Good morning, and welcome to the Vera Therapeutics Virtual Investor Event. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations. As a reminder, this call is being recorded and a replay will be made available on the Vera website following the conclusion of the event. I'd now like to turn the call over to your host, Marshall Fordyce, founder and Chief Executive Officer of Vera Therapeutics. Please go ahead, Marshall. Thank you, Tara. Good morning, and welcome to Vera's Virtual Investor Event, where we'll be discussing the long-term results from the ORIGIN Phase IIb study of atacicept in patients with IgA nephropathy or IgAN. These results were presented this past weekend at the American Society of Nephrology's annual medical conference called Kidney Week. I'm Dr. Marshall Fordyce, founder and CEO of Vera Therapeutics. This morning, I'm joined by Dr. Jonathan Barratt, Professor of the University of Leicester, an expert physician and researcher in the field of IgA nephropathy, who presented these clinical trial results for the first time as a late-breaking oral presentation on Saturday. We're also joined by our Chief Medical Officer, Dr. Robert Brenner, and our Chief Financial Officer, Sean Grant. I'll provide a brief corporate overview, Dr. Barratt will discuss the ORIGIN phase IIb long-term results and their significance, and then we'll open the call for questions for Dr. Barratt and management. Before we get started, I want to remind you that our remarks contain certain forward-looking statements under the Safe Harbor Act, and as such, we present this disclaimer regarding at-risk statements. 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 potential major advance in medicine. Our lead product candidate is atacicept, a potential best and first-in-class dual BAFF/APRIL next-generation B-cell modulator, currently in phase III for 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 our phase II data show a reduction in immune complexes, resolution of glomerulonephritis, significant reduction in proteinuria, and most importantly, kidney function, as measured by estimated GFR, 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 has two-year data from a phase II trial, 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 II and phase III, which at two years has yielded a 90% retention rate. Since our last R&D day in January, atacicept has been granted breakthrough designation by FDA, and we have completed enrollment of the primary endpoint cohort in our phase III trial, putting us on track to read out our phase III data in Q2 of next year with potential PDUFA in twenty twenty-six. With a favorable clinical profile evolving in phase II and phase III, we believe atacicept has the potential to transform the treatment of multiple other autoimmune diseases beyond IgAN. Different from steroids and different from B-cell or plasma cell ablation, in which immunosuppression occurs, atacicept's precise modulation of BAFF and APRIL 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. Earlier this month, we shared an update on the expansion of our clinical programs for atacicept beyond the IgAN population in our pivotal trial, and are exploring atacicept's clinical utility in a broader population of patients with autoimmune kidney diseases, where we project an opportunity to reach greater than 200,000 patients. Beyond kidney disease, the ability to deliver a safe and tolerable reduction of disease-causing autoantibodies may enable broader expansion into multiple indications in the rheumatology, hematology, neurology, and metabolic fields. Vera is resourced for potential commercial launch in 2026. Regarding exclusivity, we expect biologics exclusivity protection through 2038 in the U.S., which represents 12 years from launch, and given the strength of our data set and our lead time to market and our near-term strategy to demonstrate leadership in 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 B-cell modulator with broad optionality for PK/PD exploration, dosing frequency, among other benefits that may reset patent and IRA clocks. Vera is attracting fantastic talent, planning for success, and has been actively scaling our organization for potential commercial launch in 2026. This is an exciting moment for patients as Vera leads a paradigm shift in how we treat autoimmune disease, beginning with IgAN, as atacicept's clinical data support its potential to target the source of several autoimmune diseases. Vera is in a strong financial position with $384 million in cash and has 54.8 million shares outstanding. Vera has created broad optionality to expand our clinical investigation of atacicept and IgAN in non-IgAN autoimmune kidney disease and in a broader autoimmune disease population. We shared our plans for two new studies earlier this month that expanded atacicept beyond phase III to the broader IgAN population, where the prevalence in the U.S. is estimated to be 160,000 patients. You have also heard plans for our current clinical activities to expand into additional autoimmune kidney diseases beyond IgAN, where we see a strong rationale, and in the future, we may share additional clinical activities to study atacicept in non-renal autoimmune disease and further plans for additional molecules. Vera has multiple potential value-building catalysts in the near and midterm. Last month, we announced full enrollment of our phase III primary endpoint cohort, which enables phase III readout in Q2 of next year, BLA filing in the second half of next year, and estimated commercial launch in 2026. With our expansion into two new clinical trials, we will be in a position to share additional clinical data from two new studies in 2025. Next, it's my pleasure to welcome Dr. Jonathan Barratt, Mayer Professor of Renal Medicine at the University of Leicester, to present our two-year results. Thank you very much, Marshall. I'm going to present this data that I presented at the ASN, and it's fair to say it generated a great deal of