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

Good afternoon, and welcome to the Vera Therapeutics KOL Event. [Operator Instructions] As a reminder, this call is being recorded and a replay will be made available on the Vera Therapeutics website following the conclusion of the event. I'd now like to turn the call over to Dr. Marshall Fordyce, Founder and Chief Executive Officer at Vera Therapeutics. Please go ahead, Marshall.

Welcome. I'm Marshall Fordyce, Founder and CEO of Vera Therapeutics, where we're working to develop innovative new medicines and improve the standard of care for patients with immunologic disease. Today's webinar is focused on our lead program in a specific autoimmune disease of the kidney called IgA Nephropathy or IgAN. This is a disease of young people that can cause kidney failure at a young age and no disease-modifying treatment exists yet. Before we get started, next slide, please. I want to remind you that this teleconference contains forward-looking statements under the safe harbor Act. And as such, we present this disclaimer regarding at-risk statements. Next slide. This is an incredible moment for patients with IgA Nephropathy, and we have an exciting program for you today. There is an emerging evidence base in current clinical trials that targeting B-cells, the source of the bad-acting autoantibodies in IgAN could be disease-modifying and sustainably and substantially improve kidney function over time for these young patients. Vera's lead molecule in IgAN currently being evaluated in a Phase IIb randomized controlled trial is a biologic fusion protein called atacicept, which targets the B-cell lineage through dual inhibition of APRIL and BLyS, a mechanism that may potentially make it the most potent of the B-cell approaches. Today, first, we'll begin with a patient story to highlight the impact of this disease on young people and their families. Next, Dr. Jonathan Barratt, a physician researcher and leader in the field will provide an overview of IgAN in its causes and the rationale for targeting B-cells through the APRIL-BLyS mechanism. Then Vera's Chief Medical Officer, Dr. Celia Lin, will describe our ongoing Phase IIb randomized controlled trial. And finally, I'll make some summary comments and we'll open the floor to questions for all 3 of us. In this business, we aim to serve patients and improve their lives. So let's begin by listening to [ Liz ]. Please cue the video. [Presentation]

Dialysis and kidney transplant before the age of 30 years old, disease rips our autonomy away. It's a privilege to try and change the trajectory for people like Liz. So welcome back from Thanksgiving. Let's get to work. It's my great pleasure to introduce our guest speaker today, next slide, Dr. Jonathan Barratt, who leads the Renal Research Group at the University of Leicester in the United Kingdom and is a globally recognized leader in the IgAN Nephropathy field. Dr. Barratt has emerged as one of the leading voices during this revolution in therapies for IgAN patients. Dr. Barratt, thank you for your time and for your perspective today.

