Vera Therapeutics, Inc. (VERA) Earnings Call Transcript & Summary

Greetings. Welcome to the ORIGIN Phase III Top line Results Data Call. [Operator Instructions] Please note that this conference is being recorded. At this time, I'll now turn the conference over to Marshall Fordyce, CEO and Founder. Marshall, you may now begin your presentation.

Welcome. I'm Marshall Fordyce, Founder and CEO of Vera Therapeutics. And on behalf of the entire Vera team, I'm thrilled today to share with you the primary endpoint results of the ORIGIN Phase III trial of atacicept for the treatment of adults with IgA nephropathy. After my introductory results -- remarks, you will hear from Rob Brenner, our Chief Medical Officer, who will take you through the primary endpoint and safety. Next, you'll hear from Matt Skelton, our Executive Vice President of Commercial who will share with you how we see the market landscape and the potential to make a meaningful difference in the lives of patients with IgAN and beyond. Before we get started, I want to remind you that my remarks contain forward-looking statements under the Safe Harbor Act. And as such, we present this disclaimer regarding at-risk statements. Today marks an important milestone in Vera's history as we progress the development of atacicept, a potential first-in-class mechanism, dual BAFF/APRIL inhibitor, to transform treatment of autoimmune diseases. Atacicept is foundational to driving Vera's bold growth trajectory. Vera's mission is to change the standard of care for patients with autoimmune disease from 1 based on steroids and depletion of B cells to a more targeted modulation of the immune system and free patients from the burdens of their disease. I would like to thank the IgAN patients who are participating in this trial, the trial investigators, the patient advocates, our investors and the employees of Vera who have been working tirelessly to bring atacicept to the IgAN community. Vera is poised for a potential commercial launch of atacicept in 2026 and to pursue development in additional indications in other autoimmune kidney diseases and beyond. We initiated the PIONEER trial and additional IgAN cohorts in other autoimmune kidney diseases earlier this year. I am proud of the Vera team and the progress we've made towards unlocking the pipeline and a product potential of atacicept, with the positive results of our Phase III primary endpoint of reduction in proteinuria at week 36 announced today we are on track to submit a BLA to the FDA in Q4 of this year. We will also have additional data this year from ORIGIN Extend, our open-label trial in IgAN and from our PIONEER trial in multiple indications and autoimmune kidney disease. Vera today is in a strong position financially, with pro forma cash of $590 million and 63.7 million shares outstanding. Atacicept's mechanism of dual BAFF/APRIL inhibition has broad therapeutic potential for certain autoimmune diseases, which are substantially driven by abnormal B-cell function. Atacicept inhibits the 2 known cytokines circulating called BAFF and APRIL, which are both important for the survival and maturation of the B-cell lineage. Elevation of both BAFF and April are found in patients with IgAN, lupus and other autoimmune diseases and both play a role in disease pathophysiology, driving autoantibody production and damage to the body. Patients with IgAN currently face a very challenging path ahead. On average, people with IgAN are young, 35 years old on average. And among those at high risk, rapid kidney function decline leads to end-stage kidney disease or ESKD before 50 years old. ESKD means your kidneys don't function and you need dialysis or a kidney transplant dramatically altering their lives and those of their families. The severity of ESKD is often underestimated. And as seen here, mortality over 5 years from this diagnosis is similar to cancer. Our program to develop atacicept for patients with IgAN focused on its ability to target the source of this disease, BAFF and APRIL, and inhibit the formation of immune complexes that cause kidney disease in these patients. Through rigorous clinical science, we aim to demonstrate that the inhibition of immune complex formation in IgAN through BAFF/APRIL inhibition offers the potential to avoid ESKD over a patient's lifetime. It is my great pleasure to share with you the top line results of our pivotal Phase III trial called ORIGIN 3. I would like to introduce my colleague, Rob Brenner, our Chief Medical Officer, who will take you through the data. Rob.

