being here in person, and welcome to Vera's R&D Day. It's great to be back in New York. Thanks for your interest and engagement and work with us. I'm Dr. Marshall Fordyce. I'm the founder and CEO of Vera Therapeutics. Our mission is to transform the standard of care for patients with immunologic disease, and I'm thrilled to share with you today, the substantial progress we've made towards that goal. Our lead product candidate is atacicept, a first-in-class, next-generation B-cell modulator, currently in Phase III for patients with IgA nephropathy or IgAN, but with potential to treat multiple other autoimmune diseases. IgAN is a serious progressive autoimmune disease that causes kidney failure in young patients, meaning dialysis or kidney transplant for many before the age of 50. Today, we're very pleased to present, for the first time, the 72-week results of our ongoing phase IIb ORIGIN clinical trial, which are the first results to describe the effects of a disease-modifying therapy on long-term kidney function in patients with IgAN. We believe that the rigor of our clinical trial and drug development work, the breadth and duration of our positive results supporting disease modification, a proven commercial product profile, and our speed to market set Vera apart from other approaches in IgAN. This is an exciting moment for patients with IgAN, as atacicept's clinical data support its ability to target the source of the disease and stop kidney function decline for the first time, offering potentially new transformative treatment option for these young patients. Before we get started, I'll remind you that my remarks contain certain forward-looking statements under the Safe Harbor Act, and as such, we present this disclaimer regarding at-risk statements. So this morning, I'll provide a corporate overview of Vera, including our pipeline and some of the data supporting the use of atacicept across multiple autoimmune indications, and highlight key near-term catalysts for the company as we prepare for BLA filing next year. It will then be my pleasure to introduce Dr. Jonathan Barratt, Professor of the University of Leicester, an expert physician and researcher in the field of IgA nephropathy, who will describe the scope of the problem and review the current standard of care for patients. Next, I will ask Dr. Richard Lafayette to present the week 72 results. Dr. Lafayette is Director of Stanford's Glomerular Disease Center, a recognized... Recognized as a world expert in IgA nephropathy and serves as both investigator and co-chair of our executive advisory committee, along with John, for our pivotal ORIGIN 3 trial. To close, Vera's Chief Medical Officer, Dr. Robert Brenner, will put these results in the context of our current standard of care and the developing treatment landscape, highlighting the design of our currently enrolling Phase III trial, and then we'll open the floor and the line for questions to the full panel. But first, the highlights. Atacicept is a potential first-in-class dual BAFF/APRIL B-cell modulator with pipeline-in-a- drug potential. Existing clinical results support atacicept's therapeutic potential in certain autoimmune diseases in which modulating B-cells and plasma cells could significantly improve disease. These include IgA nephropathy, lupus nephritis, systemic lupus, Sjögren's syndrome, membranous nephropathy, systemic sclerosis, and others. Atacicept is currently in a pivotal phase III trial, putting us on track for a BLA filing next year and commercialization in 2026. Atacicept's differentiation is based on its disease-modifying mechanism of action, which we believe is best supported by the totality of clinical evidence presented today and in the future, and in particular, long-term stabilization of kidney function, which is rarely, if ever, seen for new drugs in nephrology. Today, we will present 72-week results, or one and a half years, and in the fourth quarter of this year, we expect to present full 2-year results. We're making good progress on our phase III trial startup and enrollment and project phase III readout in the first half of next year, putting us on track to be the first to market among B-cell modulators in IgAN. As a biologic molecule, atacicept is eligible for biologics exclusivity, which provides protection through 2038 in the U.S. We have a strong financial profile with cash to fund IgAN-focused operations into 2026. After today, we'll have further presentations at upcoming renal medicine conferences throughout the year, including our full 96-week, two-year results, which we expect to present in the fourth quarter. We also expect to announce full enrollment of our phase III primary endpoint cohort in the second half of this year, enabling the phase III readout in the first half of 2025 and estimate commercial launch in 2026. As a reminder, Vera currently holds worldwide rights to develop and commercialize atacicept in all regions and in all indications. I'm very proud to present the excellent work accomplished by the Vera team, and we're especially pleased to welcome two new executives, as announced earlier this year to our team, Dr. Rob Brenner, our new Chief Medical Officer, who's with us today, and Bill Turner, our new Chief Development Officer. Bill Turner brings 30 years of drug development and drug commercialization experience, and with a deep regulatory and quality background, has led product development through multiple drug approvals. Most recently, Bill served as Chief Regulatory and Technical Operations Officer at Sierra Oncology, which was acquired by GSK last year. Our new CMO, Dr. Brenner, is a well-known nephrologist, drug developer, and biotech executive, and I'll introduce him later in the program. Currently, our pro forma cash is $185 million, sufficient to fund us into 2026, and we have 44.4 million shares outstanding. Vera has two clinical stage molecules, atacicept and MAU868. Beyond IgA nephropathy, atacicept has therapeutic potential in several other autoimmune diseases in which atacicept's demonstrated reduction of disease-causing autoantibodies could significantly improve disease. Based on atacicept's existing clinical data, including dose-finding work and placebo-controlled clinical safety, Vera has written alignment with FDA on the 150 mg dose and study design in three separate indications: IgAN, lupus nephritis, and systemic lupus erythematosus, enabling Vera to expand the atacicept opportunity to these or other multiple autoimmune diseases. Our clinical... Our second clinical stage molecule is MAU868, a first-in-class monoclonal antibody for the treatment of polyomaviruses, including BK virus, which is a leading cause of kidney transplant failure, and JC virus, which causes the devastating neurologic disease PML, or progressive multifocal leukoencephalopathy. Both of these diseases have no approved therapies. Just a minute on MAU868. Last year, Dr. Stan Jordan, head of the Renal Transplant Division at UCLA, presented these phase II results at the American Transplant Society meeting, which was awarded Best Abstract. In patients with kidney transplant at risk of graft failure due to BK viremia, MAU868 reduced plasma BK viremia by over 1 log versus placebo on top of standard of care, representing the first demonstration of an active antiviral drug for this disease with no current treatments. Vera is currently in discussions with regulatory authorities to determine the development path forward. With low nanomolar potency, atacicept inhibits both of the two known circulating cytokines, BAFF and APRIL, which are both important for the survival and maturation of the B cell lineage. Inhibiting both B cell signals is the most elegant approach and minimizes the possibility of signal escape, in which a compensatory increase of the uninhibited pathway reduces potency or durability. Atacicept is a biologic, a fusion protein, and includes the true unaltered TACI receptor. Alterations of natural receptors like TACI are known to elicit anti-drug antibodies, creating efficacy and safety issues later in development. Elevations of both BAFF and APRIL are found in patients with IgAN, lupus, and other autoimmune diseases, and both play a role in disease pathogenesis in these diseases. In preclinical models, dual inhibition of BAFF and APRIL has been shown to be more potent in blocking BAFF or APRIL alone, as illustrated on the left, which may translate into more robust and sustained B cell modulation versus BAFF only or APRIL only approaches to B cell modulation and autoimmune disease. Clinically, in the center panel, atacicept has been studied at the 75 mg and 150 mg doses in a 300-subject, randomized, double-blind, placebo-controlled study in systemic lupus and demonstrated an almost 40% delta in clinical efficacy versus placebo, as compared across trials to the current BAFF only B-cell inhibitor, belimumab, which showed a 12% delta in similar patients at the same time point. Belimumab has also shown efficacy in patients with lupus nephritis, but with an effect size of 10% versus placebo and evidence that atacicept can improve kidney function as measured by reduction in proteinuria and stabilization in GFR, presented at ERA in 2022. In patients with lupus, we believe there's an opportunity to deliver a more potent B-cell inhibitor and improve patient outcomes in this patient population with few treatment options. Two peer-reviewed publications listed on our website highlight atacicept 150 mg clinical efficacy in patients with active systemic lupus erythematosus. On the left, significantly more patients had clinical responses to atacicept 150 mg versus placebo, as measured by... on the left by SRI-4 and SRI-6, and on the right, as measured by lupus flare prevention and by LDA or low disease activity, which is essentially remission or near remission. You can see it's the SLEDAI-2K score of 2 or less. By each of these measures, systemic lupus disease activity, atacicept 150 mg demonstrated clinically meaningful efficacy. Atacicept's target commercial product profile is a self-administered, small volume auto-injector delivered subcutaneously at home once weekly. This commercial profile has been shown to be clinically acceptable and commercially successful for multiple blockbuster biologics.... Our product presentation is unique in that it is, to our knowledge, the only treatment and development for IgAN, studied as a self-administration by the patient at home in both phase II and phase III, providing regulatory authorities the data they need that could support self-administration at home as part of our commercial launch profile. However, if some patients would prefer longer dosing intervals, atacicept's existing clinical data support that as well. Atacicept's robust data package, including substantial PK/PD work, support the 150 mg dose in three separate indications. And an analysis of atacicept's PK/PD relationships supports once monthly dosing, and Vera plans to evaluate dosing longer intervals at, as part of one of several lifecycle management opportunities for our program. As I learn every summer at the IgAN Foundation's annual conference, IgAN is a serious disease that is devastating to young people and their families. Patients are diagnosed in their thirties, and a substantial portion of them progress to end-stage kidney disease before the age of 50. End-stage kidney disease is a bad outcome for patients. It marks the beginning of life on dialysis, dramatically increases morbidity and mortality, and costs the healthcare system an average of $200,000 per patient per year. Prevalence in the U.S. is estimated at 126,000 patients, but this is based on current biopsy-based numbers and is likely an underestimate of the true addressable population. Based on existing conservative prevalence and assuming some patients will be adequately treated with RAS inhibition, we