Thanks very much, Marshall. So it's a great pleasure to talk to the listeners about IgAN Nephropathy. And I think Liz's story is very typical of the kind of patients I see. And the thing I want people to really in focus on is this is a disease that affects young people at a critical time in their lives when they're planning ideally their family, their career, they want to build a home and they want to get on and have a real vision about where their life is taking them. And unfortunately, people like me give them a diagnosis of IgAN Nephropathy and everything changes. And we have no way at the moment of treating this disease effectively and it really is a great burden on these patients to be able to deal with the uncertainty of what's going to happen to them in the future. It is the commonest pattern of primary glomerular disease in the world. It affects young adults. And we need to remember that the commonly quoted figure is up to 50% of patients progress to end-stage kidney disease. That's within 20 years of diagnosis. If we think about Liz, that would have only meant she was in her 40s. We need to start thinking and reframing the argument of a lifetime risk of kidney failure. And the data that we have would suggest that the vast majority of patients with IgAN Nephropathy have a significant lifetime risk of kidney failure. And these patients have no treatment at the moment, effective and safe treatment. If you look at this graph here, you can see the estimated prevalence of IgAN Nephropathy in the U.S., in the EU, in Japan. And you can see that a large proportion of those patients are -- have disease where we could intervene and we could prevent them from developing end-stage kidney disease. And that is what we're focusing on today in terms of an exciting new treatment that potentially could alter the lives of these patients. I've mentioned a lot of this already. We need to just remind ourselves that this is a disease that increases an incidence and prevalence as we move from the West to the East. And it's particularly common in East and Southeast Asians, it's less common in people of African descent. As you heard from Liz, this disease can be asymptomatic and present at the -- with end-stage kidney disease, which is what happened to her. But most of the patients I see are actually picked up because they have blood or protein in their urine, they've got high blood pressure. They've had a blood test showing their kidney function isn't quite right. So we do pick up people at a stage where we can intervene and we can treat them and potentially with new therapies, we could prevent them from ever developing kidney failure. So we do need to think about how we identify these patients in the community. And the challenge really is we don't have biomarkers and we require a kidney biopsy for diagnosis, but hopefully, with the evolution of new therapies and our new understanding of the pathogenesis, we will have new biomarkers available to us to help guide diagnosis and how we manage these patients. If we think about how we approach the treatment of IgAN Nephropathy, the bedrock of how we approach treatment is with supportive care. And this is not particularly nuanced. This is controlling blood pressure, maximizing renin-angiotensin system blockade. Something that we do for every patient with proteinuric kidney disease, irrespective of whether they have IgAN Nephropathy. These are not disease-specific treatments. The treatment that has been relied on in the past is systemic glucocorticoids, but we know these come with a significant risk of adverse effects in patients. And if you talk to any patient with IgAN Nephropathy who's had steroids, they will tell you often the side effects from the steroids were worse than actually living with the disease. So we need to do much better in the treatments that we have that are not associated with those significant adverse effects. We now have a treatment of topi or budesonide, which is the first FDA-approved treatment. And we have early data on proteinuria changes there, and this is an exciting new development. But when we think about how we approach treatment, what we know is that supportive care is by far the most effective treatment. But in the vast majority of patients, it's simply not enough. They have persistent levels of proteinuria and they are a persistent risk of progressive kidney disease. And we know that treatment with systemic glucocorticoids comes with significant toxicity. And actually, in all likelihood only has a short-term effect on protecting the kidney because once those steroids are finished, the proteinuria comes back and the patient then returns to that risk of progressive disease. If we look at the treatment paradigm that we came up with, with the KDIGO Working Group, you can see here that we identify patients at high risk of progression who have persistent proteinuria despite optimized care. And as Celia will touch on, these are exactly the patients we're recruiting into the ORIGIN study, those patients who have had optimized supportive care, but have been identified as being an increased risk of progression because we know those are the patients that need additional therapy. And the fundamental treatment decision we need to make in these people is to offer them inclusion in the clinical trial because we know we don't have safe and effective treatments. You can see here that we do consider glucocorticoids a potential treatment based on low-quality evidence. But actually, we need to be very cautious about which patients we offer glucocorticoids to because of the associated toxicity and therefore, there has to be a very close eye taken and a thorough assessment for a toxicity restratification, looking at prevalent infections, obesity, metabolic syndrome, conditions like diabetes, psychiatric conditions because we know systemic glucocorticoids can exacerbate all of those pre-prevalent comorbidities. And again, I just want to focus on this, the focus of how we approach IgA Nephropathy. And the reason, as Marshall said, we are so excited about where we are at the moment is because we are getting patients into clinical trials like the ORIGIN study. We are assessing new therapies and we are seeing some really exciting results. And so this has to be the focus of how we approach IgA Nephropathy now and going forward. And then actually, we should be not thinking about the core systemic glucocorticoids as being a first-line therapy in this disease in my view. These are treatments that could be offered to patients if no trials are available and only if the patients are felt to be able to tolerate them and do not have those adverse factors that might influence increased risk of toxicity. So we do have a significant unmet medical need in IgA Nephropathy. We know that the best supportive care we can give is not enough in the majority of patients. We know systemic glucocorticoids are poorly tolerated and patients tell us they do not want to have repeated courses of these because they help so poorly when they were taking them. And we know that we are really not being able to address those primary risk factors for progression, i.e., that heavy proteinuria that we see that is associated with significant declines in GFR and end-stage kidney disease in the long run. But actually, there is light at the end of the tunnel because we are getting a much better understanding of the pathogenesis of this disease, which is allowing us to identify treatments that potentially could truly be disease-modifying in IgA Nephropathy. And so if we think about an overarching view of what happens in IgA Nephropathy, I want to head backwards. We know in IgA Nephropathy, the kidney get -- the glomerular, the filters of the kidneys, get filled up with these IgA immune complexes, which essentially promote inflammation and scarring within the filters of the kidneys. And that's why we see globulin protein in the urine, and that's what drives kidney scarring. Why do these immune complexes form in the circulation? Well, they form because there's -- in the circulation, there is an increased presence of this abnormal form of IgA called galactose deficient or Gd-IgA1. And this abnormal form of IgA leads to the generation of anti- Gd-IgA1 antibodies. And those antibodies amplify the development of these immune complexes. Where do we think this Gd-IgA1 comes from? Well, all the evidence would suggest that this Gd-IgA1 comes from the mucosal immune system. So that immune system that aligns our GI tract, our [ urinary ] tract and our respiratory tract. If we think about where we would like to target in a perfect world to try and stop immune complex deposition within the kidneys, you can clearly see here marked in exposed areas where if we had a drug, it would be incredibly useful for us. If we could stop the activation of B-cells generating this Gd-IgA1, if we could stop the production of these autoantibodies, we would ultimately be able to prevent immune complex formation and that subsequent deposition in the glomeruli, which drives inflammation and scarring. And that, I think, is one of the things that we really need to focus on, have we got