Good day, everyone. Welcome to the Vera Therapeutics October 22nd investor webcast. All participants will be in listen-only mode until the question and answer session begins. Following the presentation, we will conduct a question and answer session. This call is being recorded. If you have any objections, please disconnect at this time. I would now like to turn the call over to Marshall Fordyce. Please go ahead.
Thank you, and welcome to Vera's investor webcast today. I am Dr. Marshall Fordyce, founder and CEO of Vera, and on behalf of the entire Vera team and all of our partners, I am thrilled to share with you the final efficacy results of the ORIGIN phase III trial of atacicept for the treatment of adults with IgA nephropathy. I am speaking to you from Denver, Colorado, where the annual meeting of the American Society of Nephrology, or ASN, is hosting Kidney Week. ASN is the largest association of nephrologists in the world. Our data were presented this morning by Dr. Jonathan Barratt, the Mayer Professor of Medicine at the University of Leicester and the head of the Renal Research Group.
This morning's open plenary session, with thousands in attendance in standing room only, were accompanied by pivotal trial results as published today in "The New England Journal of Medicine." I am deeply honored to have worked with Dr. Jonathan Barratt through the entirety of this research program, culminating in today's final efficacy results. Today, we will have Dr. Jonathan Barratt walk you through the presentation that was shared this morning, and then we will close and open up for Q&A from any investors and analysts on the call. Thank you so much. Dr. Barratt?
Thank you, Marshall. Let me take you through the presentation. Atacicept is a fusion protein that combines the extracellular domain of the TACI receptor with an Fc domain of IgG. The drug is designed to block the signaling of two critical cytokines, BAFF and APRIL, that drive B-cell and plasma cell proliferation, survival, and IgA class switch recombination. The rationale for using atacicept in IgA nephropathy is to address the fundamental driver of disease pathogenesis, which is dysregulated B-cell and plasma cell function that results in an excess of pathogenic IgA within the systemic circulation. This pathogenic IgA drives immune complex formation, and these immune complexes deposit within the glomerulus and mesangium where they trigger inflammation, scarring, and ultimately loss of kidney function.
The rationale for using atacicept in IgA nephropathy is to reduce and prevent formation of circulating immune complexes by suppressing pathogenic IgA synthesis, thereby protecting the glomeruli against immune complex deposition and subsequent injury. We know from KDIGO that the target for treatment success in IgA nephropathy is to return the rate of loss of kidney function to what we see in healthy individuals. That is a loss of GFR of less than 1 mL/ min/ year for the rest of the patient's life. Because we know if we do not achieve this, there remains a substantial lifetime risk of kidney failure in these young individuals. We know that supportive care treatment is simply not sufficient to achieve this.
When we look at the data for the ever-increasing number of CKD drugs that we have seen being approved over the last few years, we know that when we look at composite kidney endpoints, that they can achieve, at best, a relative reduction in risk of between 16%-55%, which means that if you have IgA nephropathy, the lifetime risk of kidney failure is barely impacted in their lifetime in terms of risk. The ORIGIN 3 trial was a global randomized placebo-controlled trial of atacicept, which was administered by the patient in their own home. It was a weekly injection of 1 mL, and given by subcutaneous injection, as I say, by the patient in their own home. It compared placebo against 150 mg of atacicept.
It recruited adult patients at risk of progression of their kidney disease, and in particular, high risk of progression because of persistent proteinuria, despite optimized, stable supportive care. When we designed the study initially, the plan was to look at the week 36 change in proteinuria, and indeed, that's what we did. Those data were presented last year and have been published. The initial plan was to look at the week 104 effect on GFR. But when we saw the results of our phase II-B study, which showed profound GFR protection, returning the rate of loss of kidney function to what we see in the healthy individual, we as a group felt uncomfortable exposing placebo-treated patients to standard of care only for two years. Because we had seen in multiple clinical trials that supportive care treatment alone was associated with significant loss of kidney function.
What we wanted to do was to protect the patients that had committed to being involved in our study. So we explored other alternatives, and in agreement with the FDA, we changed our GFR endpoint from a week 104 endpoint to a week 52 endpoint. As you can see on your screen, the secondary endpoints, which were tested in a pre-specified fixed sequence, were eGFR change from baseline at week 52 for all patients in the trial, annualized eGFR slope through to week 104 using all available data, and then changes in proteinuria Gd-IgA1 and hematuria at week 52, a long time to sustained 30% reduction in GFR decline through to week 104, and time to the first composite kidney disease progression endpoint. Of course, we were evaluating safety.
This is the first trial that has adopted this approach, but it's a very patient-centric approach in terms of protecting patients with IgA nephropathy from continued loss of kidney function. Of course, this is going to presage every other IgA nephropathy clinical trial to come because the FDA are now looking at 52-week endpoints for approval going forward. But this is a paradigm shift in how we approach clinical trials in IgA nephropathy. Here's the patient disposition, I really just want you to notice the three times greater discontinuation of treatment in the placebo arm. Predominantly, and almost exclusively due to the fact that patients were losing kidney function, the patients or the clinicians were clearly concerned about this, and the adverse events similarly reflected loss of kidney function.