interest from my nephrology colleagues. IgA nephropathy is an important cause of kidney failure, particularly in young adults, and we know that this disease is an immune complex-mediated disease with the formation and the circulation of IgA-containing immune complexes that deposit within the kidneys, where they promote inflammation, scarring, and ultimately kidney failure. The immune complex is formed because of an excess of Gd-IgA1, particular form of IgA, and this immune complex formation is amplified by the presence in the circulation of IgA and IgG antibodies that recognize this Gd-IgA1. Therefore, it is an absolutely logical approach to fundamentally modify the disease by targeting the production of these pathogenic antibodies. We know that BAFF is critical in driving B-cell and plasma cell proliferation, survival, and IgA class switch recombination, so targeting BAFF signaling is a perfectly logical choice to fundamentally alter this disease at the source. What is atacicept? Atacicept leverages the natural biology, which is that one of the major receptors for BAFF is the TACI receptor, and this binds BAFF with high affinity, so atacicept combines this extracellular domain of the TACI receptor fused to the Fc domain of an IgG1 molecule, providing a drug that is capable of binding and neutralizing the effect of BAFF, thereby downregulating the proliferation and survival of pathogenic IgA-producing cells. The goal of this will reduce immune complex formation and circulation, therefore, reduce the pressure the glomeruli are under in terms of immune complex deposition, and really stop the disease in its tracks. So this is the design of the ORIGIN Phase IIb trial. We've already published the first thirty-six data in Kidney International. That was the randomized, placebo-controlled part of the trial, and you can see that here, testing three doses of atacicept against placebo. What we're going to describe now is the ninety-six-week data for all of those patients exposed to atacicept, and you can see from week thirty-six to week ninety-six, all patients were offered the opportunity to take atacicept one hundred and fifty milligrams weekly. And we're going to show you the impact of the treatment with atacicept in this presentation. Just to remind you, this study recruited high-risk IgA nephropathy patients. They were adults. They had persistent proteinuria, despite being on optimized renin-angiotensin system inhibition and SGLT2 inhibitors were allowed, and roughly one in four of the patients was on an SGLT2 inhibitor at baseline. I'm going to show you now some of the data that we previously reported, but first, the baseline characteristic, again, showing that this is a high-risk IgA population that is typical of those populations we see in phase III clinical trials in terms of their age, the gender distribution. Very reassuringly, we have a good split in race in terms of White and Asian, and that's really important when we understand the impact of race on disease prevalence and on disease disparities. It's really important we understand how this drug is in Asian and non-Asian patients. You can see these patients already had established clinical disease with a GFR of 62 and significant proteinuria, so 1.8 grams per gram on a UPCR on a 24-hour collection, which equates to at least 2 grams per 24-hour proteinuria, so a high-risk population, despite all of them being on a RASi inhibitor, and 1 in 4 also being on an SGLT2 inhibitor. So you can see here the participant disposition, and I just want to take you through to those who are offered open-label extension, and you can see the vast majority of those offered took up the option, and the vast majority of those that took up the option completed the 96-week treatment, and I think that's really important. It shows the acceptability of a weekly subcutaneous injection, that the patient delivers a pen-fillable injector. That's really important information to have when we think about how this drug is going to be taken up and used by patients when it's available to be prescribed. And And so to remind you of the week 36 data, you can see here that treatment with atacicept, again, looking at the 50 milligram dose, led to significant and sustained reduction in the key pathogenic form of IgA, Gd-IgA1. You can see that that reduction in Gd-IgA1 was matched by a reduction in proteinuria, and in those that had hematuria at baseline, a reduction in hematuria. Really telling us that this reduction in Gd-IgA1 is translating to healthier glomeruli, less blood and protein in the urine, reflecting less disease activity. And of course, the fundamental thing we are most interested in as nephrologists is what happens in kidney function. And in that first 36-week period, we saw no change in GFR. So these are the data we presented previously, and these are now the long-term extension, and you can see that, that this drug clearly had exactly the same impact over the longer term period. So we saw that reduction in Gd-IgA1 at 36 weeks. It was maintained out to 96 weeks, so no loss of efficacy with prolonged treatment, and that reduction in Gd-IgA1 was reflected by clear evidence of improved glomerular health, with lower proteinuria that was sustained and less hematuria. But the really important feature, which is the feature that got everyone excited at the ASN, was what happened to GFR. Reminding you, this is a high-risk IgA nephropathy population. What we see here, that over the full 96 weeks of this study, the rate of loss of kidney function in an annualized manner was 0.6 mL/min/year. I just want to put this into the context of what we've seen in other clinical trials and what we see in healthy individuals. Just to remind you, if you look at any of the published phase III or even phase II studies of what the rate of loss of kidney function is in a placebo-treated population on maximum supportive care, they lose on average 6 mL/min/year. If you look at what we achieved with atacicept over a 96-week