treatments that are able to do this because those would be really beneficial in my view for patients with IgA Nephropathy. And so if we think first about B-cells, what do we know about B-cells that mean that we could potentially target them? Well, we know that there are 2 factors that are essential for B-cell maturation and survival, and these are BLyS and APRIL, and they work through a series of cell surface receptors, and they're actually very important in IgA class which is a combination to the generation of IgA secreting plasma cells. And this is exactly the system that is targeted by atacicept. So atacicept contains the extracellular domain of the TACI receptor, which allows the binding of both BLyS and APRIL and this is humanized and therefore, the function essentially is to clear the circulation of BLyS and APRIL and therefore, prevent their ability to activate B-cells to mature, to differentiate and to survive. And it does this both within the circulation, but also within tissue beds. And therefore, it is capable of inhibiting the production of pathogenic IgA. Why do we think BLyS and APRIL are important? Well, there's lots of data in the literature describing associations between the levels of BLyS and APRIL and the risk of progressive kidney disease in IgA Nephropathy patients, in the severity of kidney damage that we see on a kidney biopsy and actually in terms of APRIL into the level of the Gd-IgA1, the abnormal form of IgA. And we believe that by inhibiting BLyS and APRIL, we are likely to have a highly potent action on those pathogenic B-cells that are producing the abnormal form of IgA, but also in those autoantibody-producing cells that produce that anti-Gd-IgA1 IGD. And if we're able to do this in a potent way with a drug like atacicept, we have the potential to move to low-volume subcutaneous dosing. And there are a couple of advantages why we think hitting both APRIL and BLyS is important because we know that if you only hit one of these, particularly if you only hit APRIL, there's a potential that the BLyS may respond in a compensatory manner and therefore improve B-cell survival in the absence of APRIL and we see this actually in the context of rituximab. We give rituximab, a CD20 therapy. We know there is a rebound rise in BLyS, which has been hypothesized to be the reason why we get less response with rituximab and why we get frequent relapses because this compensatory rise in BLyS is actually negating the effect of the CD20 approach. And there is a theoretical reason why this could also occur if we just target APRIL. Of course, if we target both BLyS and APRIL, we do want to make sure that we're not causing undue toxicity effects, particularly around the production of normal healthy immunoglobulins that are there to help us fight infections. And in fact, there is a rather substantial safety database, which you can see here in front of you summarized and which has been published, which describes the safety profile of atacicept in over 1,000 patients. And importantly here, particularly with respect to IgA Nephropathy, these are in a range of patients with a range of autoimmune diseases where atacicept was given on top of baseline immunosuppression. And that's important when we think about toxicity because in IgA Nephropathy, atacicept is only being given as a monotherapy. There isn't prednisone, there isn't mycophenolates around where there would have been in the setting of lupus and other immunosuppressants in the setting of rheumatoid and others. So you can see here in this table that the frequency of infections and serious infections, which are the things we think about if we're targeting immune system, we're really no different between placebo and atacicept when you look at the totality of the data. And this again, I say is in the setting of patients where a large number will have also been on other immunosuppressants as well, exacerbating that potential risk of infectious complications. The other thing just to remind ourselves of is the experience of treatment with various drugs that target both BLyS and APRIL signaling. And you can see here the data for belimumab, Benlysta which you can see there's over 7,200 patients being treated. But you can see next, we have atacicept with around 1,500 individuals having been exposed to atacicept with that safety data. And then you see those drugs that are targeting APRIL only that have been also evaluated in IgA Nephropathy, where there's far less clinical experience and long-term clinical experience with these agents. So in terms of what we know about the impact of atacicept, well, we know from the data that I presented over 12 months, 18 months ago now that atacicept was the first to show a significant reduction in Gd-IgA1, so that key immunoglobulin that drives immune complex formation by over 60%. That was shown from data from the JANUS study, which was a Phase IIa trial in IgA Nephropathy looking at 2 doses of atacicept and placebo. Again, it was looking at high-risk patients, so patients with persistent proteinuria despite maximal RAS blockade. And what we saw here was a significant reduction in Gd-IgA1 that was sustainable out to 72 weeks. And you can see here the dose dependence of that response. We know that the level of Gd-IgA1 in cohort studies is associated with the risk of long-term kidney survival. As you can see here from this Kaplan-Meier plot and you can see that those patients with the lowest quartile of Gd-IgA1 levels at time of diagnosis, the Green Group 1 did the best and at the best kidney function survival compared to those in Group 4, who had the highest quartile of Gd-IgA1 levels at time of diagnosis. This has been repeated in other cohort studies. So a clear association between the level of Gd-IgA1 and the future risk of kidney failure. What we did when we looked at the general state was we looked at the quartiles of the Gd-IgA1 levels we saw. And what you can see here is there is a consistent reduction in Gd-IgA1 consistent with patients moving through the quartiles of Gd-IgA1 levels relevant both not only to the in-study, but also to a reference population from my research group in Leicester. And what this is telling us is that it's highly likely that this reduction in Gd-IgA1 generated by atacicept is likely to lead to better kidney function survival in the long-term when we look back at that cohort data. We've also looked, as you might expect, at the levels of anti-Gd-IgA1 antibodies immune complex formation in those patients in the JANUS study that were treated with atacicept. And indeed, I have -- or my group has presented that data this year at the ERA-EDTA meeting in Paris and just last week or the week before in Orlando at the ASN. And what we found with treatment with atacicept was that atacicept resulted in significant reductions in the anti-Gd-IgA1 autoantibodies and simultaneously in a reduction in the level of circulating IgA and IgG immune complexes. So what we have is a drug that is capable of impacting on multiple key steps in the pathogenesis of IgA immune complexes and fundamentally in the key steps that drive immune complex deposition within the kidneys in IgA Nephropathy, exactly what we would hope for, for a drug that we believe could truly modify this disease and prevent kidney inflammation and scarring. Early data we have from the JANUS study supports that in terms of changes in proteinuria at week 24. And you can see here that treatment with atacicept resulted in a reduction in proteinuria. And you can see here, although it's short-time frame at the GFR levels, you can see that actually the placebo group, there is a loss of GFR over the course of the study. And actually, the rate of GFR in this study was consistent with what we've seen in the NefIgArd study and in the testing study. Whereas for the atacicept group, being small numbers, there does appear to be a stabilization of GFR without that consistent loss seen with placebo. But of course, we're going to be looking at that in the ORIGIN study, and which Celia will talk about after myself. And so in summary, it's been a whistle-stop tour, but I think I hope I've convinced you there is a significant unmet need for disease-modifying therapies in IgA Nephropathy. The BLyS and APRIL have important roles in normal healthy biology, but also in IgA Nephropathy in driving the production of that pathogenic form of IgA and the generation of immune -- pathogenic immune complexes, that the data we have from the Phase IIa JANUS study linked what we understand about pathogenesis in terms of Gd-IgA1, immune complexes, anti-Gd-IgA1 with the clinical data that we really want to see, which is reductions in proteinuria and stabilization of GFR. The data across the whole treatment landscape of where atacicept has been studied shows that atacicept has a well-characterized safety profile. And that what we hope to see when we look at the ORIGIN study is the longer-term effects on proteinuria and GFR that we've started to see in the Phase IIa JANUS study and which look really promising. So on that note, I'm going to hand over to Celia, who's going to talk us through the Phase IIb ORIGIN study.