Of course, when we think about this, if we were to have let the trial continue, that number would unlikely have increased and jeopardized the integrity of the study because we would have had so many non-protocolized events within the clinical trial. This, of course, is another advantage of a week 52 endpoint, is that we maintain trial integrity at a much greater degree than running the trial for longer, particularly in countries where there are a surfeit of available therapies. If we look at the baseline demographics, you can see here these were predominantly a young population, a good mix of races. They already had established kidney damage with a GFR of around 65 mL/ min.
They had substantial residual proteinuria, 2.2 g/ day, despite good blood pressure control and despite almost universal use of renin-angiotensin system inhibitors, and 60%-65% also on an SGLT2 inhibitor. So an incredibly high-risk patient population, and possibly one of the highest risk populations studied to date in a randomized controlled trial in IgA nephropathy. If we look at the headline data, what you can see here is that treatment with atacicept in this high-risk IgA nephropathy population led to a return to the rate of loss of kidney function that we see in healthy individuals, compared to the dramatic loss of kidney function we see on supportive care only. When we look at the placebo-adjusted difference, we see a placebo-adjusted difference of 5.6 mL/ min at week 52.
We see a placebo-adjusted difference of 11.1 mL/ min at week 104, and an annualized eGFR difference of 5 mL/ min/ year. Importantly, if you look at the slope for atacicept, you can see that on atacicept, patients are losing less than 1 mL/min/year , which is the KDIGO target and is what we would expect to see in a healthy individual. I just want you to take time to look at the placebo group, because this really, I think, justifies our approach. Patients were losing 10% of their kidney function per year. Actually, what we are actively doing now is converting those patients who were randomized to placebo onto active therapy to preserve their kidney function, because you can see that those patients who had been involved in the study out to two years lost 12 mL of GFR.
Remember, they only started with between 60- 65 mL, with an average age of 40 years of life. This is really, I think, justifies the approach we have taken in protecting patients within our trial, and very clearly has allowed us to show substantial benefit with atacicept at both week 52 and at week 104. In terms of our pre-specified sensitivity analyses, you can see that the GFR effect was obtained across all pre-specified subgroups, both the eGFR change at week 52 and the annualized eGFR slope at week 104. All patients in all subgroups benefited equally from atacicept. If we now look at the composite kidney endpoint, you can see here a 76% reduction through week 104 in the composite endpoint.
I think this is astounding when we think that most endpoints in these trials occur in the second year of a clinical trial, because of course, they're related to GFR decline, and those GFR decline events are much more likely to occur the longer you were in a clinical study. We were seeing a 76% risk reduction, having looked at the data at week 52, with very few patients progressing through to the end of the study. Yet we were still able to see such a significant risk reduction, bearing in mind the risk reductions that have been observed, I mentioned earlier, with the general supportive CKD care. Importantly, no patient treated with atacicept developed dialysis-dependent kidney failure, needed a kidney transplant, or died during the study.
In terms of proteinuria reduction, Gd-IgA1 reduction, and hematuria resolution, you can see those data on your screens. You can see that at week 52 and week 104, we had highly significant placebo-adjusted reductions in proteinuria of 51% at week 52 and 60% at week 104. We had highly significant and relevant reductions in the pathogenic form of IgA at week 52 and week 104 of 67% and 65%, and we saw resolution of hematuria in 97% of atacicept-treated patients at week 104. In terms of safety, most adverse events that we noted in the study were mild or moderate in severity and resolved without treatment interruption or discontinuation. Injection site reactions were mild or moderate.
The rate of serious adverse events was actually lower in the atacicept group compared to the placebo, and there were no clinically relevant cases of hypogammaglobulinemia, no opportunistic infections, and no deaths occurred in the atacicept group. Importantly, because of the nature of this particular drug and drugs of this class, we saw no clinically meaningful effect of anti-drug antibodies on PK/PD safety or efficacy. These data have been published today with a simultaneous publication in The New England Journal, and if you want to access the publication, please scan the QR code. In conclusion, ORIGIN 3 demonstrates that by targeting BAFF and APRIL with atacicept, you gain comprehensive disease modification in IgA nephropathy.
Most significantly, atacicept treatment in a high-risk population of IgA nephropathy patients results in a return to the physiological rate of eGFR loss we see in the general healthy population, compared to that substantial loss I showed you that occurred with patients on supportive care only. ORIGIN 3 met all pre-specified endpoints, including placebo-adjusted eGFR and composite disease progression benefits. Atacicept was well tolerated, with a favorable safety profile and generally comparable to placebo. Study participants are now transitioning to the open label atacicept for the remainder of the trial. Submission to the U.S. FDA to support potential full approval will be happening in 2027. Additional regional regulatory submissions are to follow. With that, I am going to hand over to Marshall. I just want to take the opportunity again to thank everyone who contributed to the study, but I will pass back to Marshall now.