estimate the commercial opportunity to be in the $6 billion-$10 billion range for a therapy that can truly modify the disease, and delay the need for dialysis by not years, but by decades. In closing, I want to return to the thesis that we at Vera had four years ago when we acquired atacicept. Because IgA nephropathy is a B cell-driven disease, and B cells are driven by not one or three, but exactly two cytokines, BAFF and APRIL, and those cytokines are both elevated in IgAN. Based on the knowledge that IgAN pathophysiology is well understood. Unlike other autoimmune diseases, the autoantibodies are directed at one specific autoantigen, galactose-deficient IgA1, forming immune complexes that cause glomerulonephritis, scarring, and progressive kidney disease downstream. Based on a small phase IIa study showing that atacicept substantially reduced Gd-IgA1, we reasoned, and when I say we, I mean Team Vera and all of our supporters, that if we conducted a robust clinical development program, we would see the downstream effects of immune complexes resolve with atacicept treatment. I met Dr. Jonathan Barratt in 2020 as I was evaluating the opportunity, and when we reviewed the initial Gd-IgA1 clinical data in the summer of 2020, he was the first to suggest that unique finding might translate into sustained stabilization of kidney function, and atacicept could deliver a, quote, "functional cure for patients." This was a bold projection. If you target the source of the disease, you could resolve the active inflammation, glomerulonephritis, that leads to progressive kidney damage, and then patient's kidney function over time might be equivalent to healthy kidney function, declining only by about 1 mL per minute per surface area per year. Therefore, it's my great pleasure to ask Dr. Jonathan Barratt to the podium to review for us the IgA nephropathy disease state and the current status of the field's considerable efforts to improve outcomes for patients. Thank you, John. Thanks, Marshall. Yeah. So it's a great pleasure to be here. I don't... I normally talk to other nephrologists, so this is quite a new experience for me. So be gentle with me. I am Jonathan Barratt. I'm a nephrologist from the U.K. with a lifelong interest in glomerular disease, particularly IgA nephropathy. I'm gonna set the scene for you in terms of how you might want to think about interpreting the results that Richard's gonna present after me. Those are my declarations. So IgA was first described in 1968, so it's a relatively young disease. It's been described as an entity over the—for about 55 years now. But over that time, it's been recognized globally as the commonest cause of glomerular disease. Now, it's been around for a lot longer. These are the two oldest cases I can find. I normally ask the room if anyone knows who the guy on the left is. He is a very famous American, the father of the U.S. Navy, who famously tried to invade the U.K. at one point. But we have evidence it's been around for at least 250 years and likely longer. But as a disease, we've known about it as nephrologists for about 55 years, and it's now recognized as a major cause of kidney disease and kidney failure, particularly around young adults. I'm gonna talk you through some data that we published from the U.K. Rare Disease Registry. This is the largest rare disease registry for kidney disease in the world, and it includes patients with IgA nephropathy that live in the United Kingdom. Now, just as a, just so that you do understand, there is data now coming out from the United States that was presented at the ASN last year, showing very similar, if not worse, outcomes for a U.S. population from the Kaiser Permanente in California. So even though this is U.K. data, this is directly relevant to patients living in the U.S. And so this is the overall outcome of patients with IgA nephropathy living in the U.K. So if you look on the left-hand side, if you are a child diagnosed with IgA nephropathy, at 20 years, half of those children have developed kidney failure. So that's kidney failure in their thirties. If you're an adult diagnosed with IgA nephropathy, after 20 years, three-quarters of those adults have developed kidney failure. That's kidney failure in their fifties and sixties. If you look here on the right-hand side, this is split by age at diagnosis, or age at kidney biopsy. So the arrow here is me. I'm 55. So if you're a child diagnosed with IgA nephropathy, by the time you reach my age, 3/4 of those kids have developed kidney failure. If you're an adult diagnosed between the ages of 18 and 40 years of age, by the time you reach my age, 2/3 of those adults have developed kidney failure. And if you're diagnosed between the ages of 40 and 50, 1/2 of those adults have developed kidney failure. This is a disastrous disease that puts people on dialysis at a young age. We need to acknowledge that because these are people who could be working, they could be providing for their family, they could be developing their careers, and they're on dialysis, and that really does impact negatively on all of the opportunities those individuals have. What we did here was we took the GFR, the level of kidney function at the time of diagnosis. So that's the time me, as a nephrologist, actually get the opportunity to intervene on these patients. And what you can see here is this is a hypothetical rate of loss of kidney function for the rest of that patient's life. And we took the GFR, the time they came under a nephrologist care, and calculated the likelihood that they would develop kidney failure in their lifetime. So if you look here, at 18-30-year-olds, this is real data. You can see here that if you have a rate of loss of kidney function for the rest of your life of 5 ml, 3 ml, 2 ml per minute per year, you're gonna end up with kidney failure in your lifetime if you do not die a cardiovascular death that's been driven by the fact you've got chronic kidney disease. It's only when we get down to 1 ml per minute per year that we start to make any significant impact on the lifetime risk of kidney failure in these young people. So we need to think, when you're thinking and reviewing the data and looking at the publications, you need to be thinking about the lifetime risk of kidney failure in this young group of people. So what I'm gonna do is take you through where we are at the moment. So remember, this is the heat map. These are the papers that I'm gonna talk you through, and if you're interested in IgA, you will have looked at these papers, I'm sure, in depth. So this is the best study of conservative, optimized care, lifestyle modification, RAS inhibition, blood pressure control. It's Jürgen Floege study from Germany. It is a European cohort. And what I'm gonna do is I'm gonna take you through what happens with current standard of care treatment that is consistent with the international guidelines. And I'm gonna take the rate of loss of kidney function achieved during that study and see what that means for lifetime risk of kidney failure. So if you're in the best study we have of really optimized supportive care, what's the likelihood those patients are going to avoid dialysis in their lifetime? They're virtually all going to end up with kidney failure in their lifetime, even if we're able to maintain what we see over a 2-year study for the rest of their life. This is the TESTING study, predominantly Chinese. This is what happened in the placebo arm. All patients treated to optimized standard of care, which is what we do in clinical practice. Every single one of those patients is gonna develop kidney failure in their lifetime. There's gonna be a trend here. This is the wonder drug, DAPA-CKD, the SGLT2 inhibitors. This is the rate of loss in the placebo group in that study. They're all gonna end up with kidney failure in their lifetime. This is the NefIgArd study. Again, looking at the placebo arm, treated to standard of care, all gonna end up with kidney failure in their lifetime. This is the PROTECT study. Again, looking at the active control, the irbesartan, where actually the ARB was optimized during the study. They're all gonna end up on dialysis in their lifetime. That tells you the limitations of what we have at the moment. Now, if we look at the impact of the intervention. So when this data came out, DAPA-CKD and the kidney, we thought chronic kidney disease is sorted with the SGLT2 inhibitors. Look at the rate of loss in the DAPA arm in the IgA patients. All of those patients, even on a RAS inhibitor and an SGLT2 inhibitor, are going to develop kidney failure in their lifetime. If we now look at the STOP-IgA, which looked at immunosuppression, the story is unfortunately very familiar. The TESTING study, exactly the same. These drugs may be impacting in the short term, but they are not stopping kidney failure in the lifetime of these young adults. Again, we see the NefIgArd trial slows the rate of loss of kidney function, but that residual rate of loss of kidney function still means all those patients are gonna be on dialysis in their lifetime. Again, the same for PROTECT. So that's the challenge we face. We are making improvements, we are slowing the loss of kidney function. But when I see a patient in front of me, what they want to know is, are they going to be developing kidney failure? Do they need to start thinking as a 20-year-old or a 30-year-old... what their life is going to be like at 50. Are they going to be on dialysis or need a kidney transplant? With all of this data, we can't reassure them that they are not going to avoid kidney failure. In fact, the likelihood is they are going to develop kidney failure in their lifetime. That is the scale of the problem. What do we need to achieve? This is what we need to have as a realistic target for many therapy or combination of therapies if we are going to make an impact for those young adults in avoiding dialysis or transplantation in their lifetime. How are we going to achieve that? When we think, we're nephrologists, our whole job is to save nephrons. We have 1 million in each kidney, and our job is to make sure you preserve those so that you do not develop kidney failure. When we think about what's driving nephron loss, we have those immune-mediated processes, the autoimmunity that Marshall alluded to. And in IgA nephropathy, that's immune complex formation, deposition in the kidneys, inflammation, and scarring. But we also have a generic maladaptive response. As you accumulate nephron loss, there's a vicious cycle that develops in the kidney that drives further nephron loss independent of the underlying cause, and so we have these two drivers for the development of kidney failure. Now, this is very stylized. Don't assume this is exactly what happens, but this just to get the message across. That would be great, the minute a patient develops IgA deposition in their kidneys, they complained and came to see us and said, "I feel unwell." That doesn't happen. What generally happens is patients appear at this point, where they've already accrued significant nephron loss. The average GFR when we see patients is between 50 and 60. That means those patients have lost at least half of their functioning nephrons before I ever get my hands on them and can intervene. They're at this point here, and that really helps us understand what are our aims when we want to treat this condition. So just alluding to what Marshall said, let's just take a high view of the pathogenesis 'cause that helps us understand where we should target. So the fundamental abnormality is the presence in the circulation of IgA immune complexes that are prone to deposit in the glomeruli and trigger kidney damage. We believe the main substrate for that immune complex formation is this particular form of IgA. It's polymeric, so 2 IgA molecules joined together, and