Greetings. Welcome to the ORIGIN phase III topline results data call. At this time, all participants will be in listen-only mode. A question-and-answer session will follow the formal presentation. If anyone today should require operator assistance, please press star zero from your telephone keypad. 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 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 one 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 IgA N community. Vera is poised for a potential commercial launch of atacicept in 2026 and to pursue development and 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 the 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 in 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 two 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 do not 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 five years from this diagnosis is similar to cancer.
Our program to develop atacicept for patients with IgA N 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 IgA N 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 topline results of our pivotal phase III trial called ORIGIN phase III. I would like to introduce my colleague, Rob Brenner, our Chief Medical Officer, who will take you through the data. Rob.
Thank you, Marshall. 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 a 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 the disease process. B cells are fueled largely by two cytokines, BAFF and APRIL, and B cells produce in this disease both an autoantigen, a galactose-deficient form of IgA1, and autoantibodies that recognize this GD-IgA1 construct.
Together, these two 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 four 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. 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 II-B results that we shared last year. These were long-term 96-week results in patients who were receiving atacicept dosed at 150 milligrams in a one mL prefilled syringe at home once a week. First, we showed a two-thirds reduction in the concentration of the autoantigen GD-IgA1. On the upper right, we see that 75% of participants who had blood in their 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%. 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 one mL per minute per year. The achievement of that slope of minus 0.6 means that a population of patients with biopsy-proven kidney disease where historically they lose six to eight 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 clinical experiment where patients were randomized one-to-one 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 one 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-to-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 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 had been randomized to atacicept, and 97 had been randomized to placebo. For the 106 participants who were on atacicept, during the course of the 36 weeks, there were seven 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 phase III population on the left, and I've included the ORIGIN II-B population on the right for comparison. Overall, there are enormous similarities between the IIB and the phase III program. On average, patients are 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 eGFR at baseline for participants in the phase III and in the phase III 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 two and a half years elapsed 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 elapsed from the phase II enrollment to the phase III. Slide 15, we have the results that Marshall alluded to earlier.
In the ORIGIN phase III interim analysis, primary endpoint readout at week 36, there was a deep 46% reduction in UPCR in those individuals randomized to atacicept. 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 pre-specified endpoints achieve similar or better results compared to those observed in the ORIGIN phase II-B study. 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 to 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. 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 three 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.
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 III experience thus far has not 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, few were moderate, none were severe, none led to discontinuation of dosing, and were self-limited. Importantly, beyond injection site reactions, we looked for evidence of hypersensitivity. There we see that there was an increase in hypersensitivity reactions in patients who received placebo versus those who received atacicept. Finally, there 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. Origin phase III continues as designed, with two-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 had spent nine years at Cigen, where I was responsible for scaling the commercial organization to go from a one-product company to four products. I helped lead three successful launches. Before Cigen, I was at Amgen for 16 years in various marketing and sales leadership roles. I spent five 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 IgA N.
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 IgA N how we view the market, and important insights we are gathering from nephrologists. Let's go to the next slide. Here is the opportunity.
There's a large prevalent pool of patients, of which 90,000 are immediately addressable. This is the ORIGIN phase III population. We are confident we will compete for a meaningful share in this population. 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 needs exist. Next slide. 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. 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 the space is focused and the most unmet need.
This subset of nephs 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're encouraged by these results. Awareness of atacicept surpassed APRIL-only mechanisms, and nephs 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. Next slide. 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 II-B 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 one 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. Let's take a look at the existing market. Innovation in the IgAN space is allowing for premium pricing. Cymbalta 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 II-B, 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, the 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 will hand it back to Marshall.
Thank you, Matt. We are committed to the IgA N patients and the IgA N 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 IgA nephropathy, 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 in other autoimmune kidney disease and more broadly in other autoimmune diseases.
We believe that atacicept has pipeline and 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 IgA N patients who did not meet our phase III criteria and specifically moderate and low-risk patients, patients with low eGFR, 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 could not 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 pre-specified endpoints, atacicept treatment also demonstrated results that are consistent with or better than those previously observed in the ORIGIN phase II-B 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 of 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 a physician who still practices medicine and as a CEO of a great biotech company, it is a personal and professional aspiration that Vera evolves 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.
