Good afternoon, welcome to the Vera Therapeutics KOL event. At this time, all attendees are in a listen-only mode. A question and answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. 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. 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. As such, we present this disclaimer regarding at-risk statements. Next slide. This is an incredible moment for patients with IgA nephropathy. 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. Dr. Jonathan Barratt, a physician, researcher, and leader in the field, will provide an overview of IgAN and its causes and the rationale for targeting B- cells through the APRIL BLyS mechanism.
Vera's Chief Medical Officer, Dr. Celia Lin, will describe our ongoing phase II-B randomized controlled trial. Finally, I'll make some summary comments, and we'll open the floor to questions for all three of us. In this business, we aim to serve patients and improve their lives, let's begin by listening to Liz. Please cue the video.
Hi, my name is Liz. I'm 41 years old. I live in Mar Vista, California. I was first diagnosed with IgA nephropathy when I was 23 years old. I had no idea I was sick. I started to see spots in my vision while I was driving. I really freaked out. I scheduled an appointment with a primary physician. I went in there. He said, "Your blood pressure is very high, and I think you're just stressed out." The next morning, he called me. He told me that I needed to go to the emergency room right away. He sat next to me. He was very gentle. He said to me, "Your kidneys are failing." He said I needed to be put on dialysis right away. I didn't even know what that was.
You would think there would be some sort of hill that you go down, you know? That you feel that you're getting sick. I had no signs. What really brought me down was dialysis. I became very thin. I looked emaciated. I became so weak that if I was not on dialysis, I was in bed. What was hardest for me, as a 23-year-old that felt immortal, was that I couldn't do anything. My mother donated a kidney to me about a year later on my 24th birthday. I turned 30, and my maternal biological clock was ticking so loud inside of me that I needed to have a baby and be pregnant, like, ASAP. I told everybody I was going to have a boy, and his name was going to be Griffin. I had a boy, and his name is Griffin.
He's the reason for me. He's the reason for my everything. I understand what it means to have autonomy. I understand how it feels to have it ripped away from you. I still live an incredible life. My life is so rich. Human beings are extremely resilient. We have incredible spirit, and strength, and courage. I am grateful for every single day, because it is truly a gift, and it's unfortunate that I had to go through what I did to really realize that at such a young age. Because I do, the appreciation is that more intense. IgA nephropathy has reframed my life entirely. There were no treatments for IgA. If at any point in time there would be one, that would change lives. Incredibly change lives.
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. 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 IgA nephropathy field. Dr. Barratt has emerged as one of the leading voices during this revolution in therapies for IgA patients. Dr. Barratt, thank you for your time and for your perspective today.
Thanks very much, Marshall. It's a great pleasure to talk to the listeners about IgA nephropathy. I think Liz's story is very typical of the kind of patients I see. The thing I want people to really 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. Unfortunately, people like me give them a diagnosis of IgA nephropathy, and everything changes. We have no way at the moment of treating this disease effectively.
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, we need to remember 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 about a lifetime risk of kidney failure. The data that we have would suggest that the vast majority of patients with IgA nephropathy have a significant lifetime risk of kidney failure. 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 IgA nephropathy in the U.S., in the EU and Japan. 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. 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 in 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 with end-stage kidney disease, which is what happened to her. 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. 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. We do need to think about how we identify these patients in the community. The challenge really is we don't have biomarkers, and we require a kidney biopsy for diagnosis.
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 IgA nephropathy, the bedrock of how we approach treatment is with supportive care. This is not particularly nuanced. This is controlling blood pressure, maximizing renin-angiotensin system blockade, something that we do for every patient with proteinuria kidney disease, irrespective of whether they have IgA 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.
If you talk to any patient with IgA nephropathy who's had steroids, they will tell you often the side effects from the steroids were worse than actually living with the disease. 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 for Tarpeyo 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. 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 at persistent risk of progressive kidney disease.
We know that treatment with systemic glucocorticoids comes with significant toxicity. 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. 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 at being at increased risk of progression, because we know those are the patients that need additional therapy.
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. 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 very close eye-taken of, and a thorough assessment for a toxicity risk stratification. 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. Again, I just want to focus on this, the focus of how we approach IgA nephropathy.
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. This has to be the focus of how we approach IgA nephropathy now and going forwards. That actually we should be not thinking about glucocorticoids, 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. 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. Patients tell us they do not want to have repeated courses of these because they felt so poorly when they were taking them. 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. 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.
If we think about an overarching view of what happens in IgA nephropathy, I want to work backwards. We know in IgA nephropathy, the glomeruli, 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. That's why we see blood and protein in the urine, and that's what drives kidney scarring. Why do these immune complexes form in the circulation? Well, they form because in the circulation, there is an increased presence of this abnormal form of IgA called galactose-deficient or Gd-IgA1. 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?
All the evidence would suggest that this Gd-IgA1 comes from the mucosal immune system. That immune system that lines our GI tract, our genitourinary 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 X those 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. 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. If we think first about B -cells, what do we know about B-c ells that mean that we could potentially target them? Well, we know that there are two 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. They're actually very important in IgA class switch recombination, so the generation of IgA-secreting plasma cells. This is exactly the system that is targeted by atacicept.
atacicept contains the extracellular domain of the TACI receptor, which allows the binding of both BLyS and APRIL, and it 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. 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.
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're 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 IgG. 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. 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.
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. 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.
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. 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. That's important when we think about toxicity 'cause in IgA nephropathy, atacicept is only being given as a monotherapy. There isn't prednisolone, there isn't mycophenolate around, where there would have been in the setting of lupus and other immunosuppressants in the setting of rheumatoid and others.
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 the immune system, were really no different between placebo and atacicept when you look at the totality of the data. 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 BAFF, BLyS, and APRIL signaling. You can see here the data for belimumab, Benlysta, which you can see there's over 7,200 patients being treated. You can see next we have atacicept with around 1,500 individuals having been exposed to atacicept with that safety data.
You see those drugs that are targeting APRIL only that are being also evaluated in IgA nephropathy, where there's far less clinical experience and long-term clinical experience with these agents. 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 II-A trial in IgA nephropathy looking at two doses of atacicept and placebo. Again, it was looking at high-risk patients, so patients with persistent proteinuria despite maximal RAS blockade.
What we saw here was a significant reduction in Gd-IgA1 that was sustainable out to 72 weeks. 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. You can see that those patients with the lowest quartile of Gd-IgA1 levels at time of diagnosis, the green group one , did the best and had the best kidney function survival compared to those in group four who had the highest quartile of Gd-IgA1 levels at time of diagnosis. This has been repeated in other cohort studies. A clear association between the level of Gd-IgA1 and the future risk of kidney failure.
What we did when we looked at the JANUS data was we looked at the quartiles of the Gd-IgA1 levels we saw. 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. 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.
Indeed, 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. 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, IgG immune complexes. 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 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.
You can see here that treatment with atacicept resulted in a reduction in proteinuria. You can see here, although it's short timeframe at the GFR levels, you can see that actually the placebo group, there is a loss of GFR over the course of the study. 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, albeit small numbers, there does appear to be a stabilization of GFR without that consistent loss seen with placebo. Of course, we're going to be looking at that in the ORIGIN study and which Celia will talk about after myself.
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. 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 pathogenic immune complexes. The data we have from the phase II-A JANUS study links 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 II-A JANUS study, and which look really promising. On that note, I'm going to hand over to Celia, who's gonna talk us through the phase II- B ORIGIN study.
Great. Thank you, John. I'm gonna speak about the ongoing ORIGIN phase II-B trial. Next slide. 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 mg and 75 mg dose that you've seen in the JANUS study, and what is newly being tested is the 150 mg dose. The double-blind treatment is a 36- week period that's followed by an open -label extension of 60 weeks. Atacicept 150 mg followed by a safety follow-up. 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 mg [per milligrams or grams] per 24 hours. eGFR ≥ 30. Stable and optimized RAS inhibition for at least 12 weeks, and a blood pressure of < 150 or = 150/90. 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 mg and 150 mg 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. Of course, the change in Gd-IgA1 with safety being extremely 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, John. Next slide, please. 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. 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. Really, the importance is focused on mechanism of action. Can the new therapeutic target the source of the disease upstream? That in this disease is clearly B- cells.
There are two programs in the APRIL BLyS inhibition category. One is ours, an atacicept that you've been hearing. Another is telitacicept from the company RemeGen. Another target would be to inhibit APRIL only and leave BLyS unopposed in a mechanism also targeting B- cells. One program is Chinook BION-1301, another is Otsuka's sibeprenlimab. These are the four programs that are really in late-stage development targeting B -cells as a potential way to disease modify. 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 endothelial 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 mg and delivered as a single milliliter, making subcutaneous injection a simple and patient-convenient method. We are exploring 75 mg or 150 mg subcutaneously, 1 ml once a week. That's a key piece. We hope to contribute to the body of evidence looking at proteinuria impact. The proteinuria reduction from each of these agents, we'll continue to clarify as we read out the ORIGIN program.
For example, for atacicept, a small subset of patients, five 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. We will also look to show for the first time the proteinuria reduction with 150 mg 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 mg of telitacicept at 24 weeks. At their higher dose, 240 mg, they showed almost a 50% reduction at 24 weeks. This is data from a randomized control trial conducted in sites in China only. The important step in validating that data is to ensure a multinational set of patients.
We await further data to see 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. 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 three of the doses that they explored at 36 weeks.
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 248 mg per kilogram in the phase II data that was shared at that time. 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 mg sub- Q 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 mg um as a result seen at 24 weeks and durable over time. We've not yet seen what the 150 mg 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 mg sub- Q, sorry, 450 mg IV sub- Q every other week. In the range of similarity between these two 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 agent. 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 unopposed. We'll see that, most meaningfully in a randomized controlled trial, we hope in the future. Next slide, please.
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. 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. 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.
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. I'll hand it back to you, Tara, the operator, to help us address questions.
Great. Thank you, Marshall. At this time, we'll be conducting a Q&A session with our speakers. As a reminder, if you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. Our first question comes from Liisa Bayko from Evercore. Please go ahead, Lisa.
Hi there. How many questions can I ask?
Let's be fair and do one at a time.
Okay, I gotta ask the most interesting one here. Okay, I guess, you know, what's the bar for data? I think, Marshall, you and I have talked about that a number of times. It's gonna be a 24-week look at data. I'd like to pose this question to Dr. Barratt to get, you know, to get his take. You know, we've seen data emerging. I think Marshall just did a nice job in reviewing some of the emerging data from the other, you know, B-cell modulators, if I may call them that. Maybe you could, based on that, you know, where do you see the bar for data coming from the ORIGIN study?
I think. I hate to predict. I like to see data. I think the overwhelming evidence, in my view, looking across all the programs targeting this axis, is that this is something that's really gonna go places in IgA nephropathy in terms of targeting the APRIL BLyS pathway. you know, 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. That's why I'm so excited. It's not just IgA nephropathy. This pathway is likely to be important in other autoimmune driven diseases. The challenge is gonna 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. I think this is going to reinforce what I believe already is the importance of this pathway and the fact that this pathway is gonna be a pathway you want to inhibit long-term in IgA nephropathy.
If I could just clarify a little bit, because I think, like, you know, what we, what we know is that 30% is an important goal, right? Because that's, that level of proteinuria reduction has been linked to, you know, 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. The question is, you know, not what do we think is gonna happen, but what do you wanna see in this particular trial at six months? You know, we've got to be really careful 'cause some trials are longer, some are shorter. At six months, what do we wanna see to feel like this is gonna be a competitive compound?
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 published by Vasilenko. I think at six months, we won't know the maximal time at which we're going to get the maximal proteinuria reduction. One of the things I'll be looking at is the trajectory of proteinuria. Is it still going down? It's the key piece of information. Have we reached the maximum reduction? I think if we're in the ballpark of 20%-30% and it's still going down, that's gonna be really exciting for me because that suggests that, you know, when we talk about the other drugs that are looking at a nine-month endpoint, we could well be seeing a further improvement at nine months.
That, you know, you've touched on 30%. I think, you know, is 29% a disaster? I don't think it is. Is 27%? No. We're talking shades of gray here. The whole point that Vera have done this study is to find the optimal dose from an efficacy and safety perspective to take into phase III . I think we're going to look at the totality of the data and then decide on the optimal dose. I think we saw that 20%-25% reduction in the JANUS, a very small study. I think if we see that again or possibly even a little bit more with the 150 mg dose, that would be something that will fill me with... It'll be something that I would be very strongly supportive of taking forward into phase III .
Just one follow-up, and then I'll hop in the queue. Kind of along these lines, you know, if we fast-forward and let's say several of these B-cell depleters actually make it to the make it to the market, you know, how are you, in your mind, gonna determine, you know, which of these you use and which patient, and actually where in the treatment paradigm would you use them? Would this be something you use early on when patients are first diagnosed? Would you wait for patients who are maybe, you know, not at goal? You know, I guess two questions in there. Where would you use these, and then kinda how would you decide which one? Thanks.
That would take me the rest of the evening, but I'll try and be brief. The data we're just about to publish. 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. That means we need to be treating at a lower threshold of proteinuria, and we need to be treating earlier. Where do I think we're going to be in the next two to five years? We are going to be making a diagnosis and starting the kind of RAS blockade, but also drugs like atacicept at the time of diagnosis. Every year counts when you've got another 50 years, you need to have your kidneys working for you. I think we are going to have multiple therapies.
We need to be targeting upstream of the production of pathogenic IgA, and we need to be targeting downstream for an immediate anti-inflammatory effect. I think a drug like atacicept would be a drug that we might want to start very soon at the time of diagnosis, possibly in combination with an anti-inflammatory, like an anticomplement inhibitor. Then we would need to think about what maintenance would look like. That's the induction of remission or, then we would look at maintenance. That's another conversation altogether. I think if you ask me to rank, and this is what I'm going to do. If you take all those drugs that Marshall presented, I will look at safety first. I will then look at efficacy.
If they're head to head, I'll look at acceptability to the patient, which is mode of administration, frequency of administration, volume of administration. That's my thought process.
Okay.
Safety 51%, efficacy 49%, and then if they're all identical, is my patient gonna want to take this drug in the way that I have to give it to them? That will then be where that will then fit. 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 safe.
Great. Thank you very much.
Thanks for the questions, Lisa. Our next question comes from Priyanka Grover from JP Morgan. Please go ahead, Priyanka.
Hi, guys. This is Priyanka Grover on for Anupam Rama, and I have a question for Dr. Barratt. Based on your experience and 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?
I think that's what we've talked about in the previous. I think we talk about a delta here is what I'm talking about when I mentioned, you know, the 25%, the kind of 25%-30% range at six months is the difference between what we see in placebo and what we see with treatment. Again, as equally important is the trajectory. If we see that the proteinuria is declining still at six months, we don't know what the true anti-proteinuric impact of that therapy is going to be. Therefore, we may well get a maximum rate of reduction in proteinuria if we treat and we look at nine months.
It will be around the 25%-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 nine months perhaps it would have hit whatever in terms of what you might extrapolate.
Understood. Just a quick question to management, because I know Anupam wanted me to ask this. Could the ORIGIN data be possibly read out early in the quarter at, say, this small healthcare conference in early January in San Francisco?
No. Thanks for the question. We haven't been more specific than early in the quarter.
Thank you.
Thanks for the questions, Priyanka. Our next question comes from Ritu Baral from Cowen. Please go ahead, Ritu.
Hi, guys. Apologies for that. Thanks for taking the question. Dr. Barratt, I wanted to just round back to 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.
You know, what, how should we be thinking about what a well-run study should yield? The follow-up is for Marshall and Celia. As we think about what you're going to release, Marshall, you mentioned that it was gonna be the 24- week. What other secondary endpoints might we see at the same time, like biomarkers, Gd-IgA1, et cetera? When, when could we see that 36- week to see any time-dependent trends? Thanks.
I think in terms of the placebo effect on proteinuria is what you're talking about, yeah?
Yes. Mm-hmm.
I think if you look at the NefIgArd and NEFIGAN studies, those were, I think, two well-run studies. The effect, the placebo effect on proteinuria was about 5% at most, if that. If you look at the VISIONARY data, you will see that the placebo effect was 15%. Actually, that's not the same trial design as any other study because they protocolized supportive care, and they altered the baseline RAS inhibition that patients were re-receiving. 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 NEFIGAN or the NefIgArd studies, which is less than 5% change in proteinuria in the placebo-treated arms.
That's what I would suggest would be what you might observe over a six to nine -month follow-up period.
To answer Ritu's second question, what do we expect to share? We do expect to have a press release, we will share the primary endpoint, which is week 24 proteinuria. 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 mg before. 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.
That's a small data set with large error bars. We'll now have six months or week 24 data, and we would hope that we would see similar information with that group. 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 six-month data. 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. These data come from very sick populations, rheumatoid arthritis, relapsing multiple sclerosis, where patients are on high-dose steroids or other immunosuppressive medicines.
We are curious, as are others, about what the safety profile looks like in these subjects, about, you know, over 100 subjects in IgAN. This should be a meaningful data set, a randomized controlled trial data set in IgAN patients in this type of population. That's an outline of what we plan to share early next quarter.
Thanks, Marshall. 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.
Got it. Thanks again, everyone.
Yeah.
Thanks for the questions, Ritu. Our next question comes from Rami Katkhuda from LifeSci Capital. Please go ahead, Rami.
Hey, guys. Thank you for taking my questions as well. first for Dr. Barratt, can you touch upon the use of SGLT2 inhibitors in the treatment of IgA nephropathy and what % of patients require additional therapy after optimized RAS blockade as well as a SGLT2 inhibitor?
Yeah, good question. 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. I think it will change over time. 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.
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. Absolutely we will be using them. It does not solve the problem, though. 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, and I can see no argument for why this would alter the efficacy of a drug like atacicept or its safety profile. You know, we welcome better supportive care, but fundamentally, we want to give disease-modifying therapies, which is why drugs like atacicept are so exciting. We would use them in top of SGLT2 inhibitors.
John, 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? How do SGLT2 inhibitors change that? How do you expect them to change that?
It depends how you define persistent heavy proteinuria. If we talk about 1 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 g of proteinuria. That's the kind of where we're looking at. That's assuming 1 g is the right amount, and we're gonna present data that I've already said, which suggests that actually 0.5 g is the number we should be aiming for. Therefore, we're not gonna get many patients below 0.5 g with a RAS inhibitor and SGLT2 inhibitor.
We need that data to come out. We need to have a conversation within the academic community about the implications. RAS inhibitors and SGLT2 inhibitors are going to be beneficial, get no doubt about that. They are not gonna take this problem away for the vast majority of patients with IgA nephropathy.
Do you guys mind if I ask one more?
Go ahead.
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?
Yeah. Rami, good question. Because atacicept has been studied in systemic lupus and rheumatoid arthritis, we have substantial data between the 25 mg, 75 mg, and 150 mg doses about the impact on immunoglobulins, IgG, IgA, IgM. The short answer, it's in the 5%-10% range in terms of a deepening of that reduction when you move from 75 mg to 150 mg. To the degree that we're gonna see the same biomarker effect as we explore 150 mg in a new population, I think that's a safe projection to make.
Got it. Thank you, guys.
Thanks, Rami. Our next question comes from Farzin Haque from Jefferies. Please go ahead, Farzin.
Hi, everyone. Thank you for taking my question. A question for Dr. Barratt. What are your expectations for phase III trial design, given that you know the safety profile is good? If you expect the Vera's trial to be different or streamlined versus Chinook's 1301.
Thanks for the question. I think the trial design is, at the moment, is a nine-month proteinuria endpoint with a two-year eGFR-based endpoint is what the FDA regard as acceptable for an accelerated approval pathway. I think as we've already mentioned, we're gonna have to modify our inclusion criteria to reflect current standard of care and the fact it's changing. The one thing I want to just put out there is if we get two or three studies that have shown a reduction in proteinuria maps completely to the predicted protection in GFR with different drugs, with different mode of actions. Remember, we're gonna have the two-year GFR data for the NefIgArd and the PROTECT studies in 2023. Will the FDA start thinking that proteinuria reduction is a drug, is a true surrogate?
Actually, we will be able to get a full drug approval based on proteinuria. Suddenly that transforms the trial landscape in that you need a study that is half the size with a readout at nine months rather than two 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. I won't say anything more than that, but I think I would watch this space. That if we're thinking about a trial that might read out in two or three years time or even two years, we might be looking at a different regulatory landscape. That's if we use the data that's been generated.
Got it. Thank you so much.
Marshall, I'm really sorry. It's 8:00 P.M. now, so I am going to scoot. Very nice. I'm happy to take any follow-up questions, through email, if that's okay.
Thank you, Dr. Barratt, for your time and for your perspective today.
All right.
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 other avenues to do so. Appreciate everyone's interest and your time today. With that, we'll close the call.