Dr. Barratt, thank you so much for your collaboration with Vera Therapeutics and the design and conduct, and now final efficacy analysis of this landmark study with landmark efficacy results. I will give a little bit of an overview of what is next within Vera Therapeutics with these data. Then Dr. Barratt, perhaps we could ask you to make a few comments on the meaning of these data for the evolving landscape of treatment options for patients with IgAN. Then we will open up the line to questions with analysts. First, this marks a very important moment, as TRUTAKNA was approved on the basis of accelerated approval on July 7 of this year, and we have now been in commercial mode, launching in the United States.
That launch is going well, and we will be providing an update to investors in November, regarding the close of the third quarter on our first earnings call in November. We look forward to that update. Meanwhile, operationally, on the regulatory side, the Vera team has now started to put together a supplemental BLA, which will be submitted this quarter, and we would anticipate that would be reviewed by FDA, leading to what we anticipate being a full approval and updated label in the middle of 2027. Those are the next key data points for the clinical regulatory progress. Also importantly, this week at ASN, the Vera team has released additional data on atacicept, or TRUTAKNA now, in adolescents with IgA nephropathy, as well as the first data will be presented of TRUTAKNA in an adjacent autoantibody-driven kidney disease, membranous nephropathy, which should be presented on Saturday afternoon.
We look forward to sharing those results as well. With that, Dr. Barratt, I would love for you to put these data into some context for the evolving treatment landscape, and then we will open it up for questions. Dr. Barratt?
Yeah. Thank you. I think the results are absolutely outstanding. I think you saw the impact of being managed on supportive care only and the loss of kidney function, and it had always been an aspiration to return the rate of loss of kidney function to the physiological norm. In fact, we put that in as an aspirational target, never expecting to achieve it in, certainly in the next few years, into the KDIGO guideline, because that data tells us if you can achieve that, you will prevent kidney failure in the lifetime of many patients with IgA nephropathy. The data shows quite clearly that atacicept is capable, in an extremely high-risk population, of returning the rate of loss of kidney function to what we see in healthy individuals. Importantly, it does it in a way that is safe for patients and that patients tolerate.
Indeed, I have been meeting with people in the United States, looking at the auto-injector that is being used. It is incredibly patient-friendly. Patients have no issue taking the drug in the real world. I think this is just a fantastic addition to what we use to treat IgA nephropathy, and it would be the first thing I would think of in a patient I think about in terms of treating to prevent lifetime risk of kidney failure. The data are truly outstanding.
Thank you, Dr. Barratt. With that, I'll turn it over to the operator, and open up the line for questions.
We will now begin the question and answer session. If you would like to ask a question and have joined via the webinar, please use the raise hand icon, which can be found in the black bar at the bottom of the webinar application screen. When you hear your name called, you will be prompted to unmute your line and ask your question. We will take a moment to allow the queue to form. Our first question comes from Anupam Rama with JP Morgan. Your line is open. Please unmute and ask your question.
Hey, guys. Can you hear me?
Yes.
All right, cool. Thank you. Thanks for taking the question. And congrats on the plenary session, the data, and the publication as well this morning. So one for the company, and then one for Dr. Barratt. Can you speak to how you think about the composite data presented earlier today for atacicept and sibeprenlimab that we saw this morning at the plenary, and how we should put population differences, time point differences, and composite endpoint definition differences into context? And then for Dr. Barratt, I'd love to hear your perspective on that topic as well. Thanks so much, guys.
Thanks for the question, Anupam. I'd actually like to ask Dr. Barratt to answer that question really in both contexts. He's been an important collaborator and, as he highlighted, this is likely one of the patient populations that we were really concerned about throughout the program on those on standard of care. And you can see in the GFR decline in patients on placebo, what we faced when we asked patient volunteers to join the trial. And it was really the company in collaboration with Dr. Barratt and the steering committee for ORIGIN 3, to end the trial before all 428 patients made it to two years in the randomization phase and give everyone an opportunity to benefit from TRUTAKNA. That was the thinking as Dr. Barratt has highlighted. But Dr. Barratt, maybe you can highlight some of the differences across study trial comparisons.
Yeah. So I think whenever I'm looking at data, first of all, I want to understand how sick the patient population was that was included in the trial. So I look at the baseline proteinuria, I look at the baseline GFR. I look at the distribution of patients because we know patients from Asia progress faster. And I look at the background therapy and the use of background therapy. And you can see when you look at the data for ORIGIN 3, that this is probably the highest risk population recruited to a phase III clinical trial to date. And that's backed up by the fact that you look at the deterioration in the placebo arm, which is losing close to 6 mL/ min/ year.
When I look at that, I compare against other phase III trials. You can see that actually there were potentially lower risk populations included in other trials. That then helps me interpret the protection that is achieved by a particular therapy in terms of that delta in GFR slope that we see. Of course, in terms of the composite kidney endpoint, that is very much a function of how long you follow patients out. If you follow patients for longer, you are going to have more events. That's the whole fundamental of a trial that's endpoint-driven. It takes time to accumulate those endpoints. We made the strategic decision to protect the patients in our trial who were taking placebo because we knew that they were going to be losing substantial proportion of their kidney function.