period, we see the rate of loss of kidney function was 0.6 mL/min/year. Just to put this into context, it's estimated that after you reach forty years of age, you lose on average, a healthy individual with no kidney disease, loses on average one ml per minute per year. So what you're seeing is that we have transformed the relentless decline in kidney function we see in young people with IgA nephropathy. The rate of loss of kidney function that the general population has, who do not actually have a kidney disease, and this is something that is unprecedented, and it's never been shown before. Again, just putting this into context from the ORIGIN data that we've published. If we work out what the rate of loss of kidney function needs to be to prevent kidney failure in the lifetime of our patients, you can see here where we need to get to. We need to get to less than one ml per minute per year if we're going to make any appreciable impact in the lifetime risk of kidney failure in our patients with IgA. You can see what has been achieved with other agents that we currently think of in terms of treatments for IgA nephropathy: endothelin receptor antagonists, SGLT2 inhibitors, systemic steroids, other supportive therapy. None of them come close to achieving that target of less than one ml per minute per year. And this data for atacicept is the first time we have ever seen a treatment that comes close to what we want to achieve in terms of preventing kidney failure in the lifetime of our patients. So clearly, safety is critically important, and you can see the safety data here for the first double-blind period up to week 36, and then you can see the open-label extension for the following 60 weeks. And you can see here a very good safety profile. The drug was well-tolerated. Remember, the vast majority, over 90% of patients, continued to take the drug through that additional 60 weeks, showing its acceptability. There were few treatment-emergent adverse events that led to study drug continuation. You can see here, one in the placebo and one in all atacicept in that initial 36-week period and two in the open-label extension period. Really, no signal here that caused concern about chronic usage of this drug. So in conclusion, participants treated with atacicept for 96 weeks demonstrated sustained and substantial reductions in the key pathogenic form of IgA, Gd-IgA1. This was reflected by by reductions in hematuria and proteinuria, reflecting an improvement in glomerular health, and that was associated with long-term stabilization of GFR. The cumulative favorable safety profile remains consistent with that we observed during the initial 36-week randomized part of the study. And the conversion, I think this is the most critical aspect that we have never seen before, the conversion of an eGFR profile in patients with IgA nephropathy from one of steady, unrelenting decline to one similar to that of the general population without kidney disease through 96 weeks, is a unique and compelling finding. And I have to say that this was the subject of many, many conversations I had at ASN after our presentation. So collectively, these data support the potential of B-cell modulation with atacicept to modify the natural history of the disease and the potential to prevent kidney failure during the lifetime of patients with IgA nephropathy. So clearly, we need to acknowledge the entire team that has delivered this study, and as you can see, it is a global team of investigators representing a good breadth of patients reflective of what has been recruited in the phase III trial.... And, for more information, the manuscript for these data is now available on the JASN website as a simultaneous publication. So thanks very much for listening. I'll hand back to Marshall, but I'm happy to take any questions, that you have. Great. Thank you so much, Dr. Barratt. Just before we open up for questions, additional color on Kidney Week at ASN these past few days. A great opportunity to connect with the investigators of the ORIGIN trial, to whom we're deeply grateful to deliver these results. And furthermore, we get a chance to engage with patients and the patient foundation, the IgAN Foundation. And to remind those on the call, patients are diagnosed in their thirties, and a substantial portion of those patients progress to end-stage kidney disease before the age of fifty. That is a diagnosis that has a five-year mortality akin to colorectal or lung cancer. End-stage kidney disease is clearly a bad outcome for patients, and it marks the beginning of life on dialysis. If you're lucky, you can access a transplant, and it dramatically increases both morbidity and mortality, and costs to the healthcare system, estimated to be an average of over $200,000 per patient per year. In the coming time, we plan to get atacicept to market as quickly as possible with these patients in mind. We're now on track to deliver phase III top-line results in the second quarter of 2025, BLA submission in the second half of 2025, and projected U.S. launch in 2026. As detailed earlier this month, we've initiated two new studies, ORIGIN Extend and PIONEER, and those data will begin to be shared in 2025 as well. With that, I'd like to open up the line for questions, operator. Questions can be directed to either our guest, Dr. Barratt, myself, Dr. Brenner, our Chief Medical Officer, or Sean Grant, our Chief Financial Officer. And I'm happy to open the line now, Tara, for questions. Great. Thanks, Marshall. So our first question comes from Anupam Rama at JPM. Please go ahead, Anupam. Yo, guys. Thanks so much for taking the question, and congrats on the update. Quick question for Dr. Barratt. Dr. Barratt, from a patient perspective, how do you think about sort of a sub-Q, weekly, at-home administration as you have with atacicept versus sort of competitive, in-clinic monthly approaches that may or may not require some amount of monitoring? Like, how do you think about those two approaches from a