Great. Thank you, Jon. So I'm going to speak about the ongoing ORIGIN Phase IIb trial. Next slide. So this is a randomized, placebo-controlled, double-blinded study in IgA Nephropathy patients, powered for proteinuria. Patients are adults with high risk of disease progression with a double-blind treatment period consisting of placebo, the atacicept 25-milligram and 75-milligram dose that you've seen in the JANUS study and what is newly being tested, the 150-milligram dose. Now the double-blind treatment is a 36-week period that's followed by an open-label extension of 60 weeks, atacicept 150-milligrams followed by a safety follow-up. And the primary endpoint is a UPCR 24-hour at 24 weeks and the key secondary is at 36 weeks. We'll have eGFR data throughout up to 96 weeks. The next slide speaks to the ORIGIN population as well as endpoints. Inclusion criteria consists of those that are greater than or equal to 18 years old, IgA Nephropathy on renal biopsy, the UPCR 24 hour is greater than 0.75 milligrams, milligrams or grams per 24 hours, eGFR greater than APRIL 230, stable and optimized RAS inhibition for at least 12 weeks and a blood pressure of less than 150 or equal to 150 over 90. Now we spoke about the endpoints already with the primary efficacy being that 24-hour UPCR at week 24. Remember, it's 80% powered to detect a 28% difference between the combined 75 milligrams and 150 milligrams of atacicept versus placebo. Key secondary is that UPCR 24-hours at 36 weeks. Exploratory endpoints include the eGFR 36 weeks versus placebo and up to 96 weeks, as you've seen and of course, the change in Gd-IgA1 with safety being certainly important as well. The primary analysis for data readout is expected first quarter of 2023. With that, I'll hand it over to Marshall for a summary as well as Q&A.