Thank you, Marshall. And first of all, I would like to congratulate all of my colleagues within research and development at Vera for enabling us to be at this exciting moment today. As a reminder, I'd like to review the disease where we have focused atacicept as our lead opportunity. That is IGA Nephropathy is a disease of B-cell origin with the kidney pathology. We've learned a lot over the years about the mechanism of this disease. And it begins and focuses on the B cell as the key contributor and driver of disease process. B-cells are fueled largely by 2 cytokines, BAFF and APRIL. And B-cells produce in this disease, both in autoantigen, a galactose-deficient form of IgA1 and auto antibodies that recognize this Gd-IgA1 construct. Together, these 2 antibodies form immune complexes, which unfortunately deposit within the kidney where they drive inflammation as measured by hematuria and increased generation of proteinuria or protein in the urine and most importantly, as Marshall mentioned, a progressive loss of kidney function, which we can measure as GFR, which puts patients at a high lifetime risk of needing renal replacement therapy with dialysis or transplantation. Vera believes that an ideal IgAN disease-modifying therapy would be expected to accomplish 4 things. First, that we would see a reduction in the burden of immune complexes, and we can measure in our clinical program, the concentration of Gd-IgA1. Two, we would also expect to see resolution of inflammation as measured by a reduction in the percentage of patients who have blood in their urine, measured by urine dipstick. Three, and importantly, a reduction in the burden of proteinuria that the patients experience. And this is the key endpoint that the FDA has used to drive accelerated approval in this indication. And most importantly, that we would achieve a stability of the eGFR profile in these patients. Next slide. As a reminder, I'd just like to review the Phase IIb results that we shared last year. These were long-term 96-week results in patients who are receiving atacicept dosed at 150 milligrams in a 1 ml prefilled syringe at home once week -- once a week. First, we showed a 2/3 reduction in the concentration of the autoantigen Gd-IgA1. On the upper right, we see that 75% of participants who have blood in the urine at baseline had resolution over that 96-week period. On the bottom left, we see that there was a reduction in proteinuria of 52% in patients who were treated through the 96 weeks. And at week 36, there was a reduction of just shy of 40%. And most importantly, an EGFR profile of minus 0.6 ml per minute per year. To provide context for that, historically, healthy individuals without biopsy-proven kidney disease lose on average about 1 ml per minute per year. So the achievement of that slope of minus 0.6 ml means that population of patients with biopsy-proven kidney disease, where historically, they lose 6 to 8 ml per minute per year, now had a GFR profile similar to healthy individuals. On Slide 12, we have an overview of the study design of the ORIGIN Phase III trial. This was a randomized -- is a randomized clinical experiment where patients were randomized 1:1 to receive either placebo or atacicept at the same dose and mode of administration as we use in the Phase II that is 150 milligrams administered by patients themselves at home as a subcutaneous injection once a week using a 1 ml volume. The primary endpoint was based on the first 203 participants who were followed for 36 weeks looking at their proteinuria here measured as urine protein and creatinine ratio. The secondary endpoint, which will drive future full approval is based on a 104-week readout for all enrolled participants, which is 431 individuals. On Slide 13, we have the patient disposition flow for the study for this analysis. There were 203 randomized and treated individuals available at the time of this analysis, and that reflects the number that were randomized back in September when we announced that we had completed the cohort for the interim readout. At the time that this analysis occurred, 106 of those 203 individuals have been randomized to atacicept, and 97 had been randomized to placebo. For the 106 participants who are on atacicept, during the course of the 36 weeks, there were 7 treatment discontinuations, meaning that 93% of those who were randomized to atacicept were dosing after the interim analysis. Of the 97 placebo randomized participants. The number of discontinuations was higher. There were 13, meaning that 87% or 84 individuals were still on ongoing treatment at the end of the interim. The difference between placebo and active is a reflection of the fact that the participants and their caregivers felt that they were not responding to treatment the way they had hoped and they thus discontinued treatment. Slide 14 has the demographics and baseline characteristics for the ORIGIN 3 population on the left, and I've included the ORIGIN IIb population on the right for comparison. Overall, there are enormous similarities between the IIb and the Phase III program. On average, patients were about 40 years of age. So it's a young population. There's a slight preponderance for male sex, consistent with the epidemiology of IgA nephropathy. The distribution of Caucasian and Asian patients reflects the global burden of the disease. The GFR at baseline for participants in the Phase III and in the Phase II was about 65 ml per minute per year. What this means is that enrolled participants have lost already about 40% of their endogenous kidney function, and they're at high risk for progression to end-stage kidney disease. Their UPCR burden was significant at about 1.7 grams per gram. And their vintage between the Phase II study and the Phase III study was similar with about 2.5 years of lapse from the time from their biopsy before they were enrolled in the trial. One parameter that differed between the Phase II and the Phase III program was the concomitant use of SGLT2 inhibitors. We were at about 14% in the Phase II study and just north of 50% in the Phase III. This reflects the evolution in standard of care during the period of time that lapsed from the Phase II enrolment to the Phase III. Slide 15, we have the results that Marshall alluded to earlier. So in the origin Phase III interim analysis, primary endpoint readout at week 36, there was a deep 46% reduction in UPCR and those individuals randomized to atacicept. And when we do a placebo adjustment accounting for the modest reduction observed in placebo the overall UPCR reduction is 42% with a highly significant p-value. Importantly, other prespecified endpoints achieved similar or better results compared to those observed in the origin Phase IIb study. but I want to highlight that per FDA guidance, Vera is not sharing eGFR results at this time. On Slide 16, we can review the safety profile of atacicept for all participants who are randomized and who had a data cut at mid-May for this interim analysis. Adverse events were similarly distributed between placebo and atacicept. However, serious adverse events were not similarly distributed. There was a single serious adverse event in the atacicept group. We've observed 11 serious adverse events in patients randomized placebo. Similarly, there were more adverse events leading to discontinuation in placebo versus atacicept. Importantly, given that this is a B-cell modulator and is impacting B-cell activity, we have had careful review of the risk of infections in patients who are treated with active drug versus placebo. And thus far in the Phase III program, we've seen similar events of infectious adverse events overall at about 30%. In terms of serious or severe infections, we haven't seen any thus far with atacicept and there have been 3 observed with placebo. Importantly, there have been no examples of opportunistic infections through the program thus far. In aggregate, this safety profile to me, looks different than what we historically see with immunosuppressive agents. And I think this starts to provide some insight into what it means to be on a B-cell modulator, which appears to be a softer gentler approach to impacting B-cell activity and reducing antibody production, but at least in the Phase II experience thus far, hasn't increased the risk of opportunistic infection. The one area where we saw differences in placebo versus active in favor of placebo was with injection site reactions. These were largely mild, fewer moderate and none were severe, none led to discontinuation of dosing and were self-limited. Importantly, beyond injection site reactions, we looked for evidence of hypersensitivity. And there, we see that there was an increase in hypersensitive reactions in patients who received placebo versus those who received atacicept. And finally, there would have been no observed deaths on study. Next steps for the Vera team will be to submit the results for presentation at the upcoming American Society of Nephrology Meeting, which occurs in Q4, and we hope to have a peer-reviewed publication for these results at that time. In the near term, we look forward to meeting with the FDA in the coming weeks to discuss these results and the regulatory pathway. As Marshall mentioned, we currently plan to submit a BLA for accelerated approval to the FDA in Q4 of this year, and ORIGIN 3 continues as designed with 2-year results expected in 2027. As Marshall mentioned, I'd like to emphasize again that these promising results would not have been possible without the study participants, their families and caregivers, the study investigators and staff, our research partners and importantly, the Vera team for their commitment and dedication to this important research. I'd now like to turn it over to my colleague, Matt Skelton, Executive Vice President of Commercial.