it carries very specific changes to the sugars attached to the hinge region. If you read the literature, it's commonly known as Gd-IgA1. We believe this form of IgA is driven predominantly from cells that live within the mucosal immune system, and that's important to understand if we're thinking about B-cell-targeted therapies, and I'll come on to that in a minute. Of course, this occurs on a genetic background that not only determines how likely you are to develop IgA nephropathy but also the speed at which you might develop kidney failure. Interestingly, in the large genome-wide association studies, genetic polymorphisms in the APRIL gene and the receptors for BAFF and APRIL are associated with an increased risk of developing IgA nephropathy. So when those immune complexes deposit, we get activation of cells within the glomeruli. They produce pro-inflammatory, pro-fibrotic mediators, drive in inflammatory cells, and make the whole situation worse. Those inflammatory mediators cross the basement membrane and cause damage to other cells within the kidney, and collectively, this drives kidney scarring. Of course, the whole process is amplified by activation of the complement system. So let's come back to what our goals are. Our goals are to prevent kidney failure in the lifetime of a patient with IgA nephropathy. We've got to address these two drivers of nephron loss, and we want to achieve a rate of loss of kidney function in this range to really impact on the risk of kidney failure. So of course, we're going to need to give optimized supportive care as we do at the moment, because that deals with these generic responses, and we're gonna have options here. But from what I've shown you of the studies, this is never going to be enough to prevent kidney failure in the lifetime of the patient. We absolutely need to do it, and in the phase III trial, patients come in on RAS inhibitors, they're allowed to be on SGLT2 inhibitors. We're broadening access to ERAs. They can also be on an ERA, but we know that's not gonna be enough, but this is what patients will start being on. What we need to do is target IgA-induced autoimmunity, and I've broken it down. The major thing, of course, is to switch off the production of that pathogenic IgA. That's the fundamental problem in this disease. But we also might want to target inflammation, and we might want to target those signals driving scarring. We are nowhere near drugs that target the scarring pathways at the moment. We failed miserably. That is definitely a work in progress. What do we do about inflammation? Well, the commonest thing that I hear is, "Well, why don't we just give everyone systemic glucocorticoids?" Satan's Tic Tacs. Well, I don't know if anyone in the room has been on steroids, but no patient has ever thanked me for giving them systemic steroids. They are toxic. They are a necessary evil if you want to target inflammation, but they don't do anything to the fundamentals of the disease. They do not affect pathogenic IgA. There is no evidence for that. So what happens when you give an anti-inflammatory and you stop it? The inflammation comes back 'cause the disease is still there. That's exactly what you see in the TESTING study. You see the proteinuria go down while they're on steroids. When you stop the steroids, what happens? Inflammation comes back 'cause the disease just carries on. You've not addressed the fundamentals of the disease, and these come at a significant cost. The original testing study had to be stopped 'cause patients were dying of infection. They used a lower dose, but still a significant dose, and you still have infection-related hospitalizations, you have issues with cardiovascular health, and you have issues with bone health. They also cause significant mental illness, and this is a great study looking at mania and depression scores with people on steroids. These change remarkably when patients are given the doses of steroids we use. These are a drug that we want to avoid at all costs across all inflammatory glomerular diseases. The hope is that complement inhibition will help us manage the inflammation, and we've got a range of different complement therapies currently being evaluated in IgA. But of course, they do nothing to the fundamental of the disease, which is stopping IgA deposition. That is the goal. That is what we talked about, Marshall and myself, when Vera were first looking at atacicept. This is the target we need to hit, which is switch off pathogenic IgA production, which will switch off immune complex formation, which will switch off deposition in the kidneys and those downstream pathways. We have two approaches. We can deplete B cells, and that's something we commonly do in ANCA vasculitis. In membranous, we use rituximab. Richard, in fact, led the study in the U.S. looking at rituximab in IgA, and it didn't do anything. And the important thing here is rituximab is very good at dealing with B cells that are situated in the bone marrow. It's much more difficult to handle tissue-resident cells that are generating pathogenic IgA. I come back to the fact that the cells generating the pathogenic IgA in IgA nephropathy are not situated in the usual places that we see in autoimmunity, and therefore, we need a different approach. There are other B cell depleters being evaluated at the moment. We have no data, but what is most exciting is the opportunity to modulate B cells. Marshall has already touched on this, and the two key cytokines that control B cell proliferation, B cell and plasma cell survival, and importantly, IgA class switch recombination are BAFF and APRIL, and these are heavily enriched in mucosal immune sites. That's likely why rituximab did not have an effect, is because it was trying to deal with pathogenic cells sat in a microenvironment that was heavily enriched for BAFF and APRIL. That's why this approach is so exciting. So I come back to this. This is the figure you need to remember when you're looking at therapies. If we want to avoid kidney failure in the lifetime of our patients, this is what we need to be thinking about in terms of rates of loss of kidney function with a therapy that's truly going to transform the outlook for patients with IgA nephropathy. So I'm gonna hand over now to Richard to take you through the clinical trial results for atacicept in the ORIGIN Phase IIb study. So thank you. All right. Well, good morning. It's great to be with you today. I'm Richard Lafayette, and again, you can see by just visual experiences, I'm just a, a brethren to Professor Barratt there. Both of us, kidney doctors, really interested in improving the outcomes of our patients, both committed to IgA nephropathy for a long time, both of us born on little islands in the Atlantic Ocean, as well. His, in the UK, mine's something called Manhattan. So, good to be back, home, and, it's really a great pleasure to be able to present the numbers, right? 'Cause I think, it's great to talk about theories of what we're targeting, and again, looking to target IgA in a disease called IgA nephropathy makes brilliant sense with a drug with a long history of safety, and tolerability makes great sense. Again, we wanna stop cold any disease progression, because all of our attempts till now has been able to slightly slow progression, leaving patients at risk for eventual need for dialysis or transplant. And while transplant's wonderful, you all should know that IgA recurs in kidney transplant patients, so it restarts the clock. But if you're getting a kidney transplant when you're 30 or 40 years of age, then you're back on that cycle. So, the great pleasure has been able to participate in this ORIGIN study, in the phase IIb IgA nephropathy study, and as you know, it was designed to compare different doses of atacicept, 25 milligrams, 75 mg, and 150 mg with placebo in very well-characterized patients who have IgA nephropathy, to look primarily if it could reduce proteinuria at 24 and 36 weeks. So the patients were randomized to these different doses, and you can see the significant focus was on the doses of 75 mg and 150 mg, 25 mg to provide some extra PK/PD data and safety and compared to placebo patients. These are adult patients with biopsy-proven IgA nephropathy at high risk of progression, and that high risk is defined by the fact that they still have substantial proteinuria despite optimized conservative therapy, RAS inhibitors, for at least three months, with a protein to creatinine ratio of greater than 0.75 g/g or greater than 750 mg/day, and GFR values greater than 30 mL/min. Blood pressure had to be well controlled. And then for these patients, they were offered, after 36 weeks of randomized treatment, open-label therapy-... Going out to 96 weeks with the atacicept 150 mg. So as you already know, and had great pleasure to already present, atacicept worked very wonderfully in the randomized controlled period. Again, it proved to be effective as expected, to reduce not only IgA, but this particular galactose-deficient IgA1, about two-thirds from the circulation of patients on the atacicept 150 mg per day dose. Again, when we talk about mechanism of inflammation in the kidneys, one of the main reporters of that clinically is blood in the urine. So as you can see, that blood in the urine resolved in 80% of participants on drug, compared to only 5% getting non-specific therapy with RAS inhibitors. Again, we met the primary endpoint with statistically significant reduction of the proteinuria, and those patients who were on placebo, on therapy, compared to those on drug, on therapy, there was a 43% reduction in proteinuria. Most exciting was the fact that the GFR appeared to be absolutely stable, where there was an 11% protection of GFR loss, which in real numbers came to a nearly 6 ml/min preservation in just those initial 36 weeks. So again, it looked really, really exciting, and equally importantly, the drug was well tolerated. The safety profile was really indistinguishable between getting the medication and getting placebo. So, that led to the company launching their phase III trial with the atacicept 150 mg dose, and that's being actively run right now, and it's very exciting. So again, looking at that 36-week data, we can see in these panels that indeed, as I mentioned, the IgA1 goes down very nice, to two-thirds of its baseline value. Hematuria is resolving, proteinuria is nicely down to a degree that predicts GFR stabilization, and importantly, we saw that GFR stabilization. So these patients, again, came from a group of 230 screened patients. Ultimately, 116 met those criteria that I mentioned before of biopsy-proven IgA with substantial proteinuria, despite, standard of care therapy and GFR above 30 mL/min. And then 82 went on the various atacicept doses, 34 to placebo. We did a per protocol and the intention to treat analysis, showing the benefits that were subscribed. And then patients were offered this open label extension, which 111 out of 116 patients accepted. And along the way, patients made it to the 72-week time point, with only five patients discontinuing during that period of time. So this is the group of patients that we're talking about, is these 116 patients, who come from the various groups during the randomized controlled trial. And again, as you already heard, these are young adults, just about 40 years of age, predominantly men, okay, but there's men and women. Very nice, and an important part of this study is that it's well-balanced because we sometimes have seen different results in European, American populations versus Asian populations, and the racial background of this population is nicely mixed and balanced overall. Again, these patients have low kidney function, averaging around 60 mL/min-65 mL/min, meaning again, they're at very high risk of progressive kidney disease, and that's amplified