Therefore, we made the decision to look at the data at week 52, accepting that we would have less follow-up on the entire cohort, and the consequence of that will be less event. That, I think, is the major driver for looking at the frequency and the relative risk reduction of these events when we look at the analyses. I think what's astounding is that even though we had relatively shorter follow-up in our patients compared to a completed two-year trial, you still saw such a highly significant reduction in the risk of endpoints events. I think those are the drivers for why there appears to be a disparity, but you're not comparing apples with apples here. I think we need to be absolutely clear in terms of how we interpret these data in the context of other clinical trials.
I think it's fair to say this population is sicker than many of the other phase III trials, and it's astounding that we saw, even with such a shorter follow-up compared to others, this protection against the composite kidney endpoint.
Thanks so much for taking our question, and congrats again.
Our next question comes from Ritu Baral with TD Cowen. Your line is open. Please unmute and ask your question.
Good afternoon, guys. Thanks for taking the question. Dr. Barratt, as you look across the data presented today at ASN and from previous conferences, since we have the first sort of comprehensive two-year data sets from an APRIL versus APRIL BAFF agent and accumulating evidence, is there any signal across the data sets that suggest differential biology in the sort of single target versus dual agents? Where could we look any
I think the only biomarkers we have to measure at the moment are proteinuria, hematuria, and GFR. They are probably not going to tell us the full story of how these drugs are impacting on biology. I think what is really pleasing for me is when we look at the two trials now, two international trials, looking at combined BAFF and APRIL inhibition that were presented this morning. Two trials targeting both BAFF and APRIL in two different populations run by two different study teams that validated almost to the decimal point the treatment effect of combining BAFF and APRIL inhibition, both in terms of treatment efficacy but also safety. That, I think, is incredibly powerful, that we now have two studies in entirely different populations showing that this is not a fluke event. This is a true finding from two completely separate clinical trials.
I think that is incredibly powerful. I think where we are potentially going to see differences are when we look mechanistically outside of the very blunt tools we use in terms of hematuria, proteinuria, and GFR. I think the other thing is this is still a relatively short timescale in terms of following patients, remembering that we are likely to need to treat patients for 30, 40 years. I think the data on BAFF inhibition, certainly in lupus nephritis, is that the role of BAFF and blocking BAFF, it becomes much more important the longer the patient is on treatment to provide continued immunological control. We are at the early stages of understanding these drugs. I think we're going to need longer-term data, and we are going to need to look from a biochemical perspective at biomarkers that we haven't had the opportunity to look at yet.
But I come back to the fact, what I think is most striking, is the fact we have had two completely independent studies targeting BAFF and APRIL that have delivered the same incredible efficacy with a safety and tolerability profile that is incredibly reassuring.
Our next question comes from Pete Stavropoulos with Cantor. Your line is open. Please unmute and ask your question.
Hi, Marshall, Rob, and Sean. Congrats on the presentation and also another publication. A question for Dr. Barratt. We had a look at TRUTAKNA's impact on subgroups for proteinuria last year at ASN, and today you provided data on subgroups for the final analyses. What are the key takeaways from those analyses, and what do they tell you about TRUTAKNA? Just sort of a follow-up on Anupam's question. I may have missed it. Maybe you said something. But was there any differences in what the composite endpoints measured for TRUTAKNA versus VOYXACT?
Well, the sensitivity analyses looking at subgroups showed a highly consistent treatment effect of atacicept across all pre-specified subgroups. I'm just looking at the other screen here. The pre-specified subgroups were age above and below 40, male versus female, region of recruitment, Americas, Europe, Australia versus Asia, white versus non-white, above or below 1.5 g/ gram of proteinuria, a GFR above or below 45 and above or below 60, and whether the patient was on SGLT2 or not. Irrespective of those subgroups, the treatment effect was identical. So nothing to suggest there are a group of patients who are going to do less well on atacicept.
In terms of the definition of the composite kidney endpoint for the ORIGIN 3 trial, it comprised a greater than or equal to 30% decline in eGFR sustained for greater than 30 days, an eGFR less than 15 sustained for greater than 30 days, chronic dialysis for greater than 30 days, kidney transplant or death. You will have to excuse me because I cannot remember, even though I am a member of the VISIONARY trial, I do not want to be misquoted for the composite kidney endpoint for that trial. It will be in The New England Journal publication.
Our next question comes from Paul Choi with Goldman Sachs. Your line is open. Please unmute and ask your question.
Hi. Thank you. Good afternoon, and congratulations on the data presentation at the plenary and The New England Journal article. I want to ask Dr. Barratt first. I guess now that we have seen the detailed data here, as well as longer-term follow-up for drugs in this class, APRIL and APRIL BAFF inhibitors, how are you and your colleagues, as well as the medical societies, thinking about shortening the watchful waiting period after using background therapies such as ACE, ARBs and SGLT2s and potentially shortening the time to getting on one of these new IgAN therapies? That is my first question.