Thank you, Celia, and thank you, Jon. Next slide, please. So with the data in hand today and the clinical trial readout that we expect early next quarter, we believe atacicept has a developing profile for a best in disease therapeutic for patients with IgA Nephropathy. And this is really based on some of the information highlighted here on the slide where we're pointing out a variety of new treatments currently in development for patients with IgAN and focusing on those that are targeting B-cells and modulating B-cell activity for the reasons that Dr. Barratt has reviewed with us today. So really, the importance is focused on mechanism of action, can the new therapeutic target the source of the disease upstream? And that in this disease is clearly B-cells. There are 2 programs in the APRIL-BLyS inhibition category. One is ours and atacicept that you've been hearing, another is telitacicept from the company RemeGen. Another target would be take inhibit APRIL only and leave BLyS unopposed in a mechanism also targeting B-cells, and one program is Chinook's BION-1301 and another is Otsuka's sibeprenlimab. So these are the 4 programs that are really in late-stage development targeting B-cells as a potential way to disease-modify. So mechanism is really the most important relative to others that are in development. Some are highlighted on the right, and there are several others, including endothelin receptor antagonists or complement activation inhibitors, which are really working downstream relative to the pathophysiology or the disease process that Dr. Barratt reviewed. The dual inhibition of APRIL and BLyS may confer important potency advantages, which is evidenced in the current dosing profile that we're highlighting in the first row of this table, where atacicept is really the only B-cell agent at less than 200 milligrams and delivered as a single milliliter making subcutaneous injection a simple and patient-convenient method. So we are exploring 75 or 150 milligrams subcutaneously, 1 ml once a week. That's a key piece. We hope to contribute to the body of evidence looking at proteinuria impact. So the proteinuria reduction from each of these agents will continue to clarify as we read out the ORIGIN program. So for example, for atacicept, a small subset of patients, so 5 subjects from the JANUS study that Dr. Barratt reviewed at 24 weeks showed a 28% reduction in proteinuria. We'll look to reproduce that number in the current program. And then we will also look to show for the first time the proteinuria reduction with 150 milligrams of atacicept, which has not been demonstrated yet to date. When you compare to telitacicept on a dose-per-dose basis, it appears that to get a 25% reduction, it would be 160 milligrams of telitacicept at 24 weeks. And at their higher dose, 240 milligrams, they showed almost a 50% reduction at 24 weeks. This is data from a randomized controlled trial conducted in sites in China only. So the important step in validating that data is to ensure a multinational set of patients. So we await further data to see how that -- how those point estimates look in a larger and more nationally diverse study population. As you look to the APRIL-only mechanisms from BION-1301, there are data showing a proteinuria reduction, but it is in an open-label phase only without a control. So we don't know what the placebo-adjusted proteinuria reduction is for the BION-1301 program over time. And we await more information to see what that delta versus placebo looks like. For sibeprenlimab, the APRIL-only inhibitor from Otsuka, we just saw at the Orlando Kidney Week presentation, a 43% reduction in proteinuria, active versus baseline, and this is combining all 3 of the doses that they explored at 36 weeks. So there is evidence in a multinational randomized controlled trial that a significant proteinuria reduction can occur and that would be at an IV dose of 2, 4, 8 milligrams per kilogram in the Phase II data that were shared at that time. So that's the current landscape of what we know about the B-cell modulating therapies that are currently in development, and we look forward to sharing the results of our randomized controlled trial early next quarter where we'll share for the first time, 150 milligrams subcu once a week. If you look to the biomarker of Gd-IgA1 or galactose-deficient IgA1, the reduction versus baseline, you can see atacicept had a 60% reduction with the 75 milligram arm as a result seen at 24 weeks and durable over time. We've not yet seen what the 150-milligram dose would show. We have not seen the data specifically from telitacicept or from sibeprenlimab. We have seen once again versus baseline in an uncontrolled trial, about a 65% reduction at their 600 milligram subcu -- sorry, 450 milligrams IV subcu every other week. So in the range of similarity between these 2 programs, but again, different experimental study design. When you look at safety, I think Dr. Barratt highlighted the significant experience in the dual APRIL-BLyS mechanism with atacicept. And certainly, BLyS alone is well understood because of the currently commercialized product, Benlysta or belimumab, an anti-BLyS agents. And we plan to see further data -- we plan to watch further data come out for the APRIL-only programs, so that we have a better sense of what it means to selectively inhibit APRIL and leave BLyS [ vas ] unopposed. And we'll see that most meaningfully in a randomized controlled trial, we hope, in the future. So next slide, please. So this year, as Dr. Barratt highlighted, we presented evidence at academic conferences demonstrating that atacicept targets the source of IgAN, showing it reduces galactose-deficient IgA1, it reduces autoantibodies and it reduces immune complexes, providing the strong biologic rationale for this mechanism. And now with the ORIGIN study that Dr. Lin highlighted with a fully enrolled trial, we do anticipate being able to publicly share the week 24 primary endpoint results early next quarter and to begin to project initiating our Phase III study in 2023. Next slide. So atacicept's mechanism of lowering levels of disease-causing autoantibodies may be important for patients with IgA Nephropathy with lupus nephritis and other autoimmune conditions in which we look to continue to expand our development pipeline. And with that, I'd like to open up the lines for questions to Dr. Barratt, Dr. Lin or myself and we'll be able to respond. So I'll hand it back to you, Tara, the operator, to help us address questions.