patient perspective? I think we need to remember, as Marshall said, these are young patients with active, busy lives, with young families, careers. They want to be out having fun, and they don't want to be tied to coming to hospital for rigid appointments. And so the ability to manage their own health with an injection that they can give at a time that suits them is gonna be critical, I think, because it needs to map around their lives. And if they have the injection in the fridge, and they give it themselves at a time that's convenient to them and doesn't impact on what they can get up to during the day or at the weekends, I think that's a really positive approach. And the bottom line is we've seen the acceptability of this approach because patients in the open-label extension, they could have left whenever they wanted, and they didn't. They stayed, and over 90% of patients continued through the whole period. If there was an issue, there was some kind of systematic issue with the home administration, we'd have seen it in the open-label extension. And I think the other thing to say is, of course, this was a global study, which shows the acceptability of this approach in all parts of the world in terms of, North America, Europe, and Asia. So I think that's really reassuring in terms of what we think the uptake will be from patients when this drug is finally able to be prescribed, clinically. Thanks so much for taking our question. Thank you for the questions, Anupam. So our next question comes from Ritu Baral at Cowen. Please go ahead, Ritu. Good morning, everyone. Thanks for taking my question. One for Dr. Barratt and one for the Vera team. Dr. Barratt, how do you see the impact of increasing SGLT2 inhibitor use going forward in the phase IIIs, both on across the B-cell modulation landscape, on the primary endpoint of UPCR as well as eGFR? And then I have a label marketing follow-up for Marshall and team. So great question. In terms of just generally speaking about phase III trials and not any particular trial in particular, patients are allowed in on an SGLT2 inhibitor. We do not want them starting an SGLT2 inhibitor once they have been randomized, because that has an impact on the outcome, and we're working very hard to stop that from happening. But we know that if you're on an SGLT2 inhibitor, there'll be a slight reduction in proteinuria. But the eligibility criteria is such that we are taking people in with that degree of proteinuria on an SGLT2 inhibitor, potentially an RAS inhibitor. And there is, the rate of loss of kidney function is determined by the proteinuria level. So someone with one gram of proteinuria on a RAS inhibitor will progress as fast as someone with one gram of proteinuria on a RAS inhibitor and an SGLT2 inhibitor. But in a clinical trial sense, there'll be less people available with one gram of proteinuria if they are on an SGLT2 inhibitor, because they'll have dropped and not become part of the inclusion criteria. What I think is very clear, certainly in the draft KDIGO guidelines that we wrote, is that CKD treatments are all well and good, absolutely fine, but they do not address the fundamental elements of this disease. And what we are going to see moving forwards is the fundamental treatment you will give to someone with IgA nephropathy, with an immune complex-mediated disease, is a treatment to stop the production of immune complexes. The first thing we're going to do is give them a therapy like atacicept to stop the production of pathogenic IgA. If they present with established CKD, we may need to layer in CKD treatments like RAS and SGLT2, but they are not the fundamental treatment. The treatment is to treat the disease, and what I hope I've shown you with the data that was being presented to the ASN is exactly what this drug does. Remember, this is a combination trial. Atacicept was given on top of a RAS inhibitor, and one, it brought them out of SGLT2 inhibitor. But the fundamental thing we are going to see is the first-line treatment for IgA will be a B-cell-directed therapy. Understood. And then, my second question, actually, it's also for you, as well as for the Vera team, but, Marshall, insofar as your phase II data showed statistically significant eGFR stabilization at nine months and beyond, compared to placebo, is there an opportunity for eGFR data to potentially be included upon an approved label based on the accelerated UPCR endpoint? Do you know what I mean? Like, could you get approved on UPCR, but with eGFR that you could detail eGFR data in the label, and how much of a difference could that make upon first launch? Ritu, good question. And we, of course, can't make formal statements around labeling at this stage. On the other hand, these are formal data from a global randomized controlled trial, and one can expect that the publication just released over the weekend is out in the public domain currently and will make a difference with respect to physicians understanding the efficacy of this drug. Understood. Thanks for taking the questions. Thanks for the questions, Ritu. Our next question comes from Liisa Bayko at Evercore. Please go ahead, Lisa. Lisa, you might be on mute. Oh, yes, I was. Sorry about that. Congratulations on the data, and thanks for taking the question. First question is around eGFR. Can you give us a little more contextualization of the eGFR change? Like, where did we start from in that new graph, which does include some of the crossover patients, and then, you know, where did we land at? And then if you could give the kind of confidence intervals around the minus point six, what are the upper and lower bounds of that at the end of the study? Thank you. And then, oh, second question, can you give us a little more detail on on safety with respect to infection risk? Thanks. Rob? Yeah. Thank you, Lisa. So in terms of GFR, the baseline, eGFR, in this study was in the low 60 mL per minute range. So these patients had already lost a good 40-45% of their