by the fact that they have substantial proteinuria. Again, aiming for more than 0.75 g/g, now seeing their 24-hour urine actually all averaging greater than 1.5 g/day. These patients have established disease roughly three years from biopsy. So again, a substantially high-risk population for bad outcomes, as you've just seen. So what happens is that the drug, again, as seen in 36 weeks on active therapy, when the drug is continued, you have nice stable control in the lower graph for the patients who were treated with active drug during the randomized period, and their reduction in this galactose-deficient IgA in that pathogenic antibody is beautifully maintained. It's not disappearing altogether from the circulation, leaving them at risk for infections. It's staying stable. And of course, those patients on placebo have the same response to the therapy with a deep, sustained reduction in pathogenic galactose-deficient IgA1. And together with that, we can see that the hematuria that was becoming resolved in the first nine months of therapy continues to be stable. It's not coming and going, and coming and going. It stays controlled in those patients who respond with continuing reductions in the overall amount of hematuria seen in treated patients. And in those placebo patients who switch over, there's also a very substantial number of them who are no longer showing hematuria. Again, a clear clinical part of IgA nephropathy and one independently linked to a bad outcome of IgA nephropathy. So this is very important in showing that inflammation in the kidney is becoming resolved because there are studies comparing kidney biopsy to the presence of hematuria, and the presence or absence of hematuria associates with inflammation within the kidney biopsy. So again, in proteinuria, we learned that atacicept is very active at reducing proteinuria, but as these patients continue on in open-label extension, you can see that there's well-controlled proteinuria reaching just about 50% reduction from baseline proteinuria, no matter where the patient started from, and those patients flipped from placebo likewise have the benefit of a 50% reduction or near 50% reduction in proteinuria. Again, one that is associated in prior studies with a remarkable preservation of kidney function. And in fact, here's the main take-home, is that Dr. Barratt said we need to deliver a therapy that preserves kidney function. And when we have a drug that targets the mechanism of action, we believe that's preserving kidney structure. And in this case, the atacicept group, after 72 weeks on therapy, has no change in kidney function. They're rock stable. You see zero change. So that's quite remarkable. Patients on placebo, who are well on their way to lose more than 5 mL/min/year, having lost 5 mL in their first nine months of observation, now also numerically are actually better than baseline, but I would say they're rock stable. So here you're showing in this 72-week period, complete stability of kidney function. And it's done in such a way that adverse events profile during this extension period looks just like baseline when we look at overall adverse events in those patients who are placebo and then look at the extension period. These adverse events in these patients with reduced kidney function on blood pressure medications is exactly what's expected for patients with IgA nephropathy, and there were no deaths, only one infection and a safety profile that really looks again, as expected for the population and not added to by this medication inhibiting their B cells. So again, what I've hoped to present to you is these 72-week results showing again, as expected, after the 36 weeks results, that there is consistent, stable, and sustained reductions in galactose-deficient IgA1, safely, not progressive and well-tolerated, resulting in sustained and improving resolution of hematuria, cardinal manifestation of the risk of IgA nephropathy and of the proteinuria, which we know is important to control, to demonstrate disease control and also as an independent risk marker of further progression. Again, we've seen that absolutely consistent and stable eGFR, which is unchanged. Okay? So no loss of kidney function in patients on therapy out to 72 weeks. And again, in aggregate, I think these data provide evidence of long-term, comprehensive, actual disease modification. Again, patients who are switched at week 36, even though now they have lower GFR, ongoing substantial proteinuria for an additional nine months, are able to also enjoy reduced hematuria, proteinuria, and complete stabilization of their kidney function. The safety profile is consistent with that observed during the randomized profile, which was well-tolerated and safe, and again, provides us investigators and our team great confidence in the ongoing accruing ORIGIN 3 study. So thanks for your attention, and hopefully, you're all as excited as we are. Thank you. Great. Thank you, Dr. Lafayette. Thank you, Dr. Barratt. Dr. Barratt, as he comes across the Atlantic, we have a good exchange on U.K. and U.S. history, and everyone should know that you can visit the John Paul Jones Tomb at the U.S. Naval Academy in Annapolis. Not to be confused with John Paul Jones, the basis for Led Zeppelin. For our closing remarks, I'd like to invite Dr. Rob Brenner, Vera's Chief Medical Officer, to the podium. Dr. Brenner brings more than 25 years of experience as a respected nephrologist and successful biotech executive. Dr. Brenner previously served in executive roles in several clinical stage biotech companies, including Chief Medical Officer at Aurinia, and SVP of Medical Affairs at AMAG Pharmaceuticals, contributing to that company's first therapeutic approval and launch for iron deficiency anemia, Feraheme. Previously, Dr. Brenner led kidney-related global development programs at Amgen, supporting the approvals of Aranesp and Sensipar, and oversaw the establishment of the Nephrology Medical Affairs organization. Dr. Brenner received his BA from Hopkins and MD from Albert Einstein, completed medical residency at Brigham and Women's Hospital, and his nephrology fellowship at Stanford University, with Dr. Lafayette. It's my great pleasure to welcome you to the Vera team, Rob, and please come up to the podium. Thanks. Thank you, Marshall, and good morning. First of all, congratulations to making it through the first three presentations. I know that we've got some folks standing in the back. There are a few seats open in the front. I see four. So if you want to come up, you're welcome to. And we'll get into the final points that we'd like to make from a corporate perspective, in our digestion of the information that you've heard today from Doctors Barratt and Lafayette. So one of the things that, I think it's particularly important for us as we digest the information that has been gleaned, and. Dr. Lafayette shared with you, is how we take a leadership role in communicating the story of IgA nephropathy and the advance that is represented by the potential for atacicept to be a foundational new therapy for patients. How we tell that story in a way that is credible, is logical, and is linear in the minds of a variety of audiences, whether they're payers, regulators, physicians, and other members of the community. To do that, I've tried to summarize in just a few points what the history of our understanding of kidney disease and IgA nephropathy looks like over time. We can begin in ancient Greece with early descriptions of what a patient with proteinuria and progressive kidney disease would look like. There's an early description of a patient who had evidence of an IgA disease, IgA vasculitis, with components of kidney failure in Vienna in the late eighteenth century. Then, as Dr. Barratt shared with us, a really foundational finding in 1968 by Jean Berger and colleagues at the Necker in Paris, where for the first time we had a tool, a stain for IgA, that we could use after a patient had undergone a biopsy. Before that, the only thing we could stain for in terms of immunoglobulins was IgG, and presumably many biopsies that had been done before that were stained for IgG stained negative because the main component of the immune complex was IgA. But Jean Berger had a new stain and was able to show that here in a patient with evidence of kidney disease, that there was a magnificent display of IgA staining on biopsy. 30 years later, we found the discovery of APRIL, and the following year, the stunning discovery of BAFF. These two cytokines that we've been talking about, which are the drivers of B-cell and plasma cell activity. And so today, we are now in a position to have a precision B-cell modulator that's able to reduce BAFF and APRIL, and thereby modulate the function of B-cells and plasma cells. So I also think it's important to provide a little context on where the discipline of renal medicine has been with drug development and why there's been so much conversation about a variety of renal diseases, coming back to how we think about interventions that attenuate urine protein excretion or proteinuria, and also the risk of kidney failure. That's been our lens to think about all new agents across different diseases. That's because historically, the kinds of drugs we've developed, which are largely mediating their effects through hemodynamics, through changes in what's going on in the glomerulus in terms of pressures, they largely have an impact on proteinuria and GFR. The first of these trials was done in the early 1990s with an ACE inhibitor, with captopril, where Ed Lewis and his colleagues showed that we could reduce the rate of doubling of serum creatinine or time to end-stage kidney failure using an ACE inhibitor versus placebo. In the early 2000s, a landmark trial called RENAL was looking at losartan in patients with Type 2 diabetes and progressive kidney disease, where we showed that we could also attenuate the risk of the progression of ESRD or doubling of serum creatinine as a composite. But we also had really fine data on urine protein excretion and showed that over time, there was about a 20%-30% reduction in UPCR in patients treated with an ARB. Finally, more recently, we've got data with SGLT2 inhibition showing that now we don't have to look and wait for doubling of serum creatinine or time to ESRD. There's been a liberal view now by the regulatory community of using eGFR as a predictor of the ultimate risk of creatinine doubling or dialysis need, and we can measure eGFR over time. And what we show with it, with this intervention, is that we can change the rate of decline. The slope of decline changes, but the slope doesn't go to zero. We don't have stasis of eGFR. We have continued progression. This is the bedrock upon which regulators and clinicians think about new therapeutics for the... in the kidney space. Reduce proteinuria, slow the rate of decline in GFR, because that's all we've been able to do. Now, let's think about IgAN. So we've heard from Dr. Barratt, that we understand the mechanism of this disease. This is absolutely a critical point. IgAN is a disease of B-cell origin with a kidney pathology. We've talked about how in response to various stimuli, there's increased levels of BAFF and APRIL, which drive the Gd-IgA1 production by B-cells. What's super interesting here, and I think very relevant as you think about the cadence of drug development with a B-cell modulator, is IgAN represents a disease where both the autoantigen and the autoantibody are produced by B cells and plasma cells, which are amenable to B cell modulation with atacicept. Not just one component, the autoantigen or the autoantibody, but both components. So from a clarity of experiment perspective, the intervention with atacicept in IgAN makes more sense than any disease we could imagine. So what we're able to do is, well, what