Thanks, Rob. I am delighted to join my first call at Vera and excited to share our progress on the commercial side. As this is my first call, I would like to take a minute and tell you about my background. I joined Vera last October. Previously, I spent 9 years at Seagen, where I was responsible for scaling the commercial organization to go from a one-product company to 4 products. I helped lead 3 successful launches. Before Seagen, I was at Amgen for 16 years in various marketing and sales leadership roles. I spent 5 of those years in Amgen's successful nephrology business. I'm happy to be back in the nephrology space and excited about atacicept and its potential to improve the lives of patients in IgAN. The last few months, I've been busy building Vera's commercial team. I'm proud to report that the commercial leadership team has been hired and that many other key hires have been made. With these strong results, we just started the process of bringing on sales leadership. We are attracting top talent, largely because of the promise of atacicept and the culture that Marshall and team have created. All of our commercial hires have recent launch experience and have worked in the specialty or rare disease space. The guiding principle for the commercial build-out is to have a competitive share of voice and we are well on our way to doing that. This morning, I want to take you through the opportunity in IgAN, how we view the market and important insights we are gathering from nephrologists. Let's go to the next slide. So here's the opportunity. They're a large prevalent pool of patients, of which 90,000 are immediately addressable. This is the ORIGIN 3 Phase III population. We are confident we will compete for meaningful share in this population and as the data continues to emerge with atacicept, we hope to eventually expand into moderate and lower risk patients. This is a market with significant growth potential. Vera is also committed to developing atacicept in other autoimmune kidney diseases where additional unmet need exists. So here I wanted to show how we're viewing the nephrology space. There are approximately 11,000 nephrologists in the U.S. and they are spread across many sites of care. But our focus will be on the office-based setting and those physicians that focus on rare causes of kidney disease. This is where the majority of innovation in this space is focused and the most unmet need. This subset of [ NEF ] will be critical to drive adoption of atacicept. More to come as we work hard to gain a deep understanding of the customer base. These findings are from a third-party survey conducted with 100 nephrologists. We are encouraged by these results, awareness of atacicept surpassed APRIL only mechanisms and [ NEF ] appreciate the potential unique benefits of dual BAFF/APRIL inhibition. We look forward to the updated KDIGO guidelines that should evolve the IgAN treatment paradigm. From the same survey, we are very pleased to see the strong ranking of atacicept amongst other pipeline assets. We are definitely punching above our weight here. I think the results today will increase this already high level of anticipation for atacicept. We have been conducting our own market research. Our product profile is compelling to nephrologists, the Phase IIb long-term eGFR data resonates the most, followed by dual inhibition MOA and disease-modifying therapy. I would also like to mention our patient-friendly presentation, at-home administration with a low 1 mL injection volume led to over 90% patient retention in the trials. This may prove to be an important differentiator for atacicept. Over the next few months, we will conduct additional research on the updated product profile. So let's take a look at the existing market. Innovation in the IgAN space is allowing for premium pricing. FABHALTA is a clear outlier, but remember, it was initially approved for PNH. The strength of our data including the unique long-term eGFR data from our Phase IIb gives us flexibility with pricing considerations. I will conclude with this slide. The market and the product are attractive. It is a large and growing market with unmet need. Nephrologists and their patients are hungry for innovation. The payer mix is mostly commercial. Remember that patients are usually diagnosed in their 30s. This payer mix reduces our exposure to government-mandated discounts. We are excited about the atacicept profile. I'm confident we will achieve significant market share with these results. I have had the good fortune to lead many successful launches and have learned that the first requirement of a successful launch is a great product. With this data, I think we've met that requirement. As we move towards filing and hopefully approval, I look forward to providing updates on commercial activities. Thanks, and I'll hand it back to Marshall.

Thank you, Matt. We are committed to the IgAN patients and the IgAN community and the potential to change the course of this devastating disease. Much broader the rationale to study atacicept in additional autoimmune kidney diseases is based on the emergence of substantial clinical evidence that several autoimmune diseases are driven by autoantibodies against a variety of antigens. In the case of IgAN, that antigen has been determined to be the galactose-deficient IgA1. In the case of membranous nephropathy, anti-PLA2R antibodies are associated with disease severity and progression in the vast majority of patients and the reduction of anti-PLA2R is associated with the slowing of disease progression. More evidence suggests a similar paradigm of autoantibodies to the glomerular antigen nephrin, suggesting patients with anti-nephrin antibodies may be an attractive target for certain patients with FSGS and minimal change disease. As Matt shared with you earlier, we are committed to interrogating the potential of atacicept and other autoimmune kidney disease and more broadly in other autoimmune diseases. We believe that atacicept has pipeline and a product potential benefiting patients affected by a variety of autoimmune diseases, beginning with nephrology and moving on to rheumatology, hematology, and beyond. Earlier, we initiated the PIONEER trial a Phase II basket trial designed to assess atacicept potential in IgAN patients who did not meet our Phase III criteria and specifically moderate and low-risk patients, patients with low GFR, with high proteinuria, patients who are adolescents and even post transplant patients whose transplanted kidney is at risk of early loss because of ongoing elevated BAFF/APRIL levels in autoimmune autoantibody production. PIONEER also expands our investigation of atacicept into new autoantibody-driven nephrotic diseases such as pMN, FSGS and MCD. Following the successes of our Phase II ORIGIN trial last year in 2024 and our Phase III pivotal trial readout today, we continue to build momentum into the second half of 2025 with the BLA filing. Preparations for a potential commercial launch in 2026 and extending our leadership position as we continue to innovate in the B-cell modulation space. We couldn't be more thrilled with the primary endpoint reduction of 46% from baseline and 42% compared to placebo with a p-value of less than 0.0001 at week 36 and with a favorable safety profile versus placebo. As Rob shared with you, for all other prespecified endpoints, atacicept treatment also demonstrated results that are consistent with or better than those previously observed in the ORIGIN Phase IIb trial. This is the first Phase III trial to demonstrate significant proteinuria reduction with a dual BAFF/APRIL inhibitor in patients with IgAN. Based on these results, we are urgently moving ahead to continue our dialogue with the FDA on the regulatory pathway for atacicept and on our current preparations to submit a BLA to the FDA in the fourth quarter this year. We've come a long way on our journey. This data readout represents an enormous potential advance for patients and validates our scientific hypothesis and corporate strategy, as the physician who still practices medicine and as a CEO of a great biotech company, it is a personal and professional aspiration that Vera evolved the practice of kidney medicine with the hope that one day, patients may no longer face a future of dialysis or transplantation. I'd like to close with the recognition that the scientific community today finds itself in a challenging environment. In that context, it is important to keep top of mind that science, medicine and our industry are driving unambiguous clinical advancement. Thank you all for your time today. It was a pleasure to share this announcement with you, and we'll now open it up for questions.