endogenous kidney function at the time of enrollment in the study. Over the course of the trial, the eGFR slope, the annualized slope, was -0.6 mL per minute per year, with a confidence interval of 0.5. So that means the range was from minus 0.1 mL- 1.1 mL per minute per year. In terms of infection, in the randomized period, we really saw very little difference in the rate of infection between those patients randomized to receive atacicept versus those received placebo. Please recall that this program began during the era of COVID, and in that period of time, we saw no difference in the rate of COVID infection, nor did we see a difference in the severity of COVID infection between placebo and atacicept-treated participants. We also know that patients who are treated with atacicept have been able to mount a robust response to vaccination. In the long-term open-label extension period, the overall infection rate was comparable to what we saw during the randomized period. Great. Thank you so much. Thanks for the questions, Lisa. Our next question comes from Pete Stavropoulos at Cantor Fitzgerald. Please go ahead, Pete. Yeah, hi, Marshall, Sean, and Robert. Congratulations on the data. Great to see atacicept's effect on eGFR. You know, a question for Dr. Barratt. You know, in the published article, you know, it states that, and sorry, I'm gonna read part of it. "The time course of reduction in hematuria and proteinuria, you know, suggests that atacicept compares favorably, you know, with the anti-inflammatory effects of corticosteroids and complement inhibitors, and that this effect is likely to be due to rapid decline in immune complexes, you know, along with possible direct effect on a BAFF and APRIL stimulation on innate immune cells." You know, can you just touch on this a bit? You know, how does atacicept compare, you know, favorably to effects of steroids and then complement inhibitors? And, you know, the statement about BAFF and APRIL stimulation of innate immune cells. You know, can you speculate on how not reducing, you know, BAFF could affect the innate arm of the immune system? And, could this impact, you know, clinical outcomes? Okay, so lots of questions there. So I think in terms of what we've seen with the reduction in hematuria and proteinuria, and in particular stability of GFR, we clearly have an impact on formation of circulating immune complexes. What I'm fascinated by is the effect that this drug may well have on BAFF and APRIL signaling within the kidney tissue itself, both within the glomeruli but also within the tubulointerstitium. And we know that there are receptors for BAFF and APRIL expressed on resident kidney cells, and there are B cells and plasma cells within the kidney tissue itself that are likely to be driving inflammation and scarring, particularly in the tubulointerstitium. And so we have lots of preclinical data to support that. When we talk about innate immune cells, what we're talking about here are predominantly monocyte macrophages, which are very much cells that promote inflammation and scarring. There is a lot of interest in delving into these mechanisms in patients with IgA nephropathy, and I think we are scratching the surface of the many ways in which this type of approach can improve kidney function above and beyond the reduction in immune complexes. You'll need to watch this space as we generate data from humans on the importance of these pathways, but I think they are undoubtedly important and are contributing to that stability in GFR, which is really unheard of. I think you need to remember, if you think about systemic steroids, that you don't get the stability in GFR that we see with this approach. You look at the testing data. You get a reduction in hematuria and proteinuria, but it comes back the minute you stop it, and even if you, even with the steroids, you see a decline in kidney function despite the massive doses that are used and the real issues with toxicity. In terms of complement inhibitors, we don't know the effect on GFR because we don't have any GFR data from the APPLAUSE study. We simply have proteinuria data, and the phase II study was so short that it's very difficult to determine what the impact will be. I think the important thing with complement inhibition, however, is that it certainly does target one of the downstream effector pathways that are activated by immune complexes. But I gave a talk at the ASN this year, talking about how immune complexes cause injury across different glomerular diseases, and they do cause injury by more than just activating the complement system. So while you may stop complement activation, there are still other ways these immune complexes can cause glomerular and tubulointerstitial injury. And, therefore, I'm not expecting necessarily to see the same degree of kidney function protection if we just target one aspect of the effector pathway that causes kidney damage. I think we need to think very much more upstream in terms of targeting those immune complexes before they even get to be formed and before they deposit in the kidney tissue. Great. Thank you for that. Just, one additional question. You know, the first question on the call, they basically asked about, how, you know, having an auto injector at home could, you know, impact. You know, you talked a little bit about quality of life, but, you know, how about in terms of compliance? You know, is there a difference between, you know, patients, you know, from your clinical experience, coming into the clinic, you know, in order to receive, in order to receive a drug, you know, versus at home? and- To be honest- How can that impact- Yes. clinical outcomes? Yes. So in my practice, patients would vote with their feet. If I gave them the choice of a treatment they could do at home or a treatment they had to come to the hospital for, I would have no one choose the one to come to the hospital. It just. We just don't do that in the UK All of these treatments are home administered