happens in IgAN is we have these productions of autoantibodies against the Gd-IgA1, this exposed hinge region, because of less sugar moieties in the IgA1, and that forms circulating immune complexes, which get trapped in the glomeruli, in the filtering component of the kidney. In particular, they get trapped in the mesangium. We get mesangial expansion and a cascade of inflammatory responses that ultimately result in clinical nephritis, which we can measure by looking at the amount of blood in the urine, and also progressive kidney injury with the attendant hematuria, proteinuria, and eGFR decline. And as I was thinking about this during Dr. Lafayette's presentation, I recalled that back in 1997 or so, a year before we even knew what APRIL was, I would sit at a four-headed microscope with John Higgins, a pathologist who I went to college with at Hopkins, who was at Stanford when I was there. We would look at these biopsy results from undoubtedly a teenager or someone in their twenties or maybe their early thirties, who had just undergone biopsy because they presented with either hematuria or evidence of progressive kidney disease, and we wanted to figure out their diagnosis. There was the evidence of IgA nephropathy under the microscope. I can't tell you how frustrating it was to be unable to come up with a thoughtful intervention that could change the course of their disease. Incredibly frustrating. We could see the immune complexes on biopsy, but we didn't know how to turn off the faucet for immune complex generation. Now, understanding the mechanism, we can hypothesize what would we hope to expect if we could actually turn off that faucet of immune complex generation and avoid immune complexes being deposited into the glomeruli, never generate the nephritis, and avoid the risk of progressive kidney disease? We'd expect to see four things. One, a reduction in the pathogenic Gd-IgA1 levels. Two, a reduction in evidence of nephritis with a reduction in hematuria. Three, a pronounced, clinically relevant, regulatory necessary reduction in proteinuria. And most importantly, stabilization of GFR, in contrast with what we've seen in other kidney agents that aren't of a specific mechanism for the underlying disease. True stability in GFR. And here are the results that Dr. Lafayette just showed you, which are consistent with a total profile, a comprehensive profile of disease modification: reduction in pathogenic Gd-IgA1, resolution of hematuria, marked reduction in urine protein levels, and stabilization of eGFR. Phenomenal result from the clinical program. One of the other things that I think is really important is to contextualize these results in the context of what we know about the eGFR decline in general. So on this slide, I have estimated what the GFR loss looks like in the general population in the community, and there are many different studies that have tried to look at this from an epidemiologic perspective. On average, patients generally lose... people, not patients, lose about one ml per minute per year of kidney function. We can compare that to the historical data from untreated IgA nephropathy, where patients are losing more in the range of 5-10 mL/min/year, and you can now map when they're going to have end-stage kidney disease. Now, one thing that hasn't come up today is in the developed world, where we have patients matriculating to this end-stage kidney disease, we can offer renal transplantation or maintenance dialysis to keep them alive. But there are still parts of the world where we don't have those tools at our disposal. And for those patients, if you follow that line to its end, that means it's a mortal event. Patients will die with kidney failure, and based on the data that we've already shown you, in those parts of the world where we can't provide renal replacement therapy and they have IgA nephropathy, that means they might be dead in their thirties, forties, fifties. Very premature. Now, we've had two new drugs approved for IgA nephropathy in recent years. Neither of them have a mechanism that's specific for the generation of immune complexes. And so, not surprisingly, both of them show that the eGFR profile is attenuated versus historical controls, but it is certainly not muted to the point where eGFR is stable. So the risk continues, but it's been tuned down a little bit. And finally, we can superimpose the results we've now shown from 18 months' worth of data collection in the IgAN open-label atacicept trial, where we show true stability of eGFR. As a nephrologist and someone who's been in drug development for a long time, this is an unprecedented event for our community and offers great promise for what the future will look like for patients with this disease. Now, there's been a lot of noise that I've come to appreciate now that I'm three weeks into my stay at Vera. A lot of noise from various competitors, one in China, some at very early stage and some more late stage. But I think it's important to summarize some of the main differences, and I'm not going to go through all of this. But there are different ways of approaching the question, of where does atacicept fit in? So first of all, in terms of mechanism, atacicept is a dual BAFF inhibitor, as Marshall shared with us earlier. We believe that dual inhibition of the two cytokines that drive B-cell and plasma cell activity is logical and appropriate, and the data that we've generated in many ways supports the hypothesis that dual inhibition will bode very well for patients. It's hard to imagine a phase II data package that would be more compelling than what Dr. Lafayette has just shared with you. In many ways, that defends the original hypothesis that Marshall and Dr. Barratt had when the decision was made to make atacicept a big part of Vera's future. Two, I'm now thinking about this from my perspective as a drug developer, as someone who is supporting late-stage, pre-approval clinical trials and where we're going to have conversations with global regulatory audiences. One of the things we want to do at the corporate level is to try and minimize overhang in a phase III program that could lead to a surprise in those results. There are many ways to try and reduce that risk. One, stable dose and administration. Use the same formulation, the same mode of administration, and the same frequency that you use in phase II, you recapitulate that in phase III. At the moment, my understanding is the atacicept ORIGIN 3 study is the only ongoing phase III program in IgA nephropathy that utilizes the same dosing strategy and the same dose, the same route of administration in phase II and in phase III. That's a really important point. Two, you'd want to use the same kind of sites and enroll the same patients that you use in phase II and in phase III. You'd like for the phase III experiment to basically be a recapitulation of a phase II experiment. The fact that the open label, placebo to atacicept switch subjects, has very similar data as the original randomized portion, means we've kind of done two phase II already. So now, a third phase III that uses the same design with the same intervention is more likely to minimize the risk that we're going to see something surprising. From an investment perspective and for the clinical team and the regulatory team at the company, that's really important. So we're in phase III. We're in phase III on a backbone of randomized, placebo-controlled data from phase II. That's not the case across the board for all of the players in the space. We think that further de-risks the phase III program because we've already been in a placebo-controlled situation. We've exposed a large number of patients in phase II. We've had robust reductions in Gd-IgA1, and so far, we are the only program, thanks to the work by Doctors Barratt and Lafayette and the vision of the team at Vera when they designed the program, to capture data on hematuria and to report it. So, so far, the only program that's shown resolution of hematuria is that with atacicept. We've had very, compelling results for urine protein excretion, far beyond the regulatory threshold of a 30% decline, now approaching 50%, as Dr. Lafayette shared. And most importantly, and transformative, is the stability of eGFR now to 18 months, and we're looking forward to having the full 24 months of data as we get to the fourth quarter of this year. So in totality, when we look at this, I think a lot of the noise that's out there gets muted, and the focus is on the totality of evidence that came from a mature phase II program. The data now speaks for itself, and the rest of it is narrative. So I've been thinking about this a lot, as I've kind of looked at the landscape and thought about what these data might mean in the future if we recapitulate these results in phase III, and through our conversations with the community, with guideline authors, with regulators, with payers, and ultimately with patients and physicians. And I think we're poised for a new disruptive framework for the management of the disease. It's a disease of immune complex formation. The two components of the immune complexes are B-cell and plasma, plasma cell-derived. We now have a B-cell modulator. Let's turn off the faucet, whether we're talking about a prevalent patient or an incident patient with a fresh biopsy. If you have an immune complex IgAN phenotype, you want to be on a drug that turns off immune complex generation, full stop. As we heard from doctors Barratt and Lafayette, I absolutely believe that there is a role for all of the supportive therapies that are relevant for patients with progressive kidney disease, for the benefits on glomerular hemodynamics, ACE inhibitors, ARBs, endothelin receptor antagonism, and now with the promise of SGLT2 inhibition. Nephrologists think those drugs should be in the water. They're good for everybody, but they're not specific to the IgAN mechanism, so the foundational therapy, in my mind, in the future, would make sense to be a drug like atacicept. Finally, if we're able to turn off the deposition of immune complexes in the glomeruli, you might hypothesize that if there's no aggressive inflammation... There may not be a need for some of the blunt instruments that have historically either been used in the clinic or are in development by other sponsors, whether those are complement inhibitors or steroids. So the hope is that patients won't have to complain to Dr. Barratt anymore about what it's like to be on systemic steroids, because instead, we can prevent immune complexes from being deposited in the kidney in the first place. So we've talked about the fact that we're now in phase III. This is a trial we're all very excited about, and my colleagues at Vera are hard at work on. The key takeaway is it's a very similar design as what we did in phase II. Lots of the same sites, same dosing administration schedule, measuring the same endpoints, and importantly, enrollment's on track per the corporate timelines that we shared earlier today. This is gonna be a fun year. We have a lot to share with the medical community. We have eyes on all of the key congresses and venues where we can engage with the medical community. And I think we will have a visible presence as we revise and modernize and tailor our communications in a way that really helps the community understand what these data mean, what is going on with phase III, and how we're thinking about the future therapeutic armamentarium in IgA nephropathy. This is a redo of the slide that Marshall began with as we think about the key catalysts. In my mind, I'm focused on the clinical and regulatory catalysts for the company. Today is a milestone day for all of us, and I think in many ways, for the nephrology community. We're really enthusiastic about the progress we're making with ORIGIN Phase III enrollment, and