Thank you. We'll now be conducting a question-and-answer session. If you'd like to ask a question at this time, please press star one from your telephone keypad, and a confirmation tone will indicate your line is in the question queue. You may press star two if you'd like to withdraw your question from the queue. For participants that are using speaker equipment, it may be necessary to pick up your handset before pressing the star keys. One moment, please, while we pull for questions. Thank you. Our first question today is from the line of Anupam Rama with JP Morgan.
Please proceed with your question.
Hey, guys. Thanks so much for taking the question and 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 II-B? And should we assume that the statement in the press release of other pre-specified endpoints achieved similar or better than phase II-B is inclusive of eGFR? Thanks so much, guys, and congrats again on the data.
Thank you, 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, CFO, Matt Skelton, our EVP of Commercial, but also Jonathan Barratt, Mayor Professor of Renal Medicine at the University of Leicester, who has joined the call. 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.
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 does not 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. Let me see if John has anything he wants to add to that.
Yeah, 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 look at what has been perceived as the potential risks of dual-BAFF/APRIL blockade with atacicept at the dose we've chosen. Actually, there is very little, if any, safety signal here at all. Of course, that is incredibly important when we're thinking about using this drug as a chronic therapy.
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.
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 -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.
Congrats again, guys.
Our next question is from the line of Pete Stavropoulos with Cantor Fitzgerald. Please proceed with your question.
Hi, Marshall, Rob, Sean, and Matt. Congratulations on these data and achievements. It's great to see. I guess for Dr.
Barratt, from sort of an efficacy, safety, benefit, risk perspective, though you slightly touched on it on the previous question, taking the safety data and the AE profiles generated in this phase III, as well as the phase II-B, how narrow or broad of a patient population would you feel comfortable prescribing atacicept to, assuming it's approved?
Yeah. I mean, I think I would feel very comfortable with prescribing this agent to people who don't necessarily fall within the ORIGIN phase III inclusion criteria. By that, I mean people with lower levels of eGFR and lower levels of proteinuria. 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 phase III.
I think this really feeds into what the FDA has shown in their first two full approvals, which is that the first labels for the first two 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. We have defined within the KDIGO guideline what we believe that to be, which is anyone with more than half a gram of proteinuria. Based on the data we have today, I would feel very comfortable prescribing atacicept in patients that fit that definition. We clearly need to generate data, and that's what the PIONEER study will do.
I think with this risk-to-benefit profile, and we know people, if we look at the radar data, one in four people with between 0.5 and one 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. I have no qualms thinking that actually this is an appropriate approach for patients with proteinuria above half a gram, even though they weren't eligible to get into ORIGIN phase III.
All right. Thank you for that. One additional question for you. We have the phase II-B placebo-controlled data, the phase II-B atacicept switch data, placebo-to-atacicept 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 the two-year time point for the phase III.
Sorry, is that meant for me?
Yes.
Yeah. 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.
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. There's nothing that I've seen published anywhere to suggest that we wouldn't expect that relationship between proteinuria and GFR protection to hold for this study in terms of the expectation for GFR protection. Of course, we need to see the data.
Okay. Thank you very much, and congratulations once again on the data.
The next question is from the line of Ritu Barral with TD Cowen. Please proceed with your questions.
Good morning, guys. Congratulations on the data. I wanted to go back to, actually, I guess this question is for Rob.
I wanted to go back to one of your 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? 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. 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 raise 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 in 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? We have 215 people who have been randomized to receive placebo for another couple of years. How do we think about that? We are looking forward to sharing the results with the FDA in a matter of weeks. 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 one that we're executing with full urgency.
I do think you raised an interesting question.
Thanks. 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? 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.
Yeah. I think this was, so if you think about it, for someone to be diagnosed with IgA nephropathy, they need a kidney biopsy.