by the patients across the whole rheumatological spectrum of anti-TNFs, et cetera, treatment for IBD, subQ therapies. Something as simple as erythropoietin, which we use in all our kidney patients when they get to progressive stages of CKD five, is home administered. That's what patients expect, and it's particularly what patients expect when they're young with active lives, child caring responsibilities, job responsibilities, is they don't want to be tied down to appointments. And that was very clear during the pandemic. The pandemic opened the Pandora's box because patients suddenly realized they could have their healthcare managed without having to come to the hospital regularly, and when the pandemic finished, the young patients I look after with glomerular disease voted with their feet. They said, "Why should I come back? Why can I not manage this remotely? Because it's much more convenient for my lifestyle," so I think that is going to be a really important aspect, and it's going to be the expectation of these young, active people that they do not want to be tied to a hospital. Great. Thank you very much for that, and thank you for taking my questions. And, once again, congratulations on the data. Thanks for the questions, Pete. Our next question comes from Rami Katkhuda at LifeSci Capital. Please go ahead, Rami. ... Hey, guys, congrats on the update, and thanks for taking my questions as well. I guess first, can you touch on the variability of absolute eGFR measurements and why eGFR slope is a kind of a more accurate endpoint at the end of the day? And then secondly, for Dr. Barratt, can you talk to the unmet need in other IgAN subpopulations that are being studied in PIONEER and whether you think atacicept will work to a similar degree in those patients? Rob, could you speak to the variability? Sure. I think over the years, as we have evolved our approach to defining the endpoints in chronic kidney disease, as a community, we've evolved to looking at eGFR slope based on an annualized window as a conventional way to do that. It's what regional health authorities look at for GFR endpoints these days. And as Dr. Barratt knows well, it's what guideline authors in IgA nephropathy have proposed as the objective of therapy. So, given the fact that there is variability in GFR, it's most helpful to think about defining the overall risk profile for an individual based on the characterization of their annualized rate of loss. And we use a year basis to contextualize evaluation of patients who have differing windows of time where they've been followed or in protocols that have a different duration. John, do you wanna touch on the different populations in PIONEER? Yeah, absolutely. So as I said at the R&D day, we in Leicester could fill up every single strata of that study because there's such a massive unmet need in terms of the people that did not meet the criteria for the phase III trial. We have a far more patients that are not eligible for the trial who need treatment than are eligible. So I think the populations that have been looked at in the add-on studies are exactly the right populations where there is a significant unmet need. And I think importantly, I have no reason to believe that atacicept is not going to be as effective in those populations. Particularly in some of those populations where the unmet need is even greater because they are so much closer to needing dialysis. I have no concern over this, and as I said, Rob, I could fill this study up with my patients alone from the populations that we have that have not been eligible or they are able to get into a clinical trial. Awesome. Thank you, guys. Thanks for the questions, Rami. Our next question comes from Vamil Divan at Guggenheim. Please go ahead. Yeah, great. Thanks for taking my questions, and let me add my congrats, too, on the data. So a couple of things, just following up on some of the questions we've been getting from investors. So just to clarify, so one on the number of patients. In one of the slides, you mentioned that there's 102 patients have completed 96 weeks, but then the charts that show the eGFR and UPCR show sort of 75 patients up to two years. Maybe you can just talk about the difference there in terms of numbers. And then, I think it was Lisa or someone asked about, you know, safety. Obviously, it looks very good overall, but just was curious on the one case specifically that's mentioned on the acute coronary syndrome. Just like if there's any more details you can share, if that was viewed as related or the grade, how that was sort of assessed, it would be helpful. Thank you. Thanks, Vamil. So let's first touch on the one safety case. It was not related. It was an uncomplicated acute coronary syndrome event. And that's really all I have to say about it. In terms of the numbers, and I hope this is also clear in the published manuscript, this was an effort that we took along with our academic collaborators to be as comprehensive as we could be with the way we reported the data. So as you'll recall, for some of these measures, we used a mixed effects model to provide the results that's conventional in clinical trials, looking at some of these endpoints. And so we had 60 weeks of atacicept treatment in subjects who were originally randomized to placebo, and we had 96 weeks of data in participants who were originally randomized to atacicept. And so we wanted to include all those, patients and all of that data from the period where they received the study drug in the mixed effects model. The way to do that is not to present the data in terms of study week, but in terms of, and if you look on the horizontal axis, it's in terms of the time from the first dose of atacicept. So that means for those patients who were originally randomized to placebo, they had 60 weeks of follow-up on atacicept, and for those participants who were originally randomized to atacicept, they had a full 96 weeks. Therefore, when we got beyond sixty weeks, we had a