we look forward to completing the first 200 subjects in the second half of this year. In the fourth quarter, we will be delighted to share the full two-year results from ORIGIN 2. And then in 2025, we'll have top-line results from the Phase III, and we'll be poised for a BLA submission in the second half of the year, with corresponding timelines, if things go well, for approval in the United States. So I wanna come back to this little mention I made about a patient in the 18th century in Vienna. A record of a 35-year-old man who was living in Vienna with a history of various infections, depression, headache, and other symptoms. Not long before his death, which was captured in writing, he was noted to have skin rash, gastroenteritis, and edema. He died on December 5, 1791, and it turns out he was born on January 27, 1756. So this Saturday will be his... would have been his 268th birthday. His name was Wolfgang Amadeus Mozart, and he might be the first described individual to succumb to an IgA-mediated death. He had a lot of the signs and symptoms of IgA vasculitis, complicated by kidney failure. He remained engaged in composing, working on the Lacrimosa of the Requiem within hours of his ultimate demise. What I take away from this is I'm trying to think about what would it be like if Mozart lived in an era where we had a B-cell modulator, where we understood the mechanism, the pathophysiology of IgA disease? And would we be able to offer him as a man in his thirties, with an intervention that would have allowed him another half century of composition for the world to enjoy? But more importantly than looking back to Mozart, I think about people today who are dealing with IgA nephropathy, and the people who are to be diagnosed in the days and weeks and months and years ahead. I couldn't be more motivated by what our opportunity is to bring this medicine forward, and that's really what the opportunity is for Vera and what our great collective opportunity is, is to make a dramatic impact on the way we're managing this disease. As a physician in industry, there's nothing more motivating than to look toward the future with open eyes and with great confidence. Thank you. Rob, thanks for bringing it home to the reason why we do drug development and really the promise of biomedical research and the stepping stones that got us to where we are today. We're very excited about the strength of the phase II results and our progress in phase III, allowing us to advance this transformative treatment to patient and to patients and to commercialization and aim to improve patients' lives. I wanna thank everyone here in person and those of you online for your attention and interest. I also, before we close, want to acknowledge all of the members of Team Vera who are with us in person and online virtually. Your dedication, rigor, and hard work have enabled the generation of these important new data. To all of the ORIGIN investigators and external partners, including the IgAN Foundation. Brian, thanks for being here. Thank you for your contributions. And finally, and most importantly, we recognize and thank those IgAN patients who have consented and participated in atacicept clinical trials. Your willingness to participate provides great hope for the global IgAN population in the future. I will now open the floor for questions and discussions. The mechanism, I think, will be able to pass a microphone around. And if there are questions online, I think they'll be sent to me. But a question is valid to anybody on the panel here. Ritu, please give us a start. Let's do one at a time. Okay, it has two parts. First, can you please address what you've been seeing on our IgG levels through the ORIGIN study, the open-label? And does that, I guess the Ig levels overall and your emphasis on hematuria. Does hematuria for the experts, does it represent something different biologically and pathologically than proteinuria? Dr. Lafayette, you mentioned inflammation, but, but you also said it was an independent process, so if you could elaborate on this. Yeah. Maybe, Rob, could you take the first part of the question on our addressing of IgG first? Let's see if we can... It's live. live. Is it live? Can you hear me? It's live. Yeah. So as we showed in ORIGIN 2b, IgG levels came down. There was really no evidence of hypogammaglobulinemia in patients. And so it appears that dual inhibition in this disease of BAFF and APRIL will reduce the portfolio of immunoglobulins, but there's still adequate circulating immunoglobulins so that the overall infectious risk doesn't change between placebo subjects and active subjects. Did you see any defined events, any... Sorry, just a quick follow-up. Did you see any clinically defined events below, like 30% or sustained reductions? Just say it again. No. And then just to follow up on the hematuria issue, again, red blood cells are very large compared to our serum proteins, so the ability to get blood into the urine really reflects a much more severe injury to the glomerular capillary than just with proteinuria. And so to resolve that is really quite a remarkable feat. And again, just suggests that, again, I mentioned studies out of Mayo Clinic had done biopsies and urinalysis comparisons and showed resolution of the mesangial proliferation and capillary proliferation that we see as part of this disease. And then there's been studies from China, Spain, and studies we've done in the United States as well, looking at hematuria. And even when you correct for patient characteristics, proteinuria, and GFR, resolution of hematuria is another very positive prognostic marker. You must always remember proteinuria can be driven by inflammation, but it doesn't have to be. It can be driven by chronic scarring. So whenever we're assessing proteinuria, we're never sure, unless we've got a kidney biopsy, whether that proteinuria is just chronic scarring, which we would not expect to alter, or it's active inflammation, and that's where the addition of hematuria and proteinuria is useful. So if you have proteinuria and no hematuria, it's likely there isn't glomerular inflammation, it's all fixed scarring. So that's really important to look at those two together. Just a note to the AV team, could we turn up the volume? I'm getting a message that those online can't quite hear well enough. Thanks. Next question. Hi, it's Liisa Bayko from Evercore ISI. Dr. Barratt, you used the term functional cure, and I'm wondering if you could elaborate on what that means and how far is this data that we've seen here today going towards that objective? I think biologically, it may- That's part A, that's part A of the question. Okay. So biologically, it makes complete sense. If we think about lupus, we think about ANCA-associated vasculitis. We want to turn off pathogenic immunoglobulin production, which is why we use a drug like rituximab. Doesn't work in IgA because the B cells and the plasma cells are somewhere different. We want to turn off pathogenic IgA production, B cell modulation, and the data you've seen for atacicept does that in the data we have. At the end of the day, what the patient wants to know is, can their kidney function be maintained for the rest of their life? And that's where the GFR data is critical. And that's what we're seeing for the very first time over the duration of this study, is the GFR is not changing. What we see in every other study, when we look at placebo patients treated with standard of care, in this group of patients, they're losing 6 mL per minute per year of GFR, and we've just not seen it with this data. So that's where I think we've got a biologically plausible mechanism that's switching off the fundamentals of the disease, and that is translating through to true kidney function protection with no change in GFR. It's the combination of the two. And then just, part B, you talked about this concept of potential escape if you're using just kind of like an APRIL or BAFF, or in this case, it's APRIL only versus the combination. Have we seen any evidence of that? Are you able to kind of like drive that in preclinical models or any evidence in any data of any kind? I'd just be curious if, you know, the kind of reality of that. Yeah. Liisa, good question. You know, first, it's the conceptual view from biology, that when you have two parallel, somewhat overlapping biologic pathways, that there can be biologic escape, and we see that throughout biology and in medicine. We've seen now in one of my slides highlighting that both APRIL and BAFF are elevated in IgA nephropathy and across certain other autoimmune diseases, and you must believe that's the important first lens that Team Vera's using to look at opportunities across additional autoimmune disease. The preclinical evidence is in. I showed that in the center or the left panel. where, a mouse model of lupus nephritis, compared directly dual BAFF/APRIL inhibition versus APRIL alone and BAFF alone, and you see a more substantial impact on plasma cells, which in a mouse you can access differently from a human. So you can look at plasma cells in bone marrow, plasma cells in spleen, and see a more robust effect of dual inhibition versus APRIL alone or BAFF alone. And the figure we shared from that paper showed a more robust, resolution of proteinuria, in those, in those mice. So, we're at a point today where we can look ahead at clinical data. We believe we're the first and have shown, very substantial, clinical impact, and we hope that will continue to be confirmed in phase three. But really, the question of biologic escape is a conceptual one that we see throughout biomedicine, and one that's supported by the preclinical data with direct comparisons, as shown earlier. That's where we are. Thanks for the question. Next question? Hi, Farzin from Jefferies. For the 72-week data, can you provide any insights on how the subgroups performed, like UPC, eGFR breakdown or SGLT use? Yeah. Most importantly, looking at subgroups, in our view, is a phase III activity. So, as you think about subgroups and relying on randomization, as you start to divide those populations thinner and thinner, you get wider error bars and more variability. So, in general, in drug development, when we think about subgroups, it really is a phase III question, and we will certainly look at that. As we reported last year, Farzin, at week 36, you know, we had the most robust phase 2 RCT data as we planned our phase III program, and of course, the Vera team made use of those subgroup analyses in designing and planning to operate the phase III trial. So, we haven't provided any disclosure of those subgroups, but we've certainly made use of them to ensure that we have the highest confidence in our phase III design and operation. Good question. Next, next question? Hi, Pete Stavropoulos with Cantor Fitzgerald. Just to sort of follow up on the hematuria. You know, is there any obvious observations, you know, when you look at the patients on atacicept that did not have resolved hematuria? Is there anything about the baseline characteristics that pop out at you? If not, can Dr. Lafayette or Barratt speculate on why those patients did not have resolved hematuria? Yeah, great question, Pete. And just to repeat the question, it's really, you know, if you track the end, Pete, you've got not all patients at baseline in the ORIGIN 2b study had hematuria at baseline, so I think that reflects a diversity of biopsy-proven IgA patients who came in. And I don't want to answer the question for... Maybe Rich, you could take this question. Hematuria may indicate more active inflammation for that patient at that time. Yeah, for sure. I think you're not going to get a very granular answer because, as you just heard, we haven't been able to really examine subgroups very closely. So trying to look at correlates of who got better