore we as nephrologists can intervene. So that's where that comes from. And that is our aspiration. In terms of how the Vera data compares, don't forget the Vera trial is a combination therapy trial, because the patients are on a RAS inhibitor, CKD treatment. One in five, I think, were on an SGLT2 inhibitor. So we're talking here about a dual approach, which is what the KDIGO guideline is saying we need to move to, which is a disease-modifying approach to treat the immunological disease. And accepting the fact that patients are presenting late with established CKD, we have to address the CKD as well. And we'll only win if we do both. So what we're seeing is in the Atacicept studies, patients are on dual approaches, CKD treatment, because by definition, they have to be on that to get into the trial, because that's consistent with KDIGO guidelines. For the very first time, we're able to add a truly disease-modifying therapy to treat the immunology of the disease. That's where we are going to head. We are going to need combination approaches. Unless we diagnose patients with GFRs of 100, when they don't have any CKD, in which case we won't need to use RAS inhibitors, SGLT2 inhibitors. We will only then need to focus on their immunology. That's where you start seeing that occurring in countries that have active screening programs. Taiwan, South Korea, Japan screen every child the minute they go to school for blood and protein in the urine. They pick up IgA nephropathy much earlier. Their focus there is only treating the disease, because they haven't had time to develop chronic CKD. Unfortunately, in my practice in Europe and your guys' practice in the U.S., by the time we get our hands on these patients, a lot of damage has already happened. So we have to give them CKD treatment. And what we can now do is also give them disease-modifying treatment. I want to just get to one or two more questions that I realize we're getting on in the morning. Malcolm from JPMorgan in the back row here. Thanks. Malcolm Kuno in for Anupam Rama, JPMorgan. So this is more for the KOLs in the room. What are you looking to learn from the PARASOL working group next week and at ASN in general on FSGS endpoints? And then would you be comfortable with proteinuria as an endpoint? And how do you think about eGFR given the heterogeneity of the population? So that's exactly what we're going to be looking at. By combining all of these data sets, we have, and I can't spoil anything by giving sort of this away, so we're very optimistic about proteinuria as a potential endpoint. We always have been, I would say, in the FSGS field. The optimism is, can we convince the FDA that that's a good endpoint? And I think by compiling these data, the answer will hopefully be yes. In terms of GFR, the way we measure GFR, let me put it this way, because we're not measuring GFR. We're estimating it. You all understand that, right? And the biggest variable in that estimate is the creatinine. And so these are very wobbly measurements or bits of data. And so we are looking at the same sort of paradigm. That's what PARASOL really stands for, is looking at GFR and proteinuria as the main endpoints going forward. We're going to see this new cut of data. We saw a cut of data earlier this year in the spring. Now it was only based on two or three data sets. Now we have integrated in all of the data sets. Those are the data that are going to be presented to us next Monday. I can't say I haven't actually seen all of it. I'm an unbiased observer that will be asked to comment on it when I see it. That'll be good. Anyway, the idea will be looking at proteinuria, looking at GFR together or separately. Proteinuria is a very strong signal for FSGS. Yeah. Yeah. And I just wanted, as a non-insider for PARASOL, I certainly think that's what the community wants to see, that, as you mentioned, that's what we've been gunning for for a long time, is for the FDA to really appreciate that a substantial reduction in proteinuria is a substantial improvement in long-term outcomes of our patients. So hopefully, that's going to be realized. I'm not sure if the agency is quite there yet. But certainly, we hope over these next two months of further data they'll get there. But one further point, when Dr. Brenner is trying to teach you about podocytopathies and minimal change disease and the type of FSGS that occurs with antibodies, when we have a very effective immunologic therapy for them, we don't just look for proteinuria improvements. We actually get complete remissions. And so that's the real difference of that sort of segment of FSGS that's truly an active immunologic disease without a lot of background damage, because often these patients present very acutely, not sort of slowly over time. They suddenly swell up and say, "Treat me, make me better." And there's really an opportunity to, again, prevent any long-term kidney damage if we can control the immunologic part of the disease. So it's a great opportunity. Great. Thank you. With that, I think time is moving on here. I want to wrap up and say thank you to Dr. Lafayette, Dr. Rovin, and Dr. Barratt for being here today, for crossing the pond, for saying maths, which always is fun for us. Really, this is an exciting moment. As I'm reflecting on the comments and the discussion today, it's just been very rich. The idea that we have a window of opportunity to move medicine forward is very evident to me, having trained in medicine here in New York City, being in the dialysis suite, remembering electron micrographs of podocytes. We actually have an opportunity to move the needle for patients. I'm really looking forward to what we're going to accomplish in the near term. Just to close, I want to thank everyone here, all of the analysts and the investors present for your engagement and attention, and particularly to the Vera team. It's such a pleasure for Rob, Sean, and I to represent the work of an incredibly dedicated and growing team, and we're thrilled for the milestones in the very near term. I'll just direct your attention to our next time that we hope to see many of you, and that will be at ASN. We were very pleased to receive notification of a late-breaking oral abstract on the Saturday of ASN, the American Society of Nephrology. That'll be in San Diego later this month, so with that, I want to close. I'm looking forward to a very catalyst-rich 2025 as well. We're excited to be sharing this new leg of the company as we grow the opportunity for atacicept and for Vera. With that, have a great day, everyone. Thanks for joining.