different number of participants than we did in the window from week zero to week 60. So I hope that makes sense. Okay. Yeah, no, it, it definitely does. So thanks for that. And maybe just one other follow-up, if I could, for Dr. Barratt. There's obviously been a lot of discussion over the past couple of years around sort of an APRIL-BAFF combination approach to treating IgAN versus APRIL-only approaches. Maybe if you can just sort of how obviously the safety looks very good, and importantly, the safety looks very good for a combination approach here. Just your views on sort of the two different perspectives, and a post-ASN input, following the updates we've received from the various sponsors. ... Yeah, I mean, that's one of the most commonest questions I get asked. I think I just let the data speak for itself. We have 96-week data on a dual approach. We don't have 96-week data for any other therapy in the targets BAFF and APRIL, and we've set the, you know, this study has set the bar, and it's up to others to show that they are as effective and as safe, and we just need to let the data speak. And so I, I don't really have much more to say. I mean, we can speculate, and depending on which side of the fence, you will come up with arguments one way or the other. But we are here with 96-week data on a dual approach, showing safety and efficacy that's really previously been unheard of. Actually, if you'd asked me five years ago, in a high-risk population, could I stabilize kidney function? I'd have thought you were mad. Actually, you see here that this is achievable by targeting the fundamentals of this disease. For me, these data have set the bar that everyone else is gonna have to see if they can match, and that's where we are. Until we see that data, we just do not know, I'm afraid. Okay, great. Thanks for taking my questions. Thank you for the questions, Vamil. Our next question comes from Ryan Deschner at Raymond James. Please go ahead, Ryan. Hi, congratulations on the dataset. I have two questions for Dr. Barratt. The first, I'd like to get your thoughts on the apparently persistent reduction trend in proteinuria, even out to two years, with atacicept treatment. And second, at least one of the APRIL-only inhibitors has reported multiple hypogammaglobulinemia events in their clinical study. How much of a concern at this point is the potential for hypogammaglobulinemia going forward, with long-term use of atacicept? Thank you. Thanks for the question. So I think what we're seeing here is if you just think about what we're trying to achieve, we're trying to stop the production of immune complexes, stop them depositing, and when they deposit, there's an immediate anti-inflammatory effect. But also, what we know will happen is as those immune complexes are reabsorbed within the glomeruli, the glomeruli will remodel. And therefore, that's why I think we're seeing continued reductions in proteinuria, 'cause we're seeing the kidney remodel without that insult of continued immune complex deposition. And we know, for instance, if I take a kidney out of someone with IgA nephropathy, and I transplant it into someone who doesn't have IgA nephropathy, but another form of kidney disease, and I look at the biopsies sequentially after that event, we will see those immune complexes disappear from the kidney. And so what I envisage and what I would really like to prove is that by giving this drug, we are stopping the immune complexes, the kidney is able to resorb those complexes that are there, remodel, and that injury signal has disappeared. That does not happen overnight. That is likely to take six, 12, 18 months, 24 months even. So I would. It doesn't surprise me at all that we're seeing a continued improvement in proteinuria because it's a sign that the kidney is getting healthier. So that doesn't surprise me. In terms of hypogammaglobulinemia and infections, that is absolutely the thing that we are thinking about when we are targeting B-cells for whatever with, with whatever target. I think this is something we are likely to see sooner rather than later, so I don't think, this is something that potentially, if we haven't seen it already, we're going to see three, four, five years down the line. I think this is something that we will see early, as has been discussed with the safety signals. Really nothing unusual in terms of either the frequency of infections or the type of infection, that we saw in the study compared to placebo. So we absolutely need to be aware of changes in IgG levels. We need to think about how we might dose adjust, if we do see those IgG levels fall. But really, there hasn't been anything in this trial that has suggested that is going to be a significant issue. I mean, I don't know whether Rob wants to kind of talk a little bit more about the safety data, but certainly the data does not support that this is a significant risk for these patients, and I don't think it's gonna be something. If we've not seen it over the two-year period, I would be surprised if it becomes more of an issue later on with chronic administration. Great. Thanks for the questions, Ryan. Our next question comes from Farzin Haque at Jefferies. Please go ahead, Farzin. Congrats on the update, and thank you for taking my question. So this is for Dr. Barratt. We have seen some initial, like, deeper proteinuria reductions with some of the other competitor B-cell pro, B-cell programs, although small sizes. But the question is whether you think deeper and faster kinetics of UPC reduction can potentially translate to better preservation of kidney function in the long run. Like, essentially, is Vera data setting the highest bar that can be achieved? In my view, it is. I mean, to be honest, when I have the 96-week GFR data, I don't really. I'm not really bothered about the data that happened at six months. What I'm bothered about is the patient is as close to dialysis at the end of the study as they were at the beginning, and therefore, the degree