in terms of hematuria versus those who didn't is really unclear right now. We did present data that the resolution of galactose-deficient IgA was correlated with the resolution of hematuria. So those patients who are responsive, which was the vast majority of patients, do well. So it does seem that the biological hypothesis is playing out, which is wonderful for the drug design, but I can't. I don't know the answer to further details about baseline characteristics. Okay. Can I go back to, you know, the scarring? So you have some patients that have greater scarring and so forth. Yeah, and, and that point is, while the hematuria does correlate with the inflammation, we do know in some non-inflammatory glomerular diseases as well, now the microphone's very loud, that you can have residual hematuria as well. And so the mechanism of all blood in the urine is not always clearly related to inflammation upstream. There can be chronic tubular or interstitial damage as well that contributes to hematuria. Thanks. Next question? Hi, Ryan Deschner, Raymond James. This is a question for... First of all, congratulations on the fantastic data. Question for Dr. Lafayette. In terms of the eGFR data that looked so rock solid out to 72 weeks, what's your interpretation of this data set from a mechanistic standpoint in terms of what's going on in the kidney at that time point? And then at what point do you expect sort of the eGFR rate profile to return to what you would expect in the general population? So again, I think it's wonderful eGFR data. Again, we're seeing complete stability. We did see, in this study, again, in these few numbers, again, an early response to the therapy where GFR does stabilize, even looks to improve. So I do think we're seeing an anti-inflammatory effect of therapy based on the resolution of hematuria. We're seeing improvement of a tiny bit in the GFR and then no further loss of nephrons. And therefore, as long as we're on drug, my expectation is that the disease will not progress because that's what we have seen so far. Again, to Dr. Barratt's point, we do know that patients with lower GFRs, with lots of chronic damage, might be expected to have progression faster than normal aging with time. Hypothetically, the field is working on a lot of anti-inflammatory therapies to actually stop that tubular interstitial progression, because part of that may also be based on B-cell, T-cell interactions and inflammation in the tubular interstitium. So there may even be hypothetical benefits of doing this, which are not directly disease-specific. But all I can say so far is 72 weeks, rock stable. So same patients, same medicine. I hope 73rd week looks like that, and maybe the 173rd or 1,073rd can look the same. And don't forget, all these patients were on a RAS inhibitor. The general population aren't. So that 1 mL per minute per year from the age of 40 is a general population untreated. So these are patients where those generic maladaptive responses are being proactively managed. So that's why I think you're seeing stability and not the decline that a normal, untreated population would be experiencing. Hi, Justin Kim from Oppenheimer. You know, maybe just for the KOLs, and congrats on the data. Given the promising updates presented today, can you just discuss what extent the historical translation of proteinuria to eGFR attenuation needs to be redefined, given this mechanism? And, you know, consequently, are there any pieces of additional clinical evidence that are necessary to shift treatment practice beyond focusing on attenuating protein excretion? So I think if you look at the data we produced for the KDIGO working group, which looked at the relationship between proteinuria reduction and GFR decline, none of those drugs were a fundamental disease modifier. They all altered glomerular hemodynamics, or in the case of steroids, impacted on inflammation, but they didn't fundamentally alter the disease, and therefore, you would not expect to see the relationship we've seen today. You would expect more is better, but actually, because you're not addressing the fundamentals, you're not seeing that stabilization. This is a brand-new class of drug, and if you think about that graph that everyone looks at, this would be a big, big outlier. You're absolutely right, we are going to need to rethink that a 50% reduction in proteinuria with one mechanism of action is not equivalent to 50% reduction in proteinuria with a different drug that is doing something fundamentally different. We've only just seen the data, so we can't put that in yet. You're absolutely right, it's going to be a big outlier to that relationship that we've published. Hi, I'm Malcolm Kuno, in for Anupam Rama, JP Morgan. Awesome data. This one's probably more for the, for the KOLs. So when you, when you look at the 72-week data in the context of the competitive, B-cell space, what do you think are going to be the most important factors in determining market share long term? So again, we sort of think about just clinical benefit, of course, more than market share. But I think exactly what we're going to be looking for are really three tenets. You know, safety, which this appears to be very well tolerated and safe. All the adverse events we see are some injection reactions, but all well tolerated, not leading to the patients leaving the study at all. In fact, leading to patients to opt in to long-term extension, which is great. So safety is there. The efficacy, as said, you know, robust reduction in proteinuria, which again, would be the starting point to say we're hopeful. But again, this beautiful, absolute stability of kidney function so far would really lead this to be the leading candidate this far along in development. Again, which then eases our ability to recruit for phase III, because now, after this meeting and, when a press release comes out, we can share this with our patients and our referring doctors as well. So I think, this is, again, as, as, Rob mentioned, this is everything we want to see. You have a disease with blood in the urine, protein in the urine, and advancing renal dysfunction. All three of those are, greatly assisted by this medication, so it's very, very exciting, and again, would be thought to be a disease-leading therapy at the moment. And then, what are your thoughts on things like site of care or modality, whether it's sub-Q administered by a physician, what are your thoughts on that? Yeah, I like to trust my patients, so I think if they can be home, get a well-tolerated therapy, that's really quite optimal. So I think this is a really reasonable delivery mechanism. Being at home, taking your medicines, meeting with your physicians and nurses on a regular basis to make sure things are going well, I think it's a very reasonable way forward. Yeah, I think if you, if you go into the rheumatology space, this is all automated. So in the UK, someone rings you, you have the drug delivered to your home. There's no need to go to the hospital. A nurse has shown you how to inject. You take complete control of your life. And remember, these are young people at work with family responsibilities. They don't want to be messing around, having to go to a hospital for their treatment. They want to have complete control and independence. And the fact that this is being evaluated in the phase 3 with home administration by the patient... is really important because that gives us an idea about the practicality of this. I just want to make a comment. It's a good question. This goes back to what Rob shared in terms of what we've done to de-risk the phase III trial, because self-administration in phase II, just confirming that in phase III, I'd point to two things. One is the study retention that we've shown today at 72 weeks is on par with, if not numerically better than oral therapies. So I think that's an important data point we haven't featured yet, is, you know, over 90% study retention for a self-administered subQ once-a-week profile is. It's that means that when in this study, patients are given, for example, a three-month supply for subQ injection, they continue on that generally. I think that's a real strength in the data set that we've shared today. Other question? Rami Katkhuda from LifeSci Capital. Question for the KOLs as well. I guess, atacicept is the only BAFF and/or APRIL inhibitor that will have proteinuria and eGFR data out to 96 weeks at commercial launch. I guess, based on your perspective, eGFR won't be on the label, for accelerated approval, but do you think this data could help early uptake of the therapy versus others in the class? Well, we look at proteinuria because it's a nice early marker, but what we're really interested in is GFR. So the GFR data is what we will look at, and if that GFR data is out there for two years or longer at the time we get the opportunity to prescribe it, it's undoubtedly going to influence us. It is also undoubtedly going to have an impact to the FDA, and that's my personal view, is if you are able to show safety, tolerability, and a sustained GFR effect in a significant number of patients over two to three years, potentially, that is going to be incredibly impactful. And that's something that we'll look at as nephrologists, the regulators will look at. But most importantly of all, when you're thinking about uptake, patients, the IgA Nephropathy Foundation are here, are going to be talking about this continually, and they are the people that will be going to their doctors saying, "Why can't I have access to this drug? Because look what it does." Within 30 minutes of the press release for new drugs in IgA nephropathy, the foundation are tweeting it, the patients are aware of it, and the patients are driving demand. And I think you shouldn't discount that. I guess, to that point, based on the totality of data, is there potential for full approval based on nine-month results, especially if the eGFR is shown to be stat sig, as it was in phase IIb? So I'm not the FDA, and I'm not Vera, but I think that's something I'm thinking very seriously about and how we might make an argument as the nephrology community for that to be considered if there is the totality of data out to that length of time. Thanks. So Vamil Divan from Guggenheim. So thanks for all the data. Very, pretty clear and solid, so I don't think I have many more questions there. Just a couple maybe for the company. One, if you can provide any sort of update on the progress of the phase III enrollment, and you touched on sort of once monthly as a possible option, maybe what the path would be to getting it once monthly to the market. And then you also shared, you have some of these other indications that are potentially phase III-ready. Maybe you can just provide an update or sort of more broader corporate plans on pursuing other opportunities beyond IgAN and beyond the U.S. alone. Sure. Good. Thanks for the question, Vamil. I'll start, and maybe, Rob, I'll ask you as well. So the first question on Phase III progress, I can't currently provide any further detail except that the projections we made last year continue to be the projections we can share today, which reflects our confidence in Phase III startup activities, site activation, global screening and enrollment continue to put us on the right trajectory to be able to announce in the second half of this year the first 200 subjects who are driving the primary endpoint and time to market. So that's what we can share today, but we're enthusiastic. I think continued positive data continues to be able to invigorate enrollment, and already it's been strong. Second question about monthly dosing. I think what you've heard today and really the data that you've seen support once weekly dosing, self-administered once a week, which a patient can give to themselves at home on a Saturday morning, is