What we're saying in KDIGO is we recommend anyone with more than half a gram of proteinuria should have a kidney biopsy to diagnose this disease, which is the same level at which defines risk of progression. If we think about the FDA approval, full approval, the current two full approvals are almost identical in their wording, which is any patient the nephrologist believes is at risk of progressive loss of kidney function. 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. 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.
I think in terms of where we are with the current approvals, this will be 90%+ of prevalent IgA nephropathy patients sat in clinic. I think the other thing which we mustn't forget is that one of the commonest diseases that has led to a kidney transplant is IgA nephropathy. We have no retreatments for recurrent disease. 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. Of course, PIONEER will be looking at that. These are the next group where I think there will be a big growth in treatments to prevent progression of recurrent disease.
In my view, I think on the basis of the full approval from the FDA, that the vast majority of patients sat 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 that answer a lot, Dr. Barratt. I think we need to be mindful of bringing the nephrology community along with this on this one. 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. 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 Lisa Bacow with Evercore ISI. Please proceed with your questions.
Hi. Congratulations, and thanks for taking the questions. 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? If they are different, maybe the team could comment. Is there anything what's driving this? Is it increased compliance? Because we saw in the per 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. I have one additional question after that. Thanks.
Hi, Lisa. Yeah.
I think what's fascinating is there are so many more patients on SGLT2 inhibitors in this study than ORIGIN phase III. Yeah. If we assume that they randomly assigned across the two groups, then we're seeing the same, if not better, proteinuria reduction, whether a patient is on an SGLT2 inhibitor or not. 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. 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.
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. I think what this is showing is it was not an unusual event in the phase II, the magnitude of proteinuria reduction. Of course, we need to see the full set of data. For me, I think the data that you have 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.
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.
Yeah. Lisa, I want to add another point about just the variability of UPCR. If you look back at our phase II-B trial, you can look at intention to treat, which was in the mid-30s, per protocol, which was in the low 40s. We had patients who were on placebo for 36 weeks who then switched to atacicept 150, and they had a significantly greater reduction in proteinuria in the mid to high 40s. I think this is about the precision you get on a number when you increase the number of repetitions.
If you flip a coin 10 times, you may or may not get five heads. If you flip a coin 100 times, you're going to get somewhere pretty close to 50 heads. 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?
Yeah. I just wanted to address Lisa's question about have we identified anything that might explain the more impressive reduction in UPCR in phase III versus what we saw in the first 36 weeks in phase II. One of the things that I've seen is I just think overall, as a suite of investigators, sites, patients, research partners, etc., we just have more familiarity with how to run the trials as well as possible.
Importantly, the results we shared here is the full intention to treat analysis. When we look at patients who had protocol deviations, it was a small number. It was only about 7% of the enrolled population. The impact was modest when we would look at a per protocol subset, which we'll do as we gear up for data submission in the fall. It tells me that we're just doing a very good job of adhering to the protocol as designed. Perhaps that has been a contributor. 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.
Yeah. The only other comment I'd make is that these results reflect at-home self-administration. To our knowledge, this is the only pivotal phase III trial in which at-home self-administration has been conducted.
Our numbers reflect that type of administration. I think that's a very strong position to be in.
Okay. That's great. Thank you. That just leads to my second question. I'm curious. You had about 24% injection site reactions. Can you qualify what proportion were mild versus moderate versus severe? 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? Thank you.
Yeah. 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. I think we've got a lot of confidence in the overall safety profile. 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. I would expect that would be the case for atacicept.
Okay. Great. Thank you so much. Again, congratulations.
Our next question is from the line of Rami Katkhuda with LifeSci Capital. Please proceed with your questions.
Hey, guys. Wanted to pass along my congratulations as well. I guess two quick questions from my end.
First, I'm not sure if you've had the time to do the analyses, but were there any subgroups in ORIGIN Phase III in which atacicept performed better or worse? Secondly, on the ISR point, I guess, were those ISRs evident at a single time point, or did they often recur with every injection?
Hey, 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. There was no real trend. In terms of your question on, oh, gosh, I'm blanking. Just repeat the first part.