[Operator Instructions] So our first question comes from Liisa Bayko from Evercore.

How many questions can I ask?

Let's be fair and do one at a time.

Okay. So I've got to ask the most interesting one here. Okay. So I guess the most frequent investor question I have is what's the bar for data? I think, Marshall, you and I have talked about that a number of times, it's going to be a 24-week look at data, but I'd like to pose this question to Dr. Barratt to just get his take. We've seen data emerging. I think Marshall just did a nice job of reviewing some of the emerging data from the other B-cell modulators. I may call them that. And maybe you could -- based on that, where do you see the bar for data coming from the ORIGIN study?

So I think -- so I hate to predict, so I like to see data. I think the overwhelming evidence, in my view, looking across all the programs targeting this access is that this is something that's really going to go places in IgA Nephropathy in terms of targeting the APRIL-BLyS pathway. And I'm here and we're talking about Vera, but essentially, the other companies, everyone is cross-validating each other in terms of the importance of this pathway. And that's why I'm so excited. And it's not just IgA Nephropathy. This pathway is likely to be important in other autoimmune-driven diseases. And so the challenge is going to be, where do you go next? Because there's so many other opportunities. What do I think the ORIGIN study is going to show? I think it is going to build on the data of the JANUS study. I think it is going to -- if I were to guess, and I can quite clearly say I've seen no data whatsoever that we will see clinically relevant, clinically meaningful reductions in proteinuria at 24 weeks. We are going to see significant changes in Gd-IgA1 again. It's early for GFR, but we may see something in GFR, but it's early by any stretch for a chronic disease. So I think this is going to reinforce what I believe already is the importance of this pathway. And the fact that this pathway is going to be a path where you want to inhibit long-term in IgA Nephropathy. So...

And maybe just clarify a little bit because I think like what we know is that 30% is an important goal, right? Because that level of proteinuria reduction has been linked to more than a decade of delayed end-stage renal disease. And we've seen a number of companies been able to get there and higher. So then the question is, not what do we think is going to happen, but what do you want to see in this particular trial at 6 months? We've got to be really careful because some trials are longer, some are shorter. But at 6, what do we want to see to feel like this is going to be a competitive compound?

So you touched on 30%, and that's because from the analysis that we've done, that links to roughly a halving of the relative risk of a kidney outcome event from the analysis [indiscernible]. I think at 6 months, we won't know the maximal time at which we're going to get the maximal proteinuria reduction. So one of the things I'll be looking at is the trajectory approach proteinuria. Is it still going down? Is the key piece of information, have we reached the maximum reduction? I think if we're in the ballpark of 20% to 30% and it's still going down, that's going to be really exciting for me because that suggests that when we talk about the other drugs that are looking at a 9-month endpoint, we could well be getting -- seeing a further improvement at 9 months. So that -- you've touched on 30%. I think -- is 29% a disaster? I don't think it is. Is 27? No. We're talking shades of gray here. The whole point that they have done this study is to find the optimal dose from an efficacy and safety perspective to take into Phase III. And so I think we're going to look at the totality of the data and then decide on the optimal dose. But I think we saw that 20% to 25% reduction in the JANUS, a very small study. But I think if we see that again or possibly even a little bit more with the 150-milligram dose, that will be something that will fill me -- would be something that I would be very strongly supportive of taking forward into Phase III.

Okay. And then just one follow-up and then I'll hop in the queue. But kind of along these lines, if we fast-forward and let's say, several of these B-cell depleters actually to make it to the market. How are you in your mind going to determine which of these you use and which patient and actually where in the treatment paradigm would you use them? Would it be something you used early on when patients are first diagnosed? Would you wait for patients who are maybe not at goal? So I guess 2 questions in there. Where would you use these? And then kind of how would you decide which one?

So that would take me the rest of the evening, but I'll try and be brief. So the data we're just about to publish and I alluded to this in my talk, but we need to start reframing the argument for 20, 30 year olds. We need to be thinking lifetime risk of kidney failure. And that means we need to be treating at a lower threshold of proteinuria and we need to be treating earlier. So where do I think we're going to be in the next 2 to 5 years? We are going to be making a diagnosis and starting to kind of rest blockade, but also drugs like atacicept at the time of diagnosis because every year counts when you've got another 50 years, you need to have your kidneys working for you. So I think we are going to have multiple therapies. We need to be targeting upstream with the production of pathogenic IgA and we need to be targeting downstream for an immediate anti-inflammatory effect. So I think a drug like atacicept would be a drug that we want to start very soon at the time of diagnosis, possibly in combination with anti-inflammatory like an anti-complement inhibitor. And then we would need to think about what maintenance would look like. That's the induction of remission or -- and then we would look at maintenance. And so that's another conversation altogether. I think if you ask me to rank and this is what I'm going to do. So if you take all those drugs that Marshall presented, I will look at safety first. I will then look at efficacy. And if they're head-to-head, I'll look at acceptability to the patient, which is mode of administration, frequency administration, volume of administration. So that's my thought process. Safety, 51%, efficacy, 49%. And then if they're all identical, is my patient going to want to take this drug in the way that I have to give it to them? And that will be where that will then fit. And you can make your own mind up when you look at the data, which one do you think as a patient you would like to have if they were equally efficacious and safety?