a fantastic commercial profile. That's what we plan to commercialize, Vamil. It's been important to share the depth of data, the PK/PD, all of what's known about atacicept. There's very substantial dose-finding that's occurred with this program, which we knew, and we brought it into the company. That's a huge strength in terms of looking at longer dosing intervals as a possibility. At this time, we don't want to provide what that plan is because we have a plan to get to commercialization, but there are certainly multiple mechanisms by which you can explore different dosing modalities in the post-market setting. Third, your question about the current pipeline. We've been, I think, and I think we see this throughout biotech and in business generally. Focus creates value. From what we're sharing today and the progress we've made, that comes from hard-won focus throughout the company, and I think you're seeing those results unfold in our almost three years as a public company. We hope that'll be recognized. Making sure that we take advantage of the broader opportunity, I would say, you know, we've shared some indication of where we could go next, how that's supported by clinical data at this stage, and we've been, I think, upfront that some of these programs are phase III ready. Some might be phase II, if it's somewhere in an autoimmune disease where we have more questions about initial efficacy. But what should be really clear is that atacicept has done enough dose finding so that further dose finding is likely unnecessary in a variety of autoimmune diseases. So I think that's really important to understand. So, we now have reductions in autoantibodies, not only in IgA nephropathy, but in systemic lupus and in others. It's not a hard leap to go from one to the next. Exactly which program will be the next program for Vera is, that's not something we're sharing today. And I would say that that's in part because we have a new Chief Medical Officer who internally will be reviewing the current strategy forward. So, give us time, and we will be forthcoming about that. So hopefully that's understandable. Rob, any other comment based on those good three-part question from Vamil? Yeah. So I think we, at Vera, we certainly recognize that there is lots of optionality for where we will go next with atacicept. In addition, we're very exuberant on the potential for MAU868, for BK virus and transplant recipients. But that said, to Marshall's point, you know, these data require that our undivided attention is on moving forward with a program that's going to bring this drug to patients as quickly as possible. It's a corporate obligation, it's also a moral obligation, and so we take that really seriously, and we'll move forward at the right time and other indications as we are absolutely confident that we're continuing to execute flawlessly to bring this to patients with IgA nephropathy. Great. Next question? Great. Ed Arce with H.C. Wainwright. Congratulations on the data. I have one question, two parts. Firstly, you know, obviously, the clinical focus is rightly on the actual kidney function and the eGFR data that you've shown this morning. But you mentioned as well that, you know, where we are in the regulatory pathway for accelerated approval, the FDA still very much looks at proteinuria, and you talked about how you're well past the sort of 30% threshold and now approaching 50%. So first part is, given that you do see incremental improvements over longer term, is there a reason to believe that you could still see further at perhaps the 96-week point? And, you know, how impactful that would be, if at all, to the FDA, given the current data? And then secondly, as we've mentioned or we've discussed before, obviously, the focus for the agency would be ITT data. Could you review for us what are some of the key things that you've implemented and give some sort of detail around those factors that lead you to have strong confidence that that data will be a lot closer to the PPP shown in phase II? Ed, thanks for the question. Rob, maybe I'll turn to you for the response first about proteinuria, extent of proteinuria reduction, and then to the analysis type, which is really relevant for the randomized phase. Yeah. I mean, I don't think I have a better crystal ball than anybody else. I would say we're really enthusiastic about seeing the full two-year data. It would be terrific if we saw even more reduction in proteinuria. But at 48% or so, UPCR reduction by both ITT and per protocol, you know, I think it's a, it's a very healthy, very clinically relevant component of the integrated profile of the drug across these four parameters in the disease. And so we'll see. In terms of the regulatory conversation, it's not lost on us that these very fresh data that we have just become privy to have lots of implications for a variety of different audiences. One of those is the regional health authorities, and we plan to think creatively, and to be a good partner with those authorities, to educate them on what we've learned, and to have a robust conversation on what it means, either in the context of historical pathways for approval or if there's an opportunity for doing something more aggressive. I don't know how that's going to go, but it's just not lost on us that we have an opportunity to have those kinds of conversations. And what was the... Was there- That's good. Are there any other questions? So, Dr. Lafayette, Dr. Barratt, you know, right now, the guidelines sort of define patients as, high risk, when they have more than 1 gram per day of proteinuria. You know, but you authored a paper, last year, and, you showed some of the data from that, basically, showing that, longer-term outcomes, for those patients with lower proteinuria measurements. You know, with that in mind, you know, what would you define as high risk, and which patients, you know, should have access to, a B-cell modulator like atacicept? So we're currently re-reviewing the KDIGO IgA guidelines, so that work is ongoing, and we will hopefully have new international guidelines for public review later this year, probably before the summer. So I can't say anything particular. I can give you my own personal view, which is if I've got a patient who justifies having a kidney biopsy, so justifies me putting a needle in their kidney, I'm going to want to act on what I find. And this data and what I've shown you is that patients with IgA present generally late, having already accrued kidney damage. I'm going to want to save as many nephrons as quickly as possible. So for me, I would be starting atacicept or a drug like atacicept the minute I get that diagnosis, alongside those RAS inhibitors and SGLT2 inhibitors, doing something very different for the kidney, with my personal view, wanting to save the kidney function over the lifetime of that patient. Now, of course, we can do that when we know a drug is safe and well-tolerated, and that's what we're going to be getting accumulated evidence. But for me, at the time of diagnosis, I will want to switch off pathogenic IgA production, and I won't be too concerned about proteinuria, because to have justified a kidney biopsy, they're sick enough for me to want to treat them. Yeah, and I just wanted to further emphasize that the prior guidelines were based on sort of the lack of therapy and looking for a population with sufficiently high risk to justify systemic immunosuppression with the risk of infection and death. As we have newer drugs and a profile like atacicept, we are going to come down on that risk and also utilize better those other risk factors beyond proteinuria, such as hematuria, kidney function, how the biopsy looks, and find other populations, probably at lower risk, who still should have lifelong preservation of kidney function. I think it's going to alter how we manage patients. I think we will have a lower threshold to biopsy. There's no point biopsying someone at the moment because we've got bugger all to give them. You know, that's the... frankly, for the last 50 years, we've had nothing. Now we're going to have safe and effective drugs. I think globally, there will be a lower threshold to actually make a diagnosis of IgA nephropathy because we can meaningfully do something for those patients. And so I think there will be a complete sea change in how we approach young adults with blood and protein in their urine. Great. Ritu? Thanks, Marshall. Ritu from TD Cowen again. Can you give us a little more granularity on how the phase III is going? Site activation, enrollment must be competitive with all the phase IIIs ongoing. And then, Sean, if you could readdress the cash position and how far that's getting you in this whole process. Yeah. I can only give you the qualitative view that we're enthusiastic about progress in Phase III and can't give granularity at this time. I think it's a competitive space out there, and I think we feel confident in our projections. That's what we can say today. And Ritu, thank you for the question. Currently, Vera is very well capitalized, with cash flow made in 2026. It funds us through multiple near-term catalysts as well as our Phase III. Great. Lisa? Hi, follow-up question. So I think we have a pretty good idea of what this compound looks like, right? As you think about phase III, yeah, it's as you said, relatively de-risked. I think we have a good, good handle on the profile. So that leads me to start thinking about how you might price something like this. And there are different benchmarks out there, right? You have, like, newer agents, and you can look at how those are priced. For example, you know, sparsentan, FILSPARI, in the kind of like $120,000 range per year. And then you have iptacopan that's been priced, you know, for the PNH market, but also will be ultimately approved in nephropathy and how that might be priced there. So, that's a pretty broad range. You do offer, you know, quite a bit of benefit on top of, you know, some of the therapies we've seen. So do you... Should we think of this as premium pricing? Kind of how do we think about pricing? You know, I think you have enough elements now to do the work there. So I'd be curious on kind of the feedback you're getting and, and how that might also play into where payers put it on, on the line. Like, do you have to kind of be at risk of progression to start a B-cell therapy if it's got a certain price? Maybe those dynamics would be really interesting to hear about. Sure. Lisa, thanks for the question. We do have a robust data set, but, we of course, will learn more at two years and learn more with a confirmatory trial. And we learn more from the evolving landscape. There are two drugs on the market right now with, premium pricing. And, and I would just say the totality of the data set is, is going to be meaningful. I don't want to make a specific comment on pricing beyond, yes, there are precedents, that exist already, that give us some sense, and, and those profiles, I think, are not, not as strong as, as what, we've shown today. One thing that should be known, and this is part of Vera's focus on IgAN, is that we have a very strong commercial planning and payer research core within the company, so that work has already been initiated and is ongoing. So we do have substantial preparations and thinking through all the way to payer and access questions. And so, we are stage appropriate for a company that is near to fully enrolling the primary endpoint cohort this year. Any other questions? Okay, Marshall, any closing comments? I just want to thank everybody. Thank you, Dr. Barratt, Dr. Lafayette, and thank you to the Vera team, and I'm happy to spend some time in person. While I have a few minutes, in person, it's always better to be face to face. So thanks so much for making the effort this rainy morning in New York. Thanks so much.