of proteinuria reduction that atacicept achieved was clearly good enough to stabilize kidney function. The degree of Gd-IgA1 reduction that atacicept achieved was good enough to translate to stable kidney function. You are never going to improve kidney function in this disease. You cannot return the nephrons that have already been lost. The hope is that you stop any further nephron loss, and the kidney function doesn't get worse, and that's what we've seen with this drug. So, what atacicept achieved in terms of magnitude of proteinuria reduction, magnitude of Gd-IgA1 reduction, speed at which those fell, really was good enough. Do we need to achieve more? In my view, we don't, because we can't do better than we have seen with the GFR. You know, it is impossible. Of course, when we don't have GFR data, we really don't know how much proteinuria and Gd-IgA1 reduction we need to achieve to get that stable GFR. Now we have it. Then I would argue, we don't need to have done any. We don't need to have got the proteinuria reduction any better because we couldn't do better in terms of GFR. So now we have the data in GFR, 96 weeks, we can work backwards and say how much proteinuria and Gd-IgA1 reduction is enough for this mechanism of action. Now, that doesn't mean that if you have a different mechanism of action, that that still holds true, so you may need more proteinuria reduction if you have a different mechanism of action to achieve the same GFR effect, but what we can say for sure is that there really was no need to get any greater degree of proteinuria reduction or GFR one reduction with this mechanism of action, because you have got the perfect result in terms of GFR stabilization, and we see this very clearly. If you look at hemodynamically acting drugs and you look at their data, they achieve more proteinuria reduction than atacicept did at the same time point, but they didn't translate to the same degree of kidney function protection. And it's the kidney function protection, the GFR, that is the absolute number one priority in terms of what clinicians are looking at, because the GFR is what puts you on dialysis. So for me, for this mechanism of action or this GFR data, everything that was achieved with proteinuria and GFR was more than enough to translate to what we really want to see. Perfect. Thank you so much. Thanks for the question, Farzin. So our final question comes from Greg Harrison at Scotiabank. Please go ahead, Greg. Hi, good morning. Thanks for taking the questions, and congrats on the impressive data. For Dr. Barratt, could you comment on the total duration of therapy that you would foresee for atacicept? And, would you foresee patients needing to take the drug consistently for life to maintain benefit, or could there be a rationale for taking a drug holiday or reduced dosing, once the disease has been stabilized for some time? And then, another one, if I can. Do you think atacicept could be used as a monotherapy in practice, maybe among newly diagnosed patients, or would you envision a continued, combination therapy paradigm? So we don't know the answer as to whether a certain period of time of atacicept usage could re-educate the immune system such that you generate a permanent change that means you don't need continued therapy. We just don't know. But what we do know is that at the moment, a chronic therapy is what we are looking at, and it will be up to us and Vera to work together to look at how that might look over the longer term. We just don't have enough data yet. We need the phase III data to see where we are. We're going to have an open label extension to that. And, you can imagine that physicians will see about drug holidays and see what happens. We don't know whether that's going to be appropriate or not. We just need to think about that when we have the drug available for us to use. So at the present time, I see this as a chronic therapy, suppressing immune complex formation and stabilizing GFR, and I would not want to jeopardize that in a young person who has already presented to me having lost 50% of their nephrons. I want to keep every nephron they have as healthy as possible. So I think for the time being, we are thinking of this being a chronic therapy. But of course, as we get more data, as we do different experiments in terms of how we might administer this drug, in terms of potentially drug holidays, we'll see whether that's that works. And I'm sorry, I've forgotten the second question. Just, if it could be used as monotherapy, maybe in newly diagnosed patients or- Uh, yeah Or continued combo. Absolutely. You know, so if this drug were available and the phase III data looks exactly like the phase II data, which there's no reason to suspect it's not, I would make a kidney biopsy diagnosis of IgAN properly, and within that week, I'd put them on atacicept, and then I would layer in CKD treatments if they still needed them. So we are gonna completely change the paradigm here. Why would we want to treat an immune complex mediated disease with a RAS inhibitor? It makes no logical sense whatsoever. We treat the CKD aspects of the disease with those drugs, absolutely fine. But if I put a needle into someone's kidney, I can see the immune complexes in the glomeruli, I wanna stop that process dead. The treatment to do that is a treatment that targets the production of pathogenic IgA immune complexes. I see this being a treatment that will be used within a week or two of making that diagnosis, and that will be the fundamental foundational treatment to treat IgA properly. Great. Thanks so much. Thanks for the questions, Greg. So this concludes our Q&A session. I'll now turn it back over to Marshall for closing remarks. I just wanna thank Dr. Jonathan Barratt for the presentation, the partnership over the years in conducting this very important clinical study. We look forward to further data in the coming time. And with that, I wanna thank you all for attending, and we'll close the call now.