Yeah. It was basically if there's any subgroups that performed better or worse in ORIGIN Phase III.
Yeah. Yeah.
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. There is a lot of additional analyses that are on our plate. I will say we've done a first-pass view of kind of tornado plots on things that might have impacted the results. Across all the parameters, it looks like there is great consistency within the data for UPCR. At the moment, I'm not seeing anything that's driving the results from one subpopulation or another.
Makes sense. Congrats again, guys.
The next question is from the line of Paul Choi with Goldman Sachs. Please proceed with your questions.
Hi. Thank you. Good morning. 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 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 phase III and just how you're thinking about potential acceleration of the pipeline development? Thank you.
Thanks, Paul, for the question. An important one that we've begun to share publicly and highlighted on slide 19, in which we begin with the strategy of the ORIGIN phase III population. That's what we're carrying forward for a Biologics License Application. And that high-risk population, we estimate around 90,000 patients prevalent in the U.S. 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. That starts to expand the potential for atacicept to help additional patients. Beyond that, the next stage is really non-IgA N autoimmune kidney disease. That builds on the strength that Vera has built in the nephrology space and our leadership position therein. That also is captured in PIONEER. The next stage of expansion is deeper into the autoantibody-driven nephrology space. Beyond that, we haven't made public comment outside of nephrology, but we are highlighting the much broader potential.
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 TACI 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. B-cell modulation really requires you to do two things. It requires you to have the efficacy not only measured in biomarkers, but does that translate into the organ-saving metric? In the case of IgA N, it is eGFR. Does it have a safety and tolerability profile and patient communities 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. Please proceed with your questions.
Great. Thank you very much for taking my questions. And congratulations from my side as well. I have a couple of questions. One is, can you talk a little bit about the efforts to develop the monthly dosing of atacicept? So far, in your conversation with the FDA, what do you think would the agency require here? The second question I have is, or maybe I'll pause and I'll take the second question later.
That's Rob.
Yeah. 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.
As we gain clarity from the results from that study, it'll 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. The program's underway. 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. The second question is regarding myasthenia gravis. I mean, this is where there seems to be some use, you have some utility of a BAFF, APRIL pathway. I mean, do you see this as a potential opportunity in the longer term? Because you talked about rheumatology and some other indications, but neurology was not one of those. Some investors have asked about this.
We'd love to understand how you think about this for either atacicept or the follow-on molecules.
Yeah. Mohit, I think it's a little early to share around further expansion beyond nephrology at this point. We'll come back to the market with further expansion when we're ready.
Got it. Thank you very much.
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. In many ways, I think we've catapulted the company forward into a leadership position in the space broadly, not just within IgA N alone. I think that creates opportunity.
I think that is a result of a number of things, one of which is the fact that we're moving broadly into other autoimmune podocytopathies. I think the breadth and depth of our clinical investment and our kind of internal footprint really has put us in a leading position. 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. John, I'd be interested in your thoughts just on where you see Vera today as one of the organizations that's engaged with the community in nephrology.
Yeah. Thanks, Rob. I mean, I think it goes without saying that there has been a lot of interest in atacicept in the nephrology community.
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. 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 appropriately. 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. You can now build on that by putting forward the proposals and building on the PIONEER project, which is to expand the indication.
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. 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. I think that's going to serve you incredibly well when you think about your prioritization of where you go next. 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. Now you've got a great opportunity to look at where you prioritize next.
Excellent. Thanks.
Our next question is from the line of Faizeen Haq with Jefferies. Please proceed with your questions.
Thank you for taking my question. I'll add my congratulations as well.
I wanted to ask on the competitive front a bit. Otsuka will have their sibeprenlimab 36-week data at ERA this Friday. Given your comments that UPCR can be variable, how much absolute difference in the treatment effects between the atacicept and the sibeprenlimab would be considered clinically meaningful? Also from a commercial optic standpoint.
Yeah. Thanks for the question. I think that Dr. Barratt maybe could comment on how meaningful % differences are in proteinuria outcomes in trials like these. Dr. Barratt?