Our next question comes from Priyanka Grover from JPMorgan.

This is Priyanka Grover on for Anupam Rama. And I have a question for Dr. Barratt. Based on your experience in the patient population that is enrolled in the trial, what do you see as a placebo performance being? And what do you see as a clinically meaningful delta on the proteinuria, competitively speaking, in the ORIGIN study?

Yes. So I think that's what we've talked about in the previous -- I think we talked about a delta here is what I'm talking about when I mentioned the 25%, the kind of 25%, 30% range of 6 months is the difference between what we see in placebo and what we see with treatment. And again, as equally important is the trajectory. So if we see that the proteinuria is declining still at 6 months, we don't know what the true anti-proteinuric impact of that therapy is going to be. And therefore, we may well get a maximum rate of reduction in proteinuria if we treat and we look at 9 months. So it will be around the 25% to 30% would be my guess in terms of would be the level that would get me really excited. But I'd be prepared to accept a slightly lower level if that trajectory was moving in the way that meant at 9 months, perhaps it would have hit whatever in terms of what you might extrapolate.

And just a quick question to management, I know Anupam will want me to ask this. Could the ORIGIN data be possibly read out early in the quarter at, say, the small health care conference in early January in San Francisco?

Thanks for the question. We haven't been more specific than early in the quarter.

Our next question comes from Ritu Baral from Cowen.

Dr. Barratt, I wanted to just round back to the potential placebo that may -- the placebo effect that may come out of ORIGIN. What's the range of placebo effect that might come out of that? I mean, we've seen some pretty big error bars across the different studies. How should we be thinking about what a well-run study should yield? And then the follow-up is for Marshall and Celia. As we think about what you're going to release, Marshall, you mentioned that it was going to be the 24-week. What other secondary endpoints might we see at the same time like biomarkers Gd-IgA1, et cetera? And when could we see that 36 week to see any time-dependent trends?

So I think -- so in terms of the -- so the placebo effect on proteinuria is what you're talking about, yes?

Yes.

So I think if you look at the NefIgArd and Nefecon studies, those were, I think, 2 well-run studies and the effect -- the placebo effect on proteinuria was about 5% at most, if that. If you look at the [ Trevi ] data, you will see that the placebo effect was 15%. But actually, that's not the same trial design as any other study because they protocolize supportive care and they altered the baseline RAS inhibition that patients were receiving. So you've got to be really cautious about using the PROTECT study as using that as the kind of standard for what you might expect proteinuria to change. What I would expect is what you would see in the Nefecon or the NefIgArd studies, which is less than 5% change in proteinuria in the placebo-treated arms. So that's what I would suggest would be what you might observe over a 6- to 9-month follow-up period.

Thanks, Jon. And to answer Ritu's second question, what do we expect to share? We do expect to have a press release and we will share the primary endpoint, which is week 24 proteinuria and that would, as Celia reviewed, compare atacicept to placebo, not to baseline. We may provide dose-specific information, data depending. We will include the important biomarker of Gd-IgA1 as we haven't shown data with 150 milligrams before and we also will likely show, as Dr. Barratt pointed out, it's early to look at GFR. We have a preliminary trend with the JANUS study showing that patients on atacicept maintain their GFR over a significant period of time, over 72 weeks. But that's a small data set with large error bars. We'll now have 6 months or week 24 data and we would hope that we would see similar information with that group. But it's not long enough to show that placebo patients start to decline as you would expect them to do over a year and beyond since this is 6-month data. And then finally, we will make a summary comment about what we see in terms of safety. As was reviewed today, we have a well-characterized safety database that shows balance between atacicept and placebo. But these data come from very sick populations, rheumatoid arthritis, relapsing multiple sclerosis where patients are on high-dose steroids or other immunosuppressive medicine. So we are curious as are others about what the safety profile looks like in these subjects about, over 100 subjects in IgAN. So this should be a meaningful dataset, a randomized controlled trial dataset in IgAN patients in this type of population. So that's an outline of what we plan to share early next quarter.

And just remind me again, that primary endpoint, that primary analysis on the primary endpoint, that's the 75 plus 150 blended versus placebo?

That's correct.

Our next question comes from Rami Katkhuda from LifeSci Capital.

First, for Dr. Barratt, can you touch upon the use of SGLT2 inhibitors in the treatment of IgA Nephropathy and what percent of patients require additional therapy after optimized RAS blockade as well as SGLT2 inhibitor?