Second, for the company, for Marshall and team, can you update us on how you are thinking about uptake of TRUTAKNA might inflect once you get the full data here on the label here next year and just how that is something that doctors or insurers are waiting for at this point? Thank you.
I think we are promoting no wait and see. The KDIGO guideline is explicitly clear we want simultaneous therapy targeting the disease modification and the CKD aspects of disease. Everything that has been talked about is if you have a patient at risk of progression, which is more than half a gram of proteinuria per day, that you need to simultaneously target the disease with a drug like TRUTAKNA. Or ideally like TRUTAKNA, you might say, and target the CKD aspects of disease. No waiting and no period of measuring response. It is immediate therapy with both disease modification and CKD treatment.
Great question, Paul, and I'll address this and maybe ask Matt Skelton, our Chief Commercial Officer, to make additional comments. We're on the ground here at ASN in Denver. We're speaking to nephrologists. It was the largest collection of nephrologists in that opening plenary session. There's no doubt a shift in how nephrologists are thinking about treating their patients with IgA nephropathy. This is the creation of a new medical category. What you're seeing are the stages of validation of that data. A year ago, we had a surrogate endpoint that's now in a label, showing a reduction in proteinuria and a very broad indication statement. That really enables physicians to prescribe TRUTAKNA to all patients they believe are at risk of disease progression with a biopsy-proven IgA diagnosis.
On the other hand, important for us to advance that validation to these final efficacy analyses, now presented, and because of the good work of this team, in a peer-reviewed publication simultaneously today. That's an immediate tool for the medical community. On the commercial side, of course, the sales force is restricted in their detailing and sales work to stick to the current label. That, of course, will be enabled and unlocked next year with the full approval label and, of course, the key data points that you've seen here. I would highlight the eGFR annual slope difference of 5.0, which is a phenomenal benefit on the GFR that we've shown in this population, and the improvement and avoidance of terrible outcomes like death, dialysis, and transplant, we hope to be included in that label. Matt, would you like to make any comment on the commercial inflection we might anticipate?
Sure. Sure. Thanks, Marshall. I would expect a nice inflection point when we can actively promote the comprehensive data set, and look forward to that full approval. I do think, Paul, also, having a plenary session today, a New England Journal publication, the news of these results is going to be into the community pretty fast. I hope that answers the question, Paul.
Our next question comes from Farzin Haque with Jefferies. Your line is open. Please unmute and ask your question.
Hi. Thank you for taking my question. One question for the management. Do you have the proteinuria responder analysis? Specifically, what proportion of the patients are getting below clinically relevant thresholds, like less than 1 g, 1.3. For Dr. Barratt, I am trying to recall something. If patients are achieving, on average, 50% reduction in UPCR, this still leaves the average patient with residual proteinuria of roughly, calculating, 0.8 g, depending on the baseline. How should we think about the clinical significance of that residual proteinuria if the eGFR clearly is stabilizing? Do you need to change the definition? Should we move away from trying to drive patients to much lower absolute [inaudible] levels?
Farzin, thanks for the question. I think I will just say that that analysis is not currently available, and we believe that the more important analyses are the impact on GFR and renal composite endpoints. Dr. Barratt maybe could speak about the relevance of residual proteinuria, in the context of standard care as designed in this trial, ACE or ARB, plus an SGLT2 inhibitor, which is about 60% in trial, plus TRUTAKNA versus placebo, with the results that we are presenting today, and the meaningfulness of a residual proteinuria.
Yeah, I think it's a great question, and it's a real hot topic. I think we are redefining our understanding of the significance of proteinuria with drugs like atacicept. We are seeing that actually, you can have residual proteinuria and maintain your GFR or return your GFR loss to physiological rates. That's not true with drugs of other classes. It's important also to understand that the proteinuria reduction you achieve with atacicept translates to, as Marshall said, a 5 mL/ min/ year protection against declining kidney function. An identical reduction in proteinuria with a predominantly hemodynamically acting drug delivers less than 1 mL/ min/ year protection against continued kidney function decline. This is making us completely rethink the interpretation of reductions in proteinuria and residual proteinuria. We need to think about these in the context of the drug that achieved that change.
The implications for proteinuria, if you are on a drug like atacicept, are completely different to the implications of a proteinuria reduction, residual proteinuria, if you're on a hemodynamically acting drug. So I would say watch this space, because we are doing a lot of work behind the scenes, looking at the implications of this disassociation between proteinuria and GFR protection that we're seeing with drugs like atacicept, which fundamentally target the base pathophysiology of IgA nephropathy.
Our next question comes from Ryan Deschner with Raymond James. Your line is open. Please unmute and ask your question.