[Operator Instructions]. Our first question today is from the line of Anupam Rama with JPMorgan.

Congrats on the data. Two quick ones from me. The first is, can you expand a little bit on the safety profile here you're seeing of atacicept and how to think about that in the context of the commercial landscape? And then two, I know you're probably not going to expand too much on eGFR. But remind me if I'm wrong here, but wasn't there a stat sig difference on eGFR at 36 weeks in the Phase IIb? And should we assume that the statement in the press release of other prespecified endpoints achieved similar or better than Phase IIb is inclusive of eGFR. Congrats again on the data.

Anupam, I just want to remind the audience that for Q&A, the available respondents are myself, Rob Brenner, our Chief Medical Officer; Sean Grant, our CFO; Matt Skelton, our EVP of Commercial, but also Jonathan Barratt, Mayer Professor of Renal Medicine at the University of Leicester, who has joined the call. So thank you very much. I'd like Rob to respond to Anupam's question. And Dr. Barratt, if you have additional comments, we would welcome them as well. Rob?

Thank you Marshall. Anupam, I think the safety profile that we're seeing thus far in the Phase III study is enormously encouraging. We have conceptualized atacicept as a chronic therapy for patients. And in a historical view, many have thought about drugs that have the potential to reduce inflammation in patients with kidney disease, such as corticosteroids to not be drugs that are amenable to chronic administration because of the toxicity profile and the burden of adverse experiences for patients. In contrast, it appears thus far that B-cell modulation using a dual BAFF/APRIL inhibitor, specifically atacicept at a dose of 150 milligrams has a different safety profile. One that is not associated with a risk of opportunistic infection and one that doesn't change the overall adverse event experience in terms of infectious risk. This really enables us to think about the realization of the hope that this could be a long-term chronic therapy. And let me see if Jon has anything he wants to add to that.

Yes. Thanks, Rob. I mean I think, the most startling thing for me. I mean, clearly, the proteinuria is fantastic, but it was really the safety profile of atacicept when we have -- where we look at what has been perceived as the potential risks of dual BAFF/APRIL blockade with atacicept at the dose we've chosen. But actually, there is very little, if any, safety signal here at all. And of course, that is incredibly important when we're thinking about using this drug as a chronic therapy. And I think that's really a standout result for me is the safety profile that you're seeing with regard to infections, with regard to serious events or rather the lack of them with continuous atacicept exposure, which is highly representative of what we saw in the Phase II. As indeed, is the efficacy in terms of proteinuria reduction, if not a little bit greater. Which gives us great confidence that when we think about the other things that we will be measuring in this study that we're likely to see similar, if not better outcomes in other measures that we might want to be looking at in the future.

And just to come back to the question about GFR, I just want to be very clear that we are aligned with the agency and won't be talking about the GFR results from the Phase III study at this time. That said, in Phase II, as you asked, at week 36, there was statistical significance in the GFR result at the week 36 time point and the 96-week result of minus 0.6, I think, has really led the field and demonstrates the most impressive GFR result that we've seen through Phase II in any of the programs and gives us great confidence for what we might see at the end of the Phase III study.

Our next question is from the line of Pete Stavropoulos with Cantor Fitzgerald.

Marshall, Rob, Sean and Matt. Congratulations on these data and achievements. It's great to see. I guess, for Dr. Barratt, from sort of efficacy safety benefit risk perspective, though you slightly touched on it on the previous question. Taking the safety data and the AE profile generated in the Phase III as well as the Phase IIb, how narrow or broad of a patient population would you feel comfortable prescribing atacicept to, assuming it's approved?

Yes. I mean I think I would feel very comfortable with prescribing this agent to people who don't necessarily fall within the ORIGIN 3 inclusion criteria. By that, I mean people with lower levels of GFR and lower levels of proteinuria. And I think that's the whole rationale for the PIONEER study is to start getting some idea of efficacy and safety in those groups that are outside the ORIGIN 3. And I think this really feeds into what the FDA has shown in their first 2 full approvals, which is that the first labels for the first 2 full approvals have been for any -- that the drug is indicated for anyone where the nephrologist feels the patient is at risk of progressive loss of kidney function. And we have defined within the KDIGO guideline what we believe that to be, which is anyone with more than 0.5 gram of proteinuria. And so based on the data we have today, I would feel very comfortable prescribing atacicept in patients that fit that definition. And we clearly need to generate data and that's what the PIONEER study will do. But I think with this risk-to-benefit profile and we know people -- if we look at the RaDaR data, 1 in 4 people with -- between 0.5 and 1 gram of proteinuria will be on dialysis after 10 years, which means taking a typical IgA patient in their 30s, they'll be on dialysis in their 40s, which is an absolute unmitigated disaster. So I have no qualms thinking that actually this is an appropriate approach for patients with proteinuria above 0.5 gram, even though they weren't eligible to get into ORIGIN 3.