Yes. Good question. So SGLT2 inhibitors, I'm sure you'll have seen the EMPA-KIDNEY data that was presented at ASN, which is highly consistent with the DAPA-CKD data. Actually, penetration of SGLT2 inhibitors in the IgA Nephropathy population is very low. It's in fact, quite low in diabetics. But I think it will change over time. And certainly, I would imagine by the time of the Phase III study for atacicept, we will be talking about SGLT2 inhibitors being part of supportive care. Does that mean that it's going to completely cure IgA Nephropathy? Absolutely not. SGLT2 inhibitors reduce albuminuria, proteinuria by about 20%, if you look at the data from DAPA-CKD and EMPA-KIDNEY. So it really -- it impacts and is protective, but it doesn't really deal with the fundamental problems that we're trying to address with a drug like atacicept and it doesn't reduce the risk of progressive kidney disease in the vast majority of patients. So absolutely, we will be using them. It does not solve the problem though. And actually, we need to future-proof our studies such that SGLT2 inhibitors would be allowed in the context of a Phase III with atacicept. There's no reason to suggest that I can see no argument for why this would alter the efficacy of a drug like atacicept or its safety profile. And we welcome better supportive care. But fundamentally, we want to give disease-modifying therapies, which is why drugs like atacicept are so exciting. But we would use them in top of SGLT2 inhibitors.

Jon, if I could jump in and ask a question that came in online here that's an extension to your answer, which is what proportion of patients have persistent proteinuria on optimal RAS blockade? And how do SGLT2 inhibitors change that or how do you expect them to change that?

So it depends on persistent heavy proteinuria. So if we talk about a gram of proteinuria, then in my practice, I can get new patients with IgA Nephropathy. I can get about 40% of my patients down to below a gram with RAS inhibitor and good blood pressure control alone. I think with SGLT2 inhibitors, that's likely to give me another 10% at most, which means I've still got over half of my newly diagnosed IgA Nephropathy patients at above 1 gram of proteinuria. So that's the kind of where we look at. And that's assuming 1 gram is the right amount. And we're going to present data that I've already said, which suggests that actually 0.5 grams is the number we should be aiming for. And therefore, we're not going to get many patients below 0.5 with a RAS inhibitor and SGLT2 inhibitor. So we need that data to come out. We need to have a conversation within the academic community about the implications. But RAS inhibitors and SGLT2 inhibitors are going to be beneficial, no doubt about that. They are not going to take this problem away for the vast majority of patients with IgA Nephropathy.

I guess for Marshall and Celia, based on atacicept's clinical development history, can you touch upon expectations with the 150 mg dose compared to the 75 mg dose in terms of both immunoglobulin reductions and how that may translate into proteinuria benefit?

Yes. Rami, good question. Because atacicept has been studied in systemic lupus and rheumatoid arthritis, we have substantial data between the 25, 75 and 150-milligram doses about the impact on immunoglobulins IgG, IgA, IgM. And the short answer, it's in the 5% to 10% range in terms of a deepening of that reduction when you move from 75 milligrams to 150 milligrams. So to the degree that we're going to see the same biomarker effect as we explore 150 in a new population, I think that's a safe projection to make.

Our next question comes from Farzin Haque from Jefferies.

So a question for Dr. Barratt. So what are your expectations for Phase III trial design, given that the safety profile is good? And if you expect the Vera's trial to be different or streamlined versus Chinook's 1301?

Thanks for the question. So I think the trial design is, at the moment, is a 9-month proteinuria endpoint with a 2-year eGRF-based endpoint is what the FDA regard as acceptable for an accelerated approval pathway. I think as we've already mentioned, we're going to have to modify our inclusion criteria to reflect current standard of care and the fact it's changing. But the one thing I want to just put out there is, if we get 2 or 3 studies that have shown a reduction in proteinuria mabs completely to the predicted protection in GFR with different drugs with different mode of actions, remember, we're going to have a 2 year eGFR data for the NefIgArd and the PROTECT studies in 2023, will the FDA start thinking that proteinuria reduction is a drug -- is through surrogate? And actually, we will be able to get a full drug approval based on proteinuria. And suddenly, that transforms the trial landscape in that you need a study that is half the size with a readout at 9 months rather than 2 years. Now that's not certain, but I think that's something certainly we've been discussing within the IgA Nephropathy circles and something that we've been having informal discussions with on a wider kind of basis and I won't say anything more than that. But I think I would watch this space. But if we're thinking about a trial that might read out in 2 or 3 years' time, or even 2 years, we might be looking at a different regulatory landscape. And that's if we use the data that's been generated. So Marshall, I'm really sorry. I'm -- it's 8:00 now. So I am going to scoot -- very nice. I'm happy to take any follow-up questions through e-mail, if that's okay.

Thank you, Dr. Barratt for your time and for your perspective today. And at the top of the hour, Tara, I think we should close the call. Apologies to anyone who didn't get their questions answered and we can make time through our avenues to do so. I appreciate everyone's interest and your time today. And with that, we'll close the call.