Hi, thanks for the question, and congrats on the data. It looks like the UPCR, the proteinuria reduction over time approved out to the two-year endpoint, but also the overall longitudinal profile also appeared to improve over all time points in general with this more mature data set. I'm curious what your current thinking is on what the drivers behind this are. Also, what can you tell us about the general timing of the onset of the kidney composite endpoints in both the treatment and the placebo groups? Thanks.
We haven't shown the timings of the events, and that will be something that will be something for the future. In terms of the continued improvement in the parameters you mentioned, the understanding is that the atacicept is reducing pathogenic IgA, reducing immune complexes, and these are depositing less frequently in glomeruli. We have resolution of inflammation and tissue injury, and we have remodeling of those injured glomeruli, and that all takes time. All of those processes are reflected in the urine by blood and protein. What we're seeing is what I think is the natural history of resolution of glomerular injury with a truly disease-modifying therapy, that you are cutting out that incessant deposition of immune complexes into the glomeruli, giving the glomeruli time to recover. But it's not something that will happen overnight. It may take 12 months, it may take 24 months.
It may even take longer to get complete resolution of that injury that has, in all likelihood, been going on for the last 10, 20, 30 years. It doesn't surprise me at all that you're seeing continued improvements, because I think what that's reflecting is the remodeling and improvement in the glomeruli within the kidneys. Now they're not just being faced with immune complex deposition every day of every week of every year.
Our next question comes from Mohit Bansal with Wells Fargo. Your line is open. Please unmute and ask your question.
Great. Thank you very much for taking my question, and congrats on the data. Really, really impressive data. Just wanted to understand, Dr. Barratt, trying to tie your two comments here. One, the observation that despite 50% proteinuria reduction, you are observing a near flattening or near physiological level of kidney function decline. But then you also said that probably you need to use both disease modify and something that treats CKD part of the disease simultaneously. If the other drug is only, like ARBs and all, are only having a 1 mL improvement on kidney function, GFR, what is the need for adding two drugs simultaneously from the get-go for these patients? Thank you.
That's a great question, and you've kind of prefaced my next trial that I would love to run, which is make a diagnosis of IgA nephropathy, put the patient on atacicept, don't bother with RAS inhibitors, SGLT2 inhibitors, and come in after a year if there's still evidence of kidney function decline with CKD treatments. But that, at the moment, is a step too far for nephrologists, because we have lived for 30+ years with the mainstay of treatment of kidney disease being a RAS inhibitor. So getting them to not do that is a big task. But you're absolutely right in bringing that up, and I would love to do a trial where I give brand-new patients with a new kidney biopsy diagnosis on no treatment, atacicept from the get-go. And I only bring in the CKD treatments if I've got evidence they need them.
That will be something we will be thinking about in the future. But you're exactly right with your reasoning behind the question.
Dr. Barratt, maybe we could follow up on that and think about your history with the IgA nephropathy patient population. You've done some work on genetic susceptibility to IgAN. We at Vera provide, I think, a relatively conservative prevalence estimate of about 160,000 biopsy-proven cases. But your own data would suggest that it could be the true prevalence of biopsy-proven IgAN in the United States alone could be close to two times that. We find that patients are diagnosed late. They're misdiagnosed. We hear this anecdotally. We've now seen it in our own baseline characteristics in two global trials where patients are, on average, 40 years old. They've already lost close to 50% of their kidney function when they have the opportunity to come into the trial. Remember, time from diagnostic biopsy in our phase II and phase III trials was two and a half years.
These patients are diagnosed late. They've already lost a lot of kidney function. And as you say, it's a little too soon to say, "Let's try this," because these patients already have Stage 3 CKD. So I love the question. The question speaks to the future of what we could offer patients if they're identified earlier and brought to care earlier. Do you agree with that, and would you add anything to that perspective?
I absolutely think there is a gross underestimate of the prevalence of IgA nephropathy in the States We did a study of the UK Biobank, half a million U.K. people, all genotyped. We looked at the IgA nephropathy genetic risk score, and in those patients who'd ever had a positive dipstick for hematuria, and we found close to 30,000 of those, one in four is likely to have undiagnosed IgA nephropathy based on their genetic risk. I think there is a big push by academics and multiple sponsors to educate the community, general practitioners, urologists, obstetricians, ED doctors, that they need to be thinking about glomerular disease when they're seeing patients with what might seem, on the face of it, benign abnormalities in terms of blood and protein in the urine or a marginally changed creatinine.
That is a massive focus, and chatting informally to people who report kidney biopsies and in units across the United States, I'm hearing that they are making more diagnoses of IgA nephropathy. They're doing more kidney biopsies because the message is getting through that there is a mass of patients out there that we can now transform their lives with safe and effective treatment if we can get our hands on them. That is the push in all parts of the world to promote earlier diagnosis, early referral to nephrologists, earlier kidney biopsies, and earlier treatment. Watch this space, because I think you're going to see publications over the next couple of years from the United States, certainly, that we are going to be seeing far more kidney biopsies and therefore far more diagnoses of IgA nephropathy because of the messaging we've been sending out over the last five years.