Yeah. Thanks, Marshall. Of course, we need to wait to see the data from sibeprenlimab. I think for me, as has already been mentioned, there is an inherent variability in proteinuria.
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 15-20% range of a difference between the two, I think at least, simply because of the inherent variability. We need to see the data. The bottom line is we use proteinuria as a surrogate for future kidney function protection. For me, the thing I am most interested in is GFR. 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, then in the phase II, it took that degree of proteinuria that was seen in the phase II to achieve that. Do we gain anything by more proteinuria reduction?
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? I am 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. That gives us confidence about a dual- BAFF/APRIL approach that the magnitude of proteinuria we're seeing in phase III is likely to give us a similar effect than we saw in phase II because we're talking about an identical mechanism of action.
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. What we know is that dual- BAFF/APRIL approach and what that delivered in the phase II. I think there are many unknowns. I would be incredibly cautious about over-interpreting modest differences in proteinuria. It'd be above or below what we've heard about today. I think we need to temper that and think about what data we have on eGFR and how that is going to translate during the fullness of time. Please be cautious of over-interpretation, would be my advice.
Got it. Makes sense.
For Marshall and Rob, it's like you have a pre-BLA meeting coming up in coming weeks. What are the key points you want to get alignment on? 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. I appreciate the question, but we can't disclose that right now.
Thank you so much.
The next question is from the line of Vamil Divan with Guggenheim Securities. Please proceed with your questions.
Great. Thanks for taking the question. Let me add my congrats also on the data here.
Maybe just following up on the last question and the kind of comparison to what we might see from sibeprenlimab, this I guess would be for Dr. Barratt. Maybe you can just talk from a safety tolerability perspective. How you think about, obviously, different needle sizes, different doses, and kind of how you think about maybe what we should be looking for, at least from a relative safety tolerability perspective as we wait for the data on Friday. Also maybe just any comments around patient preference for an autoinjector approach versus a prefilled syringe approach. My second question is more on the commercial side. Matt, nice to hear your comments today.
Just 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 what you think in terms of the sales force that will be needed to effectively commercialize atacicept, especially for the IgA nephropathy indication. If there's any updated thoughts on sort of the ex-U.S. commercial opportunity and how to pursue that. Thank you.
Hi. I guess, I mean, at the moment, we have the safety data for atacicept that Rob presented. I think this is incredibly reassuring about the safety of dual- BAFF/ APRIL blockade with atacicept at this 150 milligram dose. I think it is highly consistent with what we saw in the phase II. The other thing, which I think Marshall touched on, this was a home-administration therapy.
Of course, we have to trust that the patient takes the drug. I think what you're seeing and what you saw in the phase II is that this mode of administration is acceptable to patients. Patients will take the drug. Even though there were some injection site reactions, it did not lead to massive treatment discontinuations, in fact, hardly any. 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. Also, from my interpretation of the data, this is a treatment modality that is acceptable to patients with IgA nephropathy. 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.
How this will compare with other agents, we need to wait and see that data. 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. I would want to consider for my patients over the long term. 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 buildout. We are in the midst of doing that work right now to figure that out, size and structure of Salesforce, for instance. I will say, though, that we will have a competitive share of voice in the marketplace.
Whenever that equals, we will be at that mark. We realize we're going into a competitive space, and that goes into the analysis.
Okay. All right. Thank you.
Thank you. Our final question is from the line of Ryan Dessner with Joria, Raymond James. Please proceed with your questions.
Hi. Thanks for the question and congrats on the data. Two quick questions. Were GD-IgA1 and hematuria consistent with the phase II-B profile? And also, I think you touched on it earlier, but I may have just to clarify on the proteinuria primary endpoint, was this the ITT or the protocol definition? Thanks.
Yeah. The proteinuria was measured in an ITT data set. All the results were. And as we included in the presentation, the results for the prespecified endpoints were all similar or greater than what we saw in the phase II-B.
Got it.
And then maybe just real quickly, were there any cases of hypogammaglobulinemia? Thank you. No cases of kind of clinically identifiable evidence of hypogamma.
Got it. Thank you.
Thank you. 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.