All right. And 1 additional question for you. We have the Phase IIb placebo-controlled data, the Phase IIb atacicept switch data, placebo through [ passive ] switch and now this Phase III proteinuria data. Just provide your perspective on the totality of the evidence and how it sort of impacts your confidence level that we're going to see similar effects in eGFR at a 2-year time point for the Phase III?

Sorry, is that meant for me?

Yes.

Yes. Well, I mean, I think the consistency in what we've seen between the Phase II and the Phase III is absolutely fantastic. In fact, an even greater degree of proteinuria reduction in the Phase III. My expectation is if you look at all of the published data, the relationship between proteinuria reduction and GFR protection is clear. And therefore, in terms of what we may see, I think, there's no reason to suspect that if we are seeing similar or even greater magnitude of proteinuria reduction, that, in theory, in terms of what we've seen published should translate to the same or even better GFR protection than we saw in Phase II. So there's nothing that I've seen published anywhere to suggest that we wouldn't expect relationship between proteinuria and GFR protection to hold for this study in terms of the expectation for GFR protection. But of course, we need to see the data.

Okay. And congratulations once again on the data.

The next question is from the line of Ritu Baral with TD Cowen.

Congratulations on the data. I wanted to go back to actually -- I guess this question is for Rob. I wanted to go back to 1 of your early earlier slides on trial conduct and the percentage -- the kind of imbalance of placebo patients that have discontinued the study, 87% versus 93%. Rob, assuming that, that might grow and the placebo patients dropped out because of efficacy, what does this mean for trial equipoise and the conversations that you might have with FDA in the next few weeks about potential approval and the feasibility of that final data? And then I have a question for Dr. Barratt as a follow-up.

Thanks, Ritu. We do notice that there is this increased dropout rate in the placebo randomized participants, we're looking at it closely. We're looking at it even after the interim. And we're aligned with the agency that we want to do everything that we can to continue to drive to the full readout of the study. I think you raised an important question and one that we wrestle with ourselves, which is given the totality of the data that we've seen in Phase II and Phase III and all of the different kinds of results that we look at, at what point do we have the ability to have a constructive conversation about the long-term treatment of placebo in these individuals. And we have 215 people who have been randomized to receive placebo for another couple of years. How do we think about that? So we're looking forward to sharing the results with the FDA in a matter of weeks. And I think that will provide an opportunity for us to have a robust conversation about what the implications are. At this time, nothing changes. The trial continues as designed. It's a terrific protocol and 1 that we're executing with full urgency. But I do think you raise an interesting question.

And then my question for Dr. Barratt. Dr. Barratt, in response to a prior question, you had laid out sort of clinical guidelines about who would be -- about who the appropriate patient for a drug like atacicept would be upon approval. What percentage of the overall diagnosed IgAN population, do you believe that, that represents? And Matt, good to meet you, wanted to have your opinion on that breadth of appropriate population given the market research you've done so far?

Yes. So I think this -- so if you think about it, for someone to be diagnosed with IgA Nephropathy, needs a kidney biopsy. And what we're saying in KDIGO is we recommend anyone with more than 0.5 gram of proteinuria should have a kidney biopsy to diagnose this disease, which is the same level at which defines risk of progression. And if we think about the FDA approval, full approval, the current 2 full approvals are almost identical in their wording, which is any patient the nephrologist believes is at risk of progressive loss of kidney function. So in my practice, and I think, I speak fairly for U.S. practice, that will be every patient in a nephrology clinic with IgA Nephropathy. So of course, there may be patients who are almost ready for a kidney transplant, where it may not be appropriate, where their GFRs are so low that they're destined for dialysis, but that will be a very small number. So I think in terms of where we are with the current approvals, this will be 90% plus of prevalent IgA nephropathy patients set in clinic. I think the other thing which we mustn't forget is that 1 of the commonest diseases that has led to a kidney transplant is IgA Nephropathy. And we have no retreatment for a current disease. So it is not just people with IgA Nephropathy in their native kidneys. There is a huge pool of patients with recurrent disease in their transplant. And of course, PIONEER will be looking at that. But these are the next group where I think there will be a big growth in treatments to prevent progression over the current disease. So in my view, I think, on the basis of the full approval that the vast majority of patients set in kidney clinics, both in the U.S. and in the U.K. would be eligible for. And I would be very keen to think about using atacicept as a treatment for those patients.

From a commercial side, I like to answer a lot like Dr. Barratt. And -- but I think we need to be mindful of bringing the nephrology community along with us on this one. And so far, I think, the higher-risk patients are the ones that come to mind quickly for our customers. That's where we want to go first and expand from there at initial approval and launch. So that's where we would start.

Got it. Thanks, everyone. Thanks, Dr. Barratt, see you Friday at ERA.

The next question is from the line of Liisa Bayko with Evercore ISI.

Congratulations, and I wanted to ask Dr. Barratt, do you see these results as sort of meaningfully different from the prior Phase II results, which had a lower proteinuria response? And if they are different, maybe the team could comment. Is there anything -- what's driving this? Is it increased compliance? Or because we saw in the protocol analysis of Phase II actually a result that was more consistent with what you have now. Is there any impact of SGLT2 usage? What about increased proportion of Asian patients. Just thinking about some of these things, and then I have 1 additional question after that.

Yes, so I think what's fascinating is there are so many more patients on SGLT2 inhibitors in this study than ORIGIN 3. Yet and if we assume that they randomly assigned across the 2 groups, then we're seeing the same, if not better, proteinuria reduction, whether a patient is on an SGLT2 inhibitor or not. And I think that's consistent with the Phase II because we know 87% of patients weren't on an SGLT2 inhibitor in the Phase II. Yet we saw good proteinuria reduction and most importantly, GFR protection. So if we were to look back at the Phase II, my interpretation of that data is if you want to stabilize or get the rate of loss of kidney function in an IgA patient back to the physiological state, then you need to achieve the proteinuria reduction that you saw in the Phase II and the Phase III have delivered that plus a little bit more. In time, we will know what that translates to in terms of GFR protection. My view would be, I doubt it will be less than what we saw in the Phase II. But again, we need to see the data. But I think what this is showing is it wasn't an unusual event in the Phase II, the magnitude of proteinuria reduction. So of course, we need to see the full set of data. But for me, I think, the data that you've just seen is incredibly reassuring that this is a very relevant pathway to target in patients with IgA Nephropathy. Even when we assume patients are on the best supportive care they can get RAS inhibition, SGLT2 inhibition, great blood pressure control, all of which these patients have. You are getting a significant improvement in proteinuria. And if we believe the Phase II study, which I do, this is going to translate through to something really special in terms of GFR protection. The caveat being we need to see the data, but that's my interpretation of the data at the moment.

Yes. Liisa, I want to add another point about just the variability of UPCR. If you look back at our Phase IIb trial, you can look at intention to treat, which was in the mid-30s per protocol, which was in the low 40s, but then we had patients who are on placebo for 36 weeks who then switched to TACI 150 and they have a significantly greater reduction in proteinuria in the mid- to high 40s. So I think this is about the precision you get on a number when you increase the number of repetitions. So if you flip a coin 10x, you may or may not get 5 heads. But if you flip a coin 100 times, you're going to get somewhere pretty close to 50 heads. And so I think that's an important concept when you deal with the variability around an endpoint like UPCR, that's why we run Phase III trials at this size. Rob, did you have another comment?

Yes. I just wanted to address Liisa's question about have we identified anything that might explain the more impressive production of UPCR in Phase III versus what we saw in the first 3, 6 weeks in Phase II. One of the things that I've seen is I just think, overall, as a suite of investigator sites patients, research partners, et cetera. We just have more familiarity with how to run the trials as well as possible. And importantly, when we -- the results we shared here is the full intention to treat analysis, but when we look at patients who had protocol deviations, it was a small number. It was only about 7% of the enrolled population. So the impact was modest when we would look at it per protocol subset, which we'll do as we gear up for data submission in the fall. So it tells me that we're just doing a very good job of adhering to the protocol as designed. And perhaps that has been a contributor. But at the end of the day, we just have the results, and we can't say much more than what we see and what we're sharing.

The only other comment I'd make is that these results reflect at-home self-administration. And to our knowledge, this is the only pivotal Phase III trial in which at-home self-administration has been conducted. So our numbers reflect that type of administration. And I think that's a very strong position to be in.

Okay. That's great. And that just leads to my second question. So I'm curious, so you had about 24% injection site reactions. Can you qualify what proportion were mild versus moderate versus severe? And then also, do you expect this to change at all as you go from the prefilled syringe used for at-home injection in Phase III to the auto-injector, which will be the commercial form? Do you expect any change in that kind of injection site reaction.

Yes. So close to 90% of the injection site reactions were mild. The remainder were moderate. There were none that were severe. We were trying to capture all the terms that physicians would capture from patients if they had any discomfort or any short-term redness, it would get captured. None of these ISRs led to any change in dosing or discontinuation with the protocol. So I think we've got a lot of confidence in the overall safety profile. And I would say, historically, what we know from auto-injector administration versus PFS is that there's very little difference in terms of tolerability and injection site reactions. So I would expect that would be the case for TACI Receptor.

Our next question is from the line of Rami Katkhuda with LifeSci Capital.

Guys wanted to pass along my congratulations as well. I guess 2 quick questions from my end. First, I'm not sure if you've had the time to do the analysis, but were there any subgroups in ORIGIN 3 in which atacicept performed better or worse? And then secondly, on the ISR point, I guess, were those ISRs evident at a single time point? Or do they often recur with every injection?

Rami, it's Rob. First of all, on the ISRs, no, there was no clear pattern. A participant could have gone 20 weeks without anything and then had a little discomfort that would get captured. So there was no real trend. In terms of your question on gosh, I am blanking -- just repeat the first part?

Yes. It was basically if there's any subgroups that performed better or worse in ORIGIN 3?

So we have moved at light speed from last patient, last visit to database lock to full data readout to be able to enable this conversation today. So there's a lot of additional analyses that are on our plate. But I will say we've done a first pass view of kind of tornado plot on things that might have impacted the results. And across all the parameters, it looks like there's great consistency within the data for UPCR. So at the moment, I'm not seeing anything driving the results from 1 subpopulation or another.

The next question is from the line of Paul Choi with Goldman Sachs.

Congratulations on the data. Marshall, and team, I want to ask, as you think about these top line results, is there anything from a forward-looking perspective in terms of the either adjacent nephrology indications or opportunities or rheumatology and beyond that stands out to you as sort of logical next steps to put the pedal on or step on the gas here in terms of accelerating development based on the results you're seeing here from ORIGIN 3 and how you're thinking about potential acceleration of the pipeline development?

Thanks, Paul, for the question. An important 1 that we've begun to share publicly and highlighted on Slide 19, in which we begin with the strategy of the ORIGIN 3 population. That's what we're carrying forward for a biologic licensing application. And that high-risk population, we estimate around 90,000 patients prevalent in the United States alone. Beyond that, there are the moderate and low-risk patients that we're studying in PIONEER. We consider that so-called the low-hanging fruit. These are patients in whom we already have a relationship with those sites. This is a community that we're deeply committed to and engaged with. And that starts to expand the potential for atacicept to help additional patients. Beyond that, the next stage is really non IgAN autoimmune kidney disease. And that builds on the strength that Vera has built in the nephrology space and our leadership position therein. And that also is captured in PIONEER. So the next stage of expansion is deeper into the auto antibody-driven nephrology space. Beyond that, we haven't made public comment outside of nephrology, but we are highlighting the much broader potential. And I think today's results really highlight the potential as from a corporate perspective, we think the evolving risk benefit that will be reviewed by FDA really lends itself to a broader thinking about the applicability of atacicept as the native tachy receptor binding BAFF and APRIL at the dose that we studied it has really hit the goldilocks. This is, in our view, B-cell modulation as opposed to immune suppression. So B-cell modulation really requires you to do 2 things. It requires you to have the efficacy, not only measured in biomarkers, but does that translate into the organ saving metric. And in the case of IgAN, it's GFR. And does it have a safety and tolerability profile and patient convenience profile that lends itself to ongoing benefit versus risk. We think that today's results really expand that opportunity. Thanks for the question, Paul.

Our next question is from the line of Mohit Bansal with Wells Fargo.

Congratulations from my side as well. I have a couple of questions. So 1 is -- can you talk a little bit about the efforts to develop the monthly dosing of atacicept and so far in your conversation with the FDA, what do you think would the agency require here. And the second question I have is -- or maybe I'll pause, and I'll take the second question later.

It's Rob. Yes. So we shared back in October that this year, we're moving forward with a dose range finding study, looking at a number of different potential monthly doses. That program is up and underway. And as we gain clarity from the results from that study, it will help us understand what the preferred monthly dose will be. Once we know what that is, we'll be able to design an appropriate trial in concert with the regulators to enable future label claims. So the program is underway. And until I have some results, I really don't have much more to say about it at this time.

Got it. Understood. This is helpful. And second question is regarding myasthenia gravis. I mean this is the -- there seems to be some use -- you have some utility of a BAFF/APRIL pathway, I mean so do you see this as a potential opportunity in the longer term because you talked about hematology and some other indications, but neurology was not 1 of those, but some investors have asked about this. So would love to understand how you think about this for either atacicept or the follow-on molecules.

Yes. Mohit, I think it's a little early to share around further expansion beyond nephrology at this point, and we'll come back to the market with further expansion when we're ready.

Marshall, let me add one thing to that. I think some of the information that Matt shared and maybe I'd like to hear from Dr. Barratt on this, in a relatively short period of time, Vera's real intense engagement with the nephrology community, I think, has been recognized. And in many ways, I think we've catapulted the company forward into a leadership position in the space broadly not just within IgAN alone. And I think that creates opportunity. And I think that is a result of a number of things, 1 of which is the fact that we're moving broadly into other autoimmune podocytopathies. And I think the breadth and depth of our clinical investment and our kind of internal footprint really has put us in a leading position. And I think that gives us a reason to continue to focus on broadly the full portfolio of opportunities that exist for this drug, in this therapeutic space while not ignoring what the future opportunities are outside of nephrology. But Jon, I'd be interested in your thoughts just on where you see Vera today as 1 of the organizations that that's engaged with the community in nephrology.

Yes. Thanks, Rob. I mean I think it's goes without saying that there has been a lot of interest in atacicept in the nephrology community. And I think Vera has worked very hard to engage with glomerular disease experts across the spectrum of autoimmune mediated kidney diseases, glomerular diseases. Both in native kidneys but also in transplantation in adult nephrology but also in pediatric nephrology. And so I think the data that you've just seen today is only going to strengthen the interest in atacicept. And strengthen the interest in looking at using this drug in indications outside of IgA Nephropathy. So I think that all the groundwork has been laid. You now have a vital piece of the jigsaw, which is these outstanding Phase III results. And you can now build on that by putting forward the proposals and building on the Pioneer project, which is to expand the indication. So I think you have engaged with the global IgA or glomerular disease community, particularly in the U.S., obviously, but also in Europe and in Asia. And there have been a number of meetings that I've been part of, where there have been some absolutely fantastic discussions on the expanded indications for atacicept. And I think that's going to serve you incredibly well when you think about your prioritization of where you go next because I think you've heard from many different nephrologists from many parts of the world, they're all interested in using atacicept in their particular glomerular disease. And now you've got a great opportunity to look at where you prioritize next.

Our next question is from the line of Farzin Haque with Jefferies.

I'll add my congratulations as well. I wanted to ask on the competitive front a bit. So Otsuka will have their sibeprenlimab 36-week data at ERA this Friday. So given that your comments that UPCR can be variable, like how much absolute difference in the treatment effects between the atacicept and sibeprenlimab would be considered clinically meaningful? And also from a commercial uptick standpoint.

Yes. Thanks for the question. And I think that Dr. Barratt maybe could comment on how meaningful percent differences are in proteinuria outcomes in trials like these. Dr. Barratt?

Yes. Thanks, Marshall. Of course, we need to wait to see the data from sibeprenlimab. I think -- for me, I think that as has already been mentioned, there is an inherent variability in proteinuria. And when we take that into account, for me, I think if we were talking about a clinically significant difference in proteinuria. For me, I would be thinking within the 15% to 20% range of a difference between the 2. I think, at least simply because of the inherent variability. So we need to see the data. But the bottom line is we use proteinuria as a surrogate for future kidney function protection. So for me, the thing I am most interested in is GFR. And if we look back at the Phase II study, I always come back to this. If I want to get kidney function back to the physiological state that in the Phase II it took that degree of proteinuria that was seen in the Phase II to achieve that. So do we gain anything by more proteinuria reduction? How much -- if there's more proteinuria reduction than we saw in the Phase II, what does that mean? How can you do better than the GFR protection we saw in the Phase II? So I'm very cautious about over-interpreting modest differences in proteinuria. I think you need to look at the totality of the data and where we are in terms of long-term data we have with atacicept. And therefore, that gives us confidence about a dual BAFF/APRIL approach that the magnitude of proteinuria we're seeing in Phase II is likely to give us a similar effect that we saw in Phase II because we're talking about identical mechanism of action. And I think the other thing we just need to be aware of, which I think is going to become more fascinating is what effect this drug is having directly in the kidney tissue itself, which may not translate through into an absolute proteinuria reduction but may add benefit because it's targeting the cells within the kidney tissue itself. And what we know is that dual BAFF/APRIL approach and what that delivered in the Phase II. So I think there are many unknowns, I would be incredibly cautious about over-interpreting modest differences in proteinuria, be they above or below what we've heard about today. And I think we need to temper that and think about what data we have on GFR and how that is going to translate during the fullness of time. So please be cautious of overinterpretation would be my advice.

Got it. Makes sense. And then for Marshall and Rob, you have a pre-BLA meeting coming up in coming weeks. So what are the key points you want to get alignment on? And could there be a possibility of having perhaps the EGFR data included in the label as well as what could be the baseline UPCR level like 1.5 gram is the base expectations? Or could it be lower?

I just want to make a comment. I think we're not in a position to detail what we're planning to share with FDA at this time. So I appreciate the question, but we can't disclose that right now.

The next question is from the line of Vamil Divan with Guggenheim Securities.

Let me add my congrats also on the data here. So maybe just following up on the last question and the kind of comparison to what we might see from sibeprenlimab. This I guess will be for Dr. Barratt. Maybe you can just talk from a safety and tolerability perspective. So how you think about the different needle sizes, different doses and kind of how you think about maybe what we should be looking for at least a relative safety tolerability perspective as we wait for the data on Friday? And also maybe just any comments around patient preference for an auto-injector approach versus a prefilled syringe approach? And then my second question is on the commercial side. So Matt, nice to hear your comments today as you sort of build out your team here and think about the opportunity. I don't know if you have any sort of updated thoughts on how -- on what you think in terms of the sales force that will be needed to effectively commercialize atacicept, especially for the IM indication. And if there's any updated thoughts on sort of the ex U.S. commercial opportunity, and how to pursue that?

So I guess, I mean, at the moment, we have the safety data for atacicept that Rob presented, and I think this is incredibly reassuring about the safety of dual BAFF and APRIL blockade with atacicept at this 150-milligram dose. I think it is highly consistent with what we saw in the Phase II. I think the other thing, which is I think Marshall touched on, this was a home administrated therapy. So of course, we have to trust that the patient takes for the drug. And I think what you're seeing and what you saw in the Phase II is that this mode of administration is acceptable to patients, and patients will take the drug. And even though there were some injection site reactions, it didn't lead to massive treatment discontinuations, in fact, hardly any. And so there is a drug here that is safe in the way that we think about it being safe, particularly with regard to infections and the risk of opportunistic infections. But also from my interpretation of the data, this is a treatment modality that is acceptable to patients with IgA nephropathy. and the injection site reactions that we commonly see with subcutaneous therapies really were not an issue for the patients in terms of being sufficiently significant that they would want to stop the treatment. So how this will compare with other agents, we need to wait and see that data. But what you can see from the data presented today is that this dose of atacicept given in this particular way is as far as I can see, very safe and is a drug, therefore, that I would want to consider for my patients and I'd want to consider for my patients over the long term. And how we compare that against other products that are in development. We just need to wait and see the data so that we can look at them side by side.

There was a second question on commercial build-out. We are in the midst of doing that work right now to figure that out, size and structure of sales force, for instance. I will say, though, that we will have a competitive share of voice in the marketplace, too. So whenever that equals, we will be at that mark. We realize we're going into a competitive space, and that goes into the analysis.

Our final question is from the line of Ryan Deschner with Raymond James.

Congrats on the data. Two quick questions. Were Gd-IgA1 and hematuria consistent with the Phase IIb profile. And also, I think you touched on it earlier, but I may have missed it, just to clarify on the proteinuria primary endpoint. Was this the ITT or the protocol definition?

Yes, the proteinuria was measured in an ITT data set. All the results were. And as we included in the presentation, the results for the 3 specified end points were all similar or greater than what we saw in the Phase IIb.

Got it. And then maybe just real quickly, were there any cases of hypogammaglobulinemia?

No cases of kind of clinically identifiable evidence of hypogamma.

We've reached the end of the question-and-answer session. I'll turn the call over to Marshall Fordyce for closing remarks.

Thank you, everyone, for being on today's call. We're thrilled with this announcement. Appreciate all of the engagement and a special thanks to the Vera team for all of the work that it took to get us to this place and finally, a real commitment to the IgA nephropathy community. We look forward to serving with what we hope will be a transformative new medicine in the future. With that, I'd like to close the call. Thank you, everyone, for your time today.

This concludes today's conference. You may disconnect your lines at this time. Thank you for your participation.