Dr. Barratt, it was really what we saw together close to seven years ago, the opportunity to know a disease and at what causes it, the four-hit hypothesis and the pathophysiology. Not every disease is this well-characterized. To have an opportunity to address that upstream at the source, which is why we called this trial ORIGIN, and now show the data with this type of profile, the placebo-like safety profile, and normalization of GFR in a very high-risk population. Of course, some nephrologists who followed this closely are early adopters, but it's our responsibility on the industry side, in partnership with the practicing nephrologists in the U.S. and globally, to raise awareness that this is a B-cell-driven disease, that you can intervene upstream, and you can have the downstream renal resolution that we've now characterized in two separate global trials.
This is an incredible paradigm shift for patients and practitioners. Now it's time to communicate to the field.
The nephrologists in the room at the plenary today will have seen the data that have thought, "Wait a minute, I've got patients in my clinic that I wasn't going to make much of an effort with because I didn't have a treatment for them. I now have a treatment for them. I'm going to make the effort to either make the diagnosis or intervene, because I know now I've seen the data that we have truly transformative treatment for this disease.
Do you think that steroids are a popular treatment for this patient population, and how do you see that evolving in the near term and medium term?
Steroids are a toxic treatment that we wish had never been invented, and patients wish had never been invented. They have been a default for virtually all forms of glomerular disease because we didn't have anything else. When I'm talking to nephrologists around the United States, they all acknowledge they would love to not use steroids, but they never had an alternative. Now we're seeing the use of steroids plummet because we have viable, safe, effective, and truly transformative treatments. We know the efficacy of steroids are short-lived, and if you truly want to prevent kidney failure in the lifetime of patients, that necessitates massive exposure to steroids over a lifetime, which are incredibly toxic.
I am hearing continuously across the community here in the United States and globally, and even in parts of Asia, China, for instance, where steroids are virtually the first thought when you see a patient with IgA nephropathy, that they are stopping using steroids because they have a safer alternative. I think steroids will be in the history books of the treatment of IgA nephropathy and will no longer be used, and should not be used, in my view, to treat IgA nephropathy.
For those of us who have been in drug development for many decades recognize that this shift for patients with autoimmune disease, which is about one in 10 humans on the planet, this shift from steroid-based treatment to precise immune modulation has occurred in other autoimmune disease areas where steroids are now in the past, and we can be much more precise. The profile from a safety perspective that we have shown here, I think, is really going to accelerate that transition. Let us move to the next question.
Our next question comes from Arthur He with H.C. Wainwright. Your line is open. Please unmute and ask your question.
Hey, can you hear me?
Yes.
Hey, Marshall and team, and congrats on the presentation and the publication. I just had two quick questions, one for Marshall, the other for Dr. Barratt. Marshall, I know for these current data set, you only include about one-fourth of patients for the final readout. Could you tell us when we can expect the full set of the eGFR data? Also for the rest of the 75% roughly, is there any concentration of patient population-wise in terms of the urine protein-to-creatinine ratio baseline. For Dr. Barratt, given the Vera team taking advantage and getting aligned with the FDA to get an early readout for the eGFR, what is your perspective on using early GFR, like one year or 18 months, as a primary endpoint in the later pivotal trial for IgAN?
Or, you think right now, currently two-step regular pathway, like using the proteinuria and the surrogate endpoint for conditional approval, and then convert to full approval will stay? Thank you.
Great. Arthur, thanks so much for the question. I will refer you back to the ORIGIN 3 trial design slide, where we show that the final time point for the randomized phase is two years or 104 weeks. As we have shared, alignment with FDA to unblind the trial before all 428 patients got to two years was agreed upon. You have seen today, the final efficacy analysis of the GFR data, and that includes, when you look at the slope data, all of the patients throughout all of that time point. So we have shown really three ways to look at GFR. We have taken a snapshot at 52 weeks. We have taken a snapshot at 104 weeks, and then the slope takes all GFR from all patients at all time points. That is why that is, I think, the most robust reflection of the GFR effect.
So a placebo-adjusted annualized slope of 5.0. For a patient and a physician, that means you are saving 5 mL/ year with treatment versus placebo. All patients now in the ORIGIN 3 trial are offered open-label atacicept, so we will continue to collect data. You can see in the study design slide, we follow them through 156 weeks. We also have an additional trial, where we are following phase II and phase III patients in an open-label fashion over time. So we will continue to get follow-up in an open-label fashion. But the only reason to expose these patients at high risk of disease progression is to assess what the treatment effect is. That is why that portion is now closed.
I think you asked a question about future clinical trial design. We had a meeting with the FDA and other regulators in Washington earlier in the year, and there will be a publication coming about the preferred clinical trial design going forwards. I think Vera have trailblazed this approach in a week 52 endpoint, shown it is completely feasible to have a week 52 GFR endpoint if you have a drug that is truly transformative. I think the direction of travel will be that we will be running, for future drugs in this area, a 52-week trial looking at GFR, plus or minus proteinuria, as the marker of efficacy. But for that to be viable, you need a drug with an efficacy effect similar to what we have seen with atacicept. That is the direction of travel.
Our next question comes from Dina Ramadane with Bank of America. Your line is open. Please unmute and ask your question.
Hey, guys. Thanks so much for taking our question. Congrats on the publication and the plenary presentation. I just had a couple questions for Dr. Barratt, kind of regarding the emerging detailed safety data for this class. First question is, how comfortable does two years of exposure make you with lifelong therapy? What remaining safety risk, if any, would you most want longer follow-up to answer? Do you feel comfortable that the class is in the clear in terms of any potential infection liability? My second question is that, atacicept had anti-drug antibodies in almost half of the treated patients, but there was no clinical meaningful safety effect that was identified. Is that something that you would essentially disregard clinically, or does it remain relevant for long-term monitoring? Thank you.
Okay. So, in terms of safety, we have the safety data that is available. Remember, atacicept has been around for a long time, and there have been detailed safety analyses, in multiple indications, showing a very favorable safety profile. Of course, we want more data, and of course, we want longer follow-up, and that will come, as Marshall said. There are numerous ways that patients will get a continued exposure to atacicept, both from the phase II-B study and from ORIGIN 3, and data will be collected and presented looking at continued efficacy, but also safety of prolonged exposure to atacicept. So all of those aspects regarding safety are in hand, and there is a commitment for long-term follow-up and for reporting of both the efficacy and safety data in patients exposed to atacicept over prolonged periods of time. In terms of the anti-drug antibodies, this is a protein.
It's an engineered protein that is injected into a human being, and it's not unreasonable to think that anti-drug antibodies may develop. The critical aspect is not whether they develop. It's whether they interfere with the drug being able to do what it's there for, which is block BAFF and APRIL, or whether these anti-drug antibodies deliver a safety concern. This has been looked at very thoroughly, and I presented in the safety deck that these anti-drug antibodies have been monitored very closely in all patients. They have been identified, but they have not impacted on the safety of patients or on the efficacy, PK, or PD. That is important. The presence of an antibody, you shouldn't equate with it being clinically relevant at all.
It's whether that antibody impacts on the ability of the drug, either in terms of losing efficacy or worsening safety, and we have no evidence for anti-drug antibodies doing that from the ORIGIN 3 trial. Of course, these are going to be monitored over the longer term just exactly as safety. At the moment, these are of no clinical relevance whatsoever in terms of how we interpret these data or how we would use this drug in clinical practice.
Our final question comes from Rami Katkhuda with LifeSci Capital. Your line is open. Please unmute and ask your question.
Hey, guys. I wanted to pass along my congrats as well, and thanks for taking our questions. I guess going off a previous question on subgroups, the difference in eGFR benefit with atacicept was largest between patients with baseline UPCR above and below 1.5 g/ gram. I guess, could this suggest that patients treated earlier in the disease could drive a greater benefit from treatment, or do you think the difference is more likely attributable to just variability in baseline disease severity or progression? Secondly, telitacicept demonstrated meaningful efficacy after transitioning to every other week dosing in the second portion of its study. Does that provide additional confidence in the potential for less frequent dosing with atacicept as well?
I will deal with the proteinuria, and I will hand over to Marshall for the dosing frequency. We have to be really cautious when we interpret the forest plot. These studies were not designed to look at a differential effect. They are designed to see whether there is a pattern of change, and the confidence intervals overlap, and therefore we cannot say that the drug is more or less efficacious. The bottom line is, it is efficacious in all patient subgroups. I would not over-interpret the pre-specified sensitivity analyses. They show benefit. There is nothing here that suggests that one group differentially responds to atacicept. I would just be cautious about over-interpreting point estimates and look at the confidence intervals and the fact that they overlap in these analyses. I will hand over now to Marshall to talk about the dosing frequency.
Yeah, Rami, great question. I think it is tempting when you have multiple therapies in development with similar or even putatively same mechanisms of action, whether it is, as you mentioned, telitacicept, an alternate way for BAFF and APRIL inhibition. These are distinct molecules. They are made in different ways, both drug substance and in formulation or drug product. It is very tenuous to actually make an inference between another program versus our own. While they may have the putative same mechanism, these are different molecules. They are formulated differently. They are delivered differently. If you recall, telitacicept was seen as a 240 mg initially weekly, and then every other week dose, but that is delivered as two separate 2 mL injections of 80 mg/ mL, is our understanding. Very different type of delivery, so I would be very cautious in inferring.
Just as a reminder, we are running the dose range frequency study, looking at atacicept in three separate monthly doses. We are going to start to look at that data this quarter, and we will be sharing that when appropriate with the street later on. Thanks so much for the questions today. With that, we are going to close. We really appreciate everyone's interest. This is truly a frame shift in how we get to offer a new tool for physicians treating patients who, prior to today, have had a much dimmer view of what their future could be, and now we are looking at an option that could free patients from a life of dialysis or transplant. Fantastic day. Appreciate everyone. We will close the call today now. Thanks.
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