Ladies and gentlemen, good morning and thank you for standing by. Thank you for joining the InflaRx Capital Markets event to discuss the evolving treatment landscape and unmet need in AAV, as well as our development strategy for izicopan in AAV and other renal indications. During today's presentation, all participants will be in a listen-only mode. A couple things to note here. First, that today's call is being recorded. Also, as usual, please take note of the disclaimers in our deck, which discusses the nature of our forward-looking statements.
We will hear from a few different folks today that Niels will introduce in a bit. After that, we will go to a Q&A session where you can ask questions either through the side panel, written, or audio. Also note, if you are accessing the call now, you need to really be logged in online to ask these questions, not via telephone. With that, I'd like to turn the call over to Niels Riedemann, CEO and Founder of InflaRx. Niels, please go ahead.
Thank you so much, Jan. Welcome everyone to our Capital Markets Day. Good morning and good afternoon to all the listeners. We're really happy to have you for a very exciting session here today. I would like to first welcome also two world-class experts that we feel very lucky to have with us today on the call. Professor Jörg Köhl, who's one of the most accomplished research scientists in the area of complement, particularly C5a receptor, who will talk about the science behind ANCA vasculitis and the role of the C5a receptor and C5a in this disease. So, it's really great to have Dr. Köhl with us. Then Dr. Peter Merkel, professor of medicine and chief of rheumatology at UPenn, one of the KOLs, key opinion leaders, in the world of ANCA vasculitis clinical research.
So really, really happy to have you with us and supporting this sessions here, and also our development with your advice. With me on the call, my teammates, Dr. Gabriela Alperovich, who just joined the team as senior vice president and global head of clinical development. Gabriela will be available for Q&A. She's a trained nephrologist and extremely experienced in the renal disease development space. Of course, Tom Taapken, our chief financial officer, will be giving you some insights into external market research we very recently conducted. Next slide, please. We want to talk about avacopan today. The slide is not advancing. Could you advance to the next one, please? Thank you. We really want to talk about izicopan, our small oral C5a receptor antagonist, which we believe is really a triple threat for a potential best-in-class agent.
We are saying that because this drug has a very fast onset and a very high exposure, with a potential for better efficacy. We have really within one week, a target therapeutic exposure reach, what we believe is target. We will go into this here later in the presentation, but really also flagging that we have a very good control over the signal and in vivo head-to-head data with a marketed comparator where we show a clear increase, almost double the efficacy in that animal model in hamsters. We have no safety signals of concern so far. We have really low metabolite formation, 100-fold lower than the marketed comparator in the GSH trapping assay, especially in the early phase. That really entails we are not a time-dependent liver detoxifying enzyme CYP3A4/5 inhibitor.
That is very important for us, and we have, as of today, 197 subjects dosed with no safety signals of concern. We also have the potential for better convenience here. Clearly lowered pill burden is what we believe we may achieve. We have a threefold increased drug strength, and that really allows us for less dosing. On top of it, because we are not a CYP3A4 inhibitor, we may not have the same drug-drug interaction concerns, which may also have implications later. Next slide, please. Today's takeaways upfront, we are really excited about the market opportunity. We just did external market research that indicates really a very nice $1.5 billion-$2 billion peak sales potential scenario in ANCA-associated vasculitis. Our development strategy here is prime for generating differentiated efficacy and safety data. For that, we want to do two trials here.
One, as recently announced, a placebo-controlled study in patients with renal vasculitis, i.e., renal involvement, which is a group that is most commonly affected organ is the kidney. So it is really something that we are honing in on and really looking for different efficacy signals, particularly in the kidney space. Then the second one that we just recently added, an open-label study in all comers to demonstrate the ability to replace corticosteroids. So a slightly different patient population with a slightly different goal here to excite the physicians and also patients about the outlook to have less steroid use in this disease. We also want to do a study in AAS, which is already in the making, where we believe we may have initial first data maybe already in 2027. This is exciting. We will show you some details later.
Then also in a basket study where we currently start with IgAN and rapidly progressive IgAN, and potential others that are still in the discussion. This is also expected to start and have initial readouts maybe in 2028. We do want to flag there is a phase III study ongoing with our vilobelimab cell line-derived anti-C5a monoclonal antibody BDB-001 from our license partner in China that is expected to have data in 2028, here second half 2028. This is a large ANCA vasculitis trial in China where patients do not receive any corticosteroids, and we will be excited to see these data, of course, as well. Just want to end with saying we have a strong IP position. This is all in-house owned with izicopan and a strong balance sheet of EUR 153.3 million, that is, with a cash runway through to 2029. Next slide, please.
So without further ado, we are excited to hear about the science behind ANCA vasculitis, and I turn this over to Professor Jörg Köhl, who is, as I mentioned, one of the key experts in the world in that. We are very excited to have you, Dr. Köhl, and please, the floor is yours.
Yeah. So thank you very much, Niels. I am really delighted to give you today my perspective on the role of C5a receptor, and also targeting C5a receptor in AAV. Can I have the next slide, please? So before I go into the different pathways, just very, very briefly, because you will hear about this later, more from Professor Merkel, we are talking today about ANCA-associated vasculitis as a group of rare systemic small vessel diseases, where in the center are anti-neutrophilic cytoplasmic antibodies that target proteinase 3 on the one hand, myeloperoxidase on the other. And these ANCA activate neutrophils, and the prime neutrophils promote eventually endothelial injury and organ inflammation. The disease comes in different flavors. There are three main clinical types, GPA, MPA, and EGPA, where you find the different ANCAs. And the target organs are mainly the kidney and the lungs.
And I will talk about today from about many preclinical models where the target organ is the kidney. Next slide, please. So, diving directly into the pathways that drive the pathogenesis of this disease. It starts frequently with an infectious stimulus that can activate dendritic cells, that you see in the upper part of the slide. And this drives Th17 responses, and this IL-17 then activates macrophages to produce cytokines such as TNF and IL-1 beta. And this is important to prime neutrophils because this priming means that the two autoantigens, MPO and PR3, make their way to the surface, and are now exposed so that ANCAs can bind there. On the other hand, the infectious agents activate the complement system, and I will come to this in a minute. And this is also an important trigger for priming of neutrophils.
Once the neutrophils are activated, the Fc gamma receptors then drive excessive activation of the neutrophils with release of reactive oxygen metabolites, lytic enzyme, and there is also formation of NETs. Those together then drive the damage of the vascular endothelial cells. And the neutrophil is also important with regard to the B- cell response because it is secreting, after activation, BAFF, an important survival factor of B- cells, which is then critical to maintain the B- cell response and those germinal center that produce the B- cells that produce the ANCAs. Next slide, please. So going directly into the role of complement. And I want to show you today is that complement is involved in all different parts of the disease pathogenesis, priming, neutrophil activation with regard to ROS release, but also NET formation, and finally, also in the B- cell response, which may surprise you.
Next slide. I am showing you today evidence from preclinical models, and whenever I talk about preclinical mouse models, you will see a mouse icon on the left, or when I am talking about human studies, you would see an icon for human. The evidence from the animal models comes from an MPO-induced AAV model, where, next please, the authors, back in 2007, compared wild type versus C5-deficient mice. After induction and after administration of MPO, the mice developed within a few days crescent glomerulonephritis with albuminuria, and leukocyturia, and hematuria, but also with crescentic necrotic glomeruli, as you can see in the middle. The C5-deficient animals, they were almost completely protected. Next.
In parallel, several groups looked into patients suffering from AAV, and as you can see there, from immunohistochemical analysis, there is also deposition of C3 fragments such as Bb and C3d in the glomeruli in the upper part. Not only there, but also in the small vessels, in the endothelial cells. As you may notice on the very right, there is also some deposition of C5b - 9, so of the terminal complement complex, suggesting that there may be also a role for this part, and I will come back to this in a minute. Next. The next question was then downstream of C5, which is cleaved into C5a and C5b. Is it the interaction with the C5a receptors that is critical, or is it more the terminal pathway?
In a study that was published back in 2009, it was demonstrated that in comparison to a wild-type mouse, which shows a strong damage in the glomeruli, that C5a receptor-deficient mice are almost completely protected. Also, you can see the heavily affected glomeruli in the middle, the wild-type mice, and very much preserved and looking almost healthy in the C5a receptor-deficient mice. You also can notice is that you see a massive influx of neutrophils under G, which is almost completely absent in F, in the C5a receptor-deficient mice. Next.
In a more recent study published this year, in a huge cohort of AAV patients, it was shown that when you look into the kidneys and you do a transcriptomic analysis, what you notice is that in these kidneys, there is massive upregulation, as you can see in this volcano plot, complement components, complement regulators, but also on the very top, the C5a receptor one. What this study also has shown is that both the classical pathway and, in particular, the alternative pathway are massively upregulated in such kidneys. Next. Coming back to the question of whether the terminal pathway also contributes. This has been addressed by using C6-deficient mice, and as you can see on the right, C6-deficient mice in the MPO model, they show the same behavior as wild-type mice. They are not protected from the crescent glomerulonephritis development.
In contrast, when you look at the other C5a receptor, C5aR2, surprisingly, you see an opposing effect. These mice that are lacking the second C5a receptor, they show a more severe phenotype with a higher frequency of crescent glomeruli, showing you an opposing role of the two C5a receptors. Next. These data clearly demonstrate that C5a receptors would be important for the first step, priming of neutrophils. But once these neutrophils are primed and the autoantigens are exposed, the ANCA derive the activation of these neutrophils. This has been already shown several years ago, shown here on the left-hand side, with neutrophils that have been incubated after priming with TNF-alpha with ANCA IgG.
What these authors were able to show was that these ANCA IgG, and only those ANCA IgG, are driving ROS release or superoxide release, independent of whether you have an MPO-ANCA or you have a PR3-ANCA. Next. We and others have seen that there is a synergistic effect of C5a receptor and Fc gamma receptors to promote a pro-inflammatory environment. Next. To go a little bit more into detail, when you have a complement-activating isotype in the mouse, such as IgG2a or b, that activates the complement system, generates C5a, what this does is that the activation of myeloid cells by the C5a receptor one, it has an impact on the expression of activating Fc gamma receptors, in that it upregulates activating Fc gamma receptors and downregulates the inhibitory gamma 2b receptor.
What this does is it reduces the threshold for Fc gamma receptor-mediated activation of myeloid cells, so you get a higher AI ratio. That's not the end of the story, because when the activating Fc gamma receptors are now activated, they induce production of C5, induction of a protease that cleaves C5 non-canonically into C5a, so that you have an amplification loop and a vicious cycle between Fc gamma receptors and C5a receptor. Is this important in AAV? Yes, it is. Next. Because, next please, because when you use human neutrophils, and you prime them with TNF, and then you incubate them with normal healthy IgG in the middle, or with ANCA IgG, and then you collect the supernatants and incubate them with normal serum, next, what you see is that only the ANCA IgG are activating complement. What I've shown you in the cartoon above there.
Next, when you now use the serum and the supernatant from the cells stimulated with the anti-PR3 ANCAs, in the presence or absence of a C5a receptor antagonist, what you see is that the addition of the C5a receptor antagonist blocks the release of, or the induction of reactive oxygen metabolites. So, the whole pathway of crosstalk between Fc gamma receptors and C5a receptor is operative in AAV when it comes to ROS release. Next. But this is not only true for ROS release, as I will show you in a minute, because another important feature here is that the neutrophils are activated by the ANCA IgGs to induce NETs, which are composed of DNA- matrix metalloproteinases, histones, and together with the ROS and the lytic enzymes, they drive the vascular damage.
In a study published back in 2009, it was shown that serum from AAV patients with MPO antibodies, MPO-ANCAs, they drive about 20% to 30% of the neutrophils and NET formation. Next. We and others have shown that C5a receptor itself is also able to drive NETosis, as we have shown, for example, in case of SARS-CoV-2 infection. Next. In ANCA, there was an important study published in 2015 where the authors have shown that when an MPO-ANCA serum is incubated with pre-activated TNF, pre-activated neutrophils, that they produce ANCAs, and that is something you see in the middle here on the right-hand side. But when they do this in the presence of an anti-C5a receptor monoclonal antibody, a neutralizing one, as you can see, that NET formation is almost completely inhibited. Next.
Finally, I want to draw your attention to the B- cells that produce the ANCAs. Next. We took advantage of an ex vivo model where we isolated, that is something you see on the left side, B- cells from a wild-type or a C5a receptor-deficient mouse. These naive B- cells that express IgM were co-incubated with fibroblasts that were transfected with CD40 ligand and BAFF, which is soluble and a survival factor for B- cells. In the presence of IL-4, these naive B- cells differentiate into induced germinal center B- cells, and they switch now from IgM to IgG and IgE. What we have seen is that the activation of these receptors, CD40, BAFF, and IL-4, drives the induction of C5, the cleavage of C5a.
The question was now of whether this C5a binding to C5a receptor, which we found in such germinal center B- cells, is critical for the switch. Next. Indeed, after four or six days, what we saw was that the frequency of switched germinal center B- cells was significantly reduced with the B- cells from the C5a receptor-deficient mice, and the same was true for the IgE. Next. To sum this up and give you the key messages from this. First, next, what I've shown you briefly is that genetic or pharmacological C5a receptor targeting strongly reduces disease development in several preclinical AAV disease models. Next. The second important message here is that C5a receptor primes and activates the neutrophils as the key effector cell.
It's heavily intertwined with Fc gamma receptor-mediated neutrophil activation by ANCA when it comes to ROS release and when it comes to NET formation. Next. It's not only restricted to the preclinical models, but I've also shown you some evidence for an intrarenal complement-related transcriptional program in AAV patients with increased C5a receptor gene expression. Finally, four, next, there is a tailored targeting effect because blocking C5a receptor leaves upstream and downstream complement pathways intact, such as C3, such as the terminal pathway, which is critical to deal with infections. Next. I want to give you now a brief outlook because I think it's not the end of the story. C5a receptor, on the one hand, derives acute kidney injury, as I have shown you, but the question is it also relevant for the transition to chronic kidney disease? Next.
In collaboration with colleagues in Minneapolis, we have recently figured out that in an ischemia-reperfusion injury model, where you activate complement, the activation of renal tubular epithelial cells by the C5a receptor is critical for the autophagy machinery, the mitophagy machinery, in such that these renal tubular epithelial cells, they suffer from oxidative stress, which drives them into apoptosis, and then they induce a paracrine signaling that favors the differentiation of macrophages into an M1 macrophage with high inflammatory potential and driving myofibroblast and tubulointerstitial fibrosis and eventually CKD. Next. However, when you use a tubular-specific C5a receptor knockout or you use a C5a receptor antagonist, you can preserve the function of that autophagy machinery, and the cells do not suffer from oxidative stress. Now the signaling drives the macrophages more into a reparative M2 macrophage, and you see a massively reduced fibrosis. Next.
Finally, in collaboration with Didier Portilla in Charlottesville, in a folic acid injury model, we found that when tubular damage is induced, this is associated with the upregulation of C5a receptor on macrophages and also on pericytes, and these macrophages also go into an inflammatory one, and the IL-6 and CXCL2 production from the pericytes drives myofibroblast formation, and together, this promotes interstitial fibrosis and chronic kidney disease. Next. However, when you specifically knock out C5a receptor in such macrophages or pericytes, you can inhibit the inflammatory scenario and the fibrosis, and you can preserve kidney function. Next.
Taken together, there is also now at least preclinical evidence that suggests that C5a controls the transition from acute to chronic kidney injury by different means, by a crosstalk between, as you see in the center, activation of tubular epithelial cells, tubular macrophage crosstalk on the floor, which then promotes profibrotic pathways and eventually results in tubular interstitial fibrosis, nephron rarefication, and so on. As I've also shown you, there is a therapeutic implication because C5a receptor antagonists can interrupt, at least in the preclinical model, this vicious cycle from AKI to CKD, and there is also some human relevance because some supportive clinical data link tubular C5a to nephropathy and fibrosis. Next. With that, I would like to thank you for your attention, and I would like to hand over to Professor Merkel, and I'm happy to take any questions in the Q&A session. Thank you.
Good morning. Good morning. I am Dr. Peter Merkel from the University of Pennsylvania, and I'm happy to talk to you today about clinical unmet needs in ANCA-associated vasculitis. Waiting for my slides to advance. I'm going to talk about the standard of care and unmet needs in ANCA-associated vasculitis. Today, I will briefly go through the clinical spectrum of ANCA-associated vasculitis, specifically granulomatosis with polyangiitis and microscopic polyangiitis, GPA and MPA, outline the unmet needs for the treatment of AAV, which is the overall group name, and based on current sets of consensus guidelines and key clinical trials, review the standard of care for the treatment of ANCA-associated vasculitis, discuss the results of the ADVOCATE trial of avacopan, a C5a receptor inhibitor, and then take questions in the Q&A.
This is a nomenclature that we published in 2013, the Chapel Hill group, it's a group of us internationally, of how to name and define various forms of vasculitis. Today we're talking about this group of vasculitides, but as you just heard from the previous speaker, ANCA-associated vasculitis, while it includes three different diseases, we're going to concentrate on these two because EGPA, or eosinophilic granulomatosis with polyangiitis, really acts differently, and we're using different treatment regimens for that. Just want to make it clear, this is a very heterogeneous, serious, organ and life-threatening disease. There are many different manifestations. These are just some photos to give you a sense of what's going on in the various organs. This is a list that is not even full because other things can happen as well. There are many organ systems that are involved.
However, I like to talk about the big three or four that are the most common by far, and that includes the upper airway, the sinus and nasal disease, but also narrowing of the trachea and hearing problems that are significant. Pulmonary disease can include bleeding in the lungs, known as capillaritis, which is certainly life-threatening, nodules, fibrosis, and other problems in the lungs, very common. Glomerulonephritis, which is the inflammatory vasculitis in the kidneys, this is among the most feared complications, occurs in 70%-80% of patients, and it can definitely lead to renal failure and death, and it's unfortunately very clinically silent, so you have to be monitoring for it. Neuropathy is very common, which leaves people with pain and dysfunction, and then all of these other manifestations are present in many patients.
Nobody has all of these, but most patients have several different manifestations. What are the treatment unmet needs? They include less toxic regimens. We still rely a lot on glucocorticoids, which I'll explain in a second. These are steroids or prednisone, very toxic. There's still use of cyclophosphamide at times, especially for more resistant disease, and we need drugs that are safe and reduce infections. The largest cause of death for patients with ANCA-associated vasculitis is infection, followed by the vasculitis itself, and that is almost certainly the infections are due to the glucocorticoids and the other drugs we use. We need to more rapidly induce remission. This is a big issue. We want to get the patients in remission, put the fire out as soon as possible, because that will preserve the kidney or the lung or the nerves as much as possible.
Then we want to prevent relapse. Over the years, this used to be a universally fatal disease, but our treatments have definitely improved. It is now a very commonly relapsing disease, so we need to treat for years and prevent relapse. We also want to prevent the damage by inducing remission quickly and maybe even reversing some of the damage that happens, especially in the kidneys and the nerves. There are some patients who just have very resistant disease. We need better treatments. We want to avoid the chronic immunosuppression. Right now, we put people on rituximab for years, which can be effective to some extent, but it puts people at significant risk of infections, poor vaccine response, and other problems.
There are mild to moderate disease that is actually rather annoying and persistent and also needs to be addressed, and we need to be able to treat people very quickly with their flares. We need to get some other non-drug therapies, which we won't talk about today, and I'm still holding out for a cure over time. We're not there yet, but that should be our goal. New treatments are still needed. Let's talk about glucocorticoid-sparing or steroid-sparing. These are not the bodybuilder steroids. This is the steroids that reduce inflammation. I refer to these are the best drugs we have, these are the worst drugs we have.
They work very quickly, but they cause an exceptional number of different side effects, as I've listed here, from psychosis, insomnia, cataracts, glaucoma, weight gain, hypertension, diabetes mellitus, infection, heart failure, and death of bones and osteoporosis, and especially infections. A big problem. Not all patients get all of these, but almost all patients get some of these, and this is something that we spend a lot of time trying to lower in our patients. We use them because they work, but we can do better. We also want to prevent the damage, as I've mentioned. This is an example of a diseased kidney glomerulus. This is the individual units. You saw a few of these before. If you look at a lot of these, you'll know that on the right, for example, this is a crescent formation. This is scarring. This is bad.
These kidneys are not going to do well and may be permanently damaged already, and this happens quickly. Renal disease or kidney disease in ANCA-associated vasculitis is a major source of morbidity and mortality. It is what you're left with in terms of your kidney function, if it's 100% versus 70% versus 20% of kidney function, is predictive of mortality after your first flare. The rate of end-stage kidney disease or being on dialysis remains high, and that's unfortunate because being on dialysis really reduces your quality of life, your function, and your lifespan. We need to rapidly control kidney disease, and it's a major goal of new treatment strategies, and the outcomes for kidney disease are actually easily measured. A simple blood test helps you estimate what we call the glomerular filtration rate, and that's a very clear outcome.
Additionally, the urine, you can measure protein, creatinine, and you get this nice measure, which is also very easy to follow. We also have some biomarkers beyond these which can tell you about kidney physiology, both complement-mediated ones and other ones that are helpful in early phase trials to show that your concept is working. What's the standard of care? I'm happy to say that the standard of care is based on now 25 years of high-quality, large trials that we've conducted in the field, and standard of care has been also documented by three recent guidelines, the American College of Rheumatology, the Vasculitis Foundation guideline, the European Rheumatology group, I was part of both of these actually, and then the kidney group below. These are very similar recommendations, and my recommendations will follow that. We still use a lot of glucocorticoids, prednisone, steroids, as I've said.
We taper them down as fast as we can, but we still use moderate to high doses upfront. I separate treatment to non-severe and severe. Actually, most patients, when they first present, have severe manifestations, but there are some patients who have non-severe, non-organ or life-threatening right away. However, those patients will end up with severe disease if they are not treated. We still use glucocorticoids, as I said, and then we try to get them off. It's not always possible. We still use a drug called methotrexate, which we use a lot of in rheumatology. It's still the number one drug for rheumatoid arthritis, and you can continue that. It's good, but it's not as good as using rituximab, but some patients can get away with methotrexate alone. We never use it with patients with kidney disease.
Rituximab is by far the first choice now, and it's a drug that we continue. The trouble is, we usually induce remission in three to six months, and then we want to keep people there, and now that has gone on for years. The problem has become how long to keep people in this immunosuppressed state. For severe disease, which is the majority of new presentations, and any patient with kidney disease has severe disease, we have two options to induce remission in addition to glucocorticoids, cyclophosphamide or rituximab. Cyclophosphamide is being used less and less because of our trials, but if you do use cyclophosphamide, and it's used in some parts of the world more, it is followed by a less toxic form of immunosuppression, any of these drugs, but all the trial data leads to using rituximab.
If you start with rituximab, you can use anything else. However, by far the most common strategy used now in most parts of the world is to start with rituximab and redose with rituximab for several years. Why? Because we have shown it is more effective in keeping people in remission, and it's less toxic than cyclophosphamide. However, we certainly have patients on these other drugs for a variety of reasons. Rituximab is the mainstay of treatment. It was a major advance when we did our trials to the treatment. It is usually repeated every six months so that your B- cells, these are the cells that rituximab kills, are low or eliminated from the blood. But once you stop the drug, whether it's after six months or 18 months or four years, the rate of relapse is quite high.
People relapse even on rituximab, and only about 65%-70% of patients get into a glucocorticoid-free remission at six months. There's still a lot of room for improvement, even in the first part of treatment, and definitely after that, because relapse keeps happening, and if we stop the drug, relapse is very common. This is a problem, because you either are chronically immunosuppressing a patient, or you're putting them at risk for relapse, or both. We seek new treatments beyond B-cell depletion. I'm going to talk about the ADVOCATE trial of avacopan because it's another oral C5aR1 antagonist, and it's been in the news for a variety of reasons.
I will tell you that I was one of the two academic leads in this program, and we voluntarily retracted the paper, or asked for the paper to be retracted from the New England Journal, because there were some irregularities unknown to us that occurred. There was a small number of data from a small number of patients that was looked at after unblinding. We didn't think that was appropriate, so we asked for and received retraction of the paper. This is unfortunate. However, the data were reanalyzed, readjudicated. The primary data was not affected, but the interpretation was reanalyzed by Amgen through an independent group, and the report was put out in August of the readjudicated data, and we'll have a complete report soon. This was our report. It's available online.
What we found was, again, at 26 weeks, the treatments were This is the 2019 adjudication and 2026. On top, you can see that there was no difference between the two groups. Now, you say, "Is that good?" It is good, because the patients with the avacopan got almost no glucocorticoids after they started, very low doses of glucocorticoids, so they were able to achieve a similar rate of remission, but much less prednisone or steroids. At 52 weeks, previously shown to be superior, is now shown, because of a small number of patients, to be non-inferior. They were the same, although there's clearly a trend favoring the avacopan group. Nonetheless, these patients achieved continuous remission, again, with much less glucocorticoids. Importantly, none of the secondary outcomes were affected by the problem that I [inaudible] none of them.
The data were the same for secondary outcomes, and it showed benefit, or more benefit to the patients who got avacopan in their eGFR, that measure of kidney function I referred to, the glucocorticoid toxicity, how badly they got hurt by the prednisone, and health-related quality of life. There was a greater and faster recovery of kidney function in patients who had severe kidney disease who got avacopan. So, let me just show you some of the data from the renal disease, the kidney disease. This is a report we put out, and you can see this was 80% of the patients had kidney disease at baseline. If you look at them, you can see early on, very early on, just within a week or two of getting the complement inhibitor, the protein improved. That protein's not good. You don't want to have protein in your urine.
It improved more in the avacopan group than in the other group. So it was a faster onset. Even more impressive was when you looked at the patients who had very severe kidney disease when they came into the trial. 50 patients, we were able to show that the patients, both groups improved, but the group in red with the triangles was the avacopan group. They continued to improve substantially. We've never seen this in a trial, indicating either benefit upfront from preventing damage and/or continued control of disease that was better. So, that's promising. This is, as I said, the treatment here. If we use avacopan, which is still available in the U.S., we do so with a markedly reduced dose of prednisone. As you know, there is controversy with the FDA.
We will wait to see what the FDA may say about the continued availability of the drug here in the U.S. It is no longer available in the EU. What about rapid induction of remission? I told you we really want to get people rapidly induced because we want to prevent damage. Why? What else is the benefit? Well, you want to prevent the progression to organ and life-threatening status if you're not already there. You want to preserve the kidney function, which is a predictor of long-term outcome. You want to prevent damage to other organs, such as the nerves or the airways. Some airways get blocked off. You want to allow for a more rapid reduction or elimination of glucocorticoids. This is a major goal. We want to reduce hospitalization, length of stay, and reduce costs.
New treatments are clearly still needed for the reasons I've outlined. The potential for enhanced complement inhibition is also very promising. Stronger and better complement inhibition could result in better outcomes, faster remission, faster and greater recovery of kidney function, excuse me, and less permanent damage to kidneys and other organs. An alternative to rituximab for maintenance of remission. Again, rituximab is quite useful, but it does come with a cost of chronic immunosuppression, poor vaccine response, et cetera. Reduction or elimination of the use of glucocorticoids. This is really another major goal, I keep emphasizing, but especially preservation of organ function. In summary, I'm not sure what happened here.
Treatment of patients with AAV has markedly improved over the past 25 years. However, the rates of remission, relapse-free remission, and prevention of organ damage, especially kidney function, remain unacceptably low. We can do better. Strong inhibition of complement C5a and C5aR offers the potential for substantially improving treatment of AAV and the lives of patients with this challenging disease. I'm happy to stop there, and I'll take questions at the question time. Thank you.
Yes. Thank you so much. Thank you so much, Peter and Jörg, for these great views into the disease, into the disease mechanisms, and into the clinical features, and well, also into the role of complement, particularly C5aR. Next slide, please. We will here now give you a bit, first of all, reiterate our drug strength here, that we believe we may have a potential for best in class or better efficacy than currently available. That's a potential outlook, but I mentioned the triple threat. Just in brief, we have already signals that we achieve in week one already a very fast, what we believe is therapeutic levels that exceed the levels observed in ANCA vasculitis as published with avacopan at steady state at 13 weeks. We see that very rapidly. I mentioned the tenfold higher exposure.
This is from phase I data and compared to reported data, so not head-to-head studies, please note. I mentioned the very tight signal control already very early and over the first weeks of continuous dosing compared to reported data of a competitor. Then last but not least, I mentioned an animal model where we almost doubled efficacy at the same dose. This is an interesting outlook, and we really believe we have really achieved a drug that works very fast and may provide for very tight signal control. Next slide, please. We mentioned the metabolic stability and the potential for better safety, because on the left-hand side, I mentioned that in this GSH trapping assay, we see a lot less, 100-fold lower in the early signal metabolic reactive metabolite formation.
Even if you look in the later stage, the lower left red bars, it's still a 10x difference. I mentioned we're not inhibiting CYP3A4, also not in a time-dependent manner. That's important. CYP3A4 is the detoxifying engine in the liver, so that usually predicts problems if you're a strong inhibitor or a time-dependent inhibitor there. We mentioned the metabolic stability here also from other assays. Last but not least, we have over 197 patients and humans dosed in studies already with no real signals of safety concerns. Really, this bodes well for an outlook that we don't have current concerns on the safety side, and that's great. Next slide, please. I mentioned also the better convenience. We have a threefold increased drug strength. We have the potential for once-daily dosing. That's derived from modeling we've done from so far available data.
We will have to test that in later stage clinical development. I mentioned the CYP3A4 inhibitor that we're not. Basically to say, we may not have as many drug-drug interaction problems, that that could be leading also to convenience when it comes to a potential later label. The overall drug strength on the left-hand side that shows you how much pills could be reduced in different scenarios. With that, maybe a simpler and easier and more convenient dosing regimen could be achieved here. I want to flag that one of the other key advantages of our drug compared to other complement inhibitors in general is that because we're not blocking upstream and we leave the terminal pathway otherwise intact, we don't need vaccination.
That also the projection of infection rates, which may be also to some extent linked to blocking the terminal pathway, which we're not blocking. In that case, there could also be a difference. Next slide, please. This is an interesting modeling work that our team did, that is a 3D modeling with the two molecules. You see in the center here, avacopan. On the right side, you see izicopan. We introduced a trifluoromethyl group into the molecule. That sounds pretty trivial, if you will, but it's not. It was the basis of many years of work to lead to a three-dimensional change in the molecule that we believe also brought a much more metabolic stabilization with it.
But you see here in this modeling that the model predicts that there are clashes at the part that would interact, for example, with CYP3A4/5 here with the heme part of that molecule. So in other words, with the structural changes induced, this modeling suggests and provides a molecular basis for why we've seen what we've seen. For example, that we're not a CYP3A4 inhibitor, that we're most metabolically stable, and also have less metabolite formation in the GSH trapping assay. Next slide. Here, I would now like to hand over here for some external market considerations to our CFO, Tom. Tom, the floor is all yours.
Yeah. Thank you very much, Niels. So based on the target product profile of izicopan, which revolves around the faster onset of efficacy, a clean safety profile, and a development focus on the renal vasculitis, we conducted a focused market research and interview with a dozen of prescribing physicians in the area of rheumatology and nephrology in the U.S., Europe, and in Japan. The goal was to understand the positioning of izicopan in the market, and based on the medical needs and the physician preferences, try to identify that based on that, what would the market potential of a drug like izicopan be in these key markets? I will briefly summarize the results of this market research.
So first, and that's also very important, as also came across in the presentation of Peter Merkel, the vast majority of all physicians retain confidence in the mode of action and the C5a receptor inhibition as a valid way of address this disease, and they don't consider the issues that revolved around avacopan as a class effect that would taint the field. So the mechanism remains intact, and the path forward for C5a receptor antagonist development is wide open. The second takeaway is that a high proportion of the physicians that we interviewed are very likely to prescribe a drug like izicopan to their patients, especially if you consider the potential for glucocorticoid sparing as a possibility. Also, the kidney protective effects that we learned about, why they're so important.
And last but not least, the lack of alternatives, especially if also in the U.S. avacopan is withdrawn from the market, which would make it, of course, very difficult for prescribing physicians to find other alternatives. The third argument and the third point of this summary is that izicopan can command a very high degree of utilization and market share well in excess of 50% of the patients, especially in those with renal involvement. So we feel very confident that the market is wide open for us. And there is additional upside here, especially if we can provide data on glucocorticoid reduction. That's something that would be also an additional argument for physicians to use the drug.
The expansion into the wider AAV population, not just limiting it to the renal population, and a continued clean safety profile, those would be strong arguments that would go a long way in developing this market. Next slide, please. If we translate these physician feedbacks and assume a comparable pricing to avacopan, this leads to a peak sales potential for izicopan in the base case of $1.65 billion, according to our research. This base case is the 70%-80% renal vasculitis population that Peter Merkel was just referring to. This would be also a base case in which we would not have any additional glucocorticoid-sparing data available to show for. This would also be a situation where avacopan would be withdrawn from the market, which is a potential outcome of the ongoing discussions with the FDA.
If you translate this number of 1.65, which is predominantly driven by the U.S. market, and look only at the U.S. and the European key markets, excluding the rest of the world, this would lead on the right side, on the upper left square that you see there, to EUR 1.4 billion in these major markets. We did a sensitivity analysis around this and looked at what would happen on the lower left side if, for example, avacopan would stay in the market. We feel that with our profile, this would be still a possibility to command around EUR 1.3 billion in those markets. If we would, on the other side, have additional glucocorticoid-sparing or reduction data available to show for, that market could be grown to EUR 1.5 billion.
If it would be possible to expand into the all-comer population in AAV, so basically all GPA, MPA, AAV cases, that would translate to EUR 1.8 billion, which again, by adding markets like Japan and other countries, would lead to a total global peak sales potential of about $2 billion. We feel this is an exciting commercial opportunity, and there is, of course, further upside potential, not only in AAV by broadening the target population, but also looking into other renal diseases, as we will discuss today later. With that, thank you, and I hand back to Niels for outlook on further development plans.
Yes, thank you so much, Tom. This is truly an exciting market opportunity. Next slide, please. We want to showcase now high level our development goals here and our development programs. Clearly, the goals in ANCA vasculitis here are, as on this slide depicted, we want to demonstrate a superiority with focus on renal endpoints in randomized placebo-controlled phase II trial. This really is a trial that we have envisioned before. However, we will do this on top of standard of care, and I will show you that in the next slide, in patients with renal vasculitis, i.e., renal involvement, which, as you heard, make about 70%-80% of all patients anyways. We would then implement a standard of care GC tapering on the lower end, but in all arms, and we currently project an approximately 18-month enrollment period for that.
Obviously, working on getting that done faster, but that's kind of our current base case projection here. At the same time, with B, we want to demonstrate the GC replacement opportunity with an additional phase II open-label study. Here, we really try to do a two-stage design, first rapid taper, then really take them off completely, and that was informed by a recent study with our vilobelimab-derived cell line that is a product derived in China called BDB-001, so a C5a monoclonal antibody that did just that could completely waive and cease corticosteroids at enrollment, and is now in phase III development with a large study in China with anticipated data in 2028, as mentioned before. Just want to mention, these have slightly different enrollment criteria.
The second B will enroll all-comers, so also patients without renal involvement, and we're also selecting different sites, so we don't project that this will hinder enrollment that we're doing both studies in parallel. Next slide, please. This showcases the main, the large study, the placebo-controlled study. As you can see, we have a three-arm design, two doses of izicopan, 30 mg BID and 60 mg BID, tested all the way through to 48 weeks. The key readout will be at week 24. All this is tested against placebo in a randomized placebo-controlled manner. You see the darker red part is the standardized GC tapering, which will happen in all arms, down to zero, in fact. We project currently about 35 patients per arm. Randomization ratio is 1:1:1. Obviously, these are patients with renal disease, renal involvement, so-called renal vasculitis.
The endpoints are, while this is a primary safety endpoint, the key endpoints for us are BVAS 0, eGFR change from baseline, as this is a measure that we're key interested in, but also proteinuria change from baseline and hematuria. We have various other exploratory, including composite endpoints for the renal side and others that we are also testing. I would like to reiterate that this trial design has been informed by our initial interactions with regulators in the U.S., with the FDA. The next slide shows you another objective. That's the open-label study. Not only are we happy to get open-label data in the meantime, but we also want to really prove a point that you can safely reduce corticosteroids down to a place where you can replace them. You see here it's two-stage design.
This is an open-label study, as I mentioned, where we first rapidly and aggressively will taper, and we'll have a safety analysis with an expert group at week 16, and then we're also looking at week 24 signals and week 48, obviously. But the week 16 signal can drive a switch over to the next arm, stage two, where we really stop corticosteroids. Obviously, during screening, some patients are on steroids. You can stop them at enrollment in this case. This will be really informing us about the opportunity to reduce corticosteroids, but maybe even completely replace them, which, as we know, excites a lot of people in the field and is really one of the key focus for in treating physicians, and also, of course, for the patients.
We've been in touch with various Vasculitis Foundations around the globe, and it's really mind-boggling to hear again and again the need and the importance to reduce these toxic drugs, as Dr. Merkel has outlined very elegantly in his talk. The highlights here, obviously, it's also that we are looking at endpoints. Safety is really here, including BVAS 0 assessment, meaning remission. We want to reach remission rates which are in line with expectations and with safety expectations in this area. Of course, that lays the ground for future work related to that medical need. Next slide, please. Opportunities in additional renal disorders. Next slide, please. This is one opportunity that we're concretely planning. This will be a pilot study done by us in IgAN and patients with rapidly progressive glomerulonephritis or rapid progressing IgAN. As you may know, these are different subtypes of IgAN.
IgAN in general is a well-played field. There's lots of complement inhibitors already tested, so complement plays a huge role in this chronic kidney disease. We're envisaging here an open-label trial with week 12 and week 24 readouts. The dose would be izicopan 60 mg BID, and then a short safety follow-up. But the key issue is really, can we see a proteinuria reduction in these patients that is in line with recent reports, for example, with C5 inhibition or other complement inhibitors in the field? I should mention, in this field, the placebo proteinuria rates are relatively well established. This will be a key safety measure, the key efficacy measure in this part.
But for the much more rare rapid progressive glomerulonephritis, for which we also anticipate going into enrollment also in China aside from other areas, the key outcome is really a stabilization of eGFR and, of course, ideally also proteinuria reduction. This excites us because this can generate data already most likely in 2028 that are guiding further potential development and really prove that this drug is active in this disease. We may enroll another disease in this basket, which is currently under discussion, and we are also evaluating some other diseases. But as of today, this is planned, and we're moving forward with this as a signal-searching study, obviously here with the two different foci for the two different groups. Next slide, please. This is a study that is already progressing well. We hope to have first data next year.
This is in a disease called aHUS, atypical hemolytic uremic syndrome. This, to us, is a very important study, even though it's done in an expert center that is a referral center for a whole country of this disease and is extremely experienced in this disease and is collaborating with us on this investigator-initiated study, where we will study to treat these patients with this disease with izicopan, obviously with always eculizumab, which is one of the standards of care in this disease as a treatment potential, as a rescue treatment potential underneath. This is a life-threatening disease, so you want to make safety the first priority.
But the beauty about this disease is that there's an established primary endpoint in clinical studies which are done open-label in this disease, and which is called TMA response or thrombotic microangiopathy response. What that means, you want to see a normalization of the platelet count. You want to see a normalization of an enzyme or lactate dehydrogenase in the plasma. This is usually released when cells are lysed, particularly red blood cells, so you want to see that normalize, and kidney function improvement with a drop of creatinine of 25% or more. So when you achieve this is a primary endpoint in clinical studies that led to approval, and it means you are basically working on the disease control.
We believe this study is interesting for us because it could prove the point that actually the key damage driver could be the C5a receptor. While we do not know how much role the MAC formation plans, again, normally our cells are protected from MAC lysis, so that should not play a big role in our eyes, but we have to prove it, and we are looking forward to first results here. This is exciting, and this is in the making already, and as I mentioned, maybe first results already available next year. Okay. Next slide, please. That brings me to the key takeaways of today. I mentioned already very exciting market potential in ANCA-associated vasculitis.
Our differentiated view on this really with a key renal view in renal vasculitis patients, geared to show efficacy on top of standard of care versus open label proving the point of corticosteroid replacement as key drivers of value here. Then the other studies just mentioned in aHUS and in the basket of IgAN, rapidly progressive IgAN, and potential others. I do want to mention that we expect the data in our phase III collaborator trial in China that is running, and is projected to deliver results second half in 2028. This is an exciting signal, as this proves the point of complete throw out of corticosteroids, so very meaningful for patients, and this could also inform further development for us.
Last but not least, want to reiterate, this is our IP. This is a drug developed in-house, owned by InflaRx. We have a strong balance sheet with EUR 153 million and a cash runway with all this depicted studies here into 2029. With that, I want to say big thanks to the audience for today. Also, again, big thanks for our experts contributing, and I would hand back to Jan for opening the Q&A.
Thanks, Niels. Yes, as Niels said, we can start the Q&A session. If you look at the bottom, underneath your presentation window, you have got two ways to do so. One is, you can ask a question by pressing your raise hand. That will put you into a live queue where we will select you if there is enough time. The other way is to ask your question anonymously through the Q&A button, pressing that, and then you can type something in. So, I will say given the time, we will allow our esteemed experts, Drs. Merkel and Köhl, to exit if they need to, given that we have run a bit over, and then any questions that we go from here, we can make sure that InflaRx addresses as well.
So, we can go ahead and start now. Again, once I select you for the Q&A with your raise hand icon, just unmute, and then you can go ahead and go live. With that said, just moving very quickly here, first question we have is with Yatin Suneja at Guggenheim. Yatin, if you can unmute your line and ask your question.
Thank you so much. Can you hear me?
Yes.
Perfect. This question is for Dr. Merkel, if he is still with us, so I will ask it.
Hey.
Hey, Dr. Merkel. Thank you so much for that presentation. The question is around, number one, avacopan. How have you adopted avacopan in your practice? The FDA also raised some issues around hepatotoxicity and liver or drug-induced liver injury. Has that changed your view on the drug or the mechanism? Let us say, if izicopan, the InflaRx drug, is available in the future, how would you use it versus avacopan?
Okay, those are really good questions. I will try to be relatively telegraphic with the answers. We are continuing to use avacopan. We believe, not just me, but other members of our vasculitis center, they've independently come to the same conclusion. We think the totality of the data still guides us that this drug is effective and helpful for patients with ANCA-associated vasculitis. That being said, if taken off the market, we obviously won't be using it. The hepatotoxicity issues are of concern. There was some significant toxicities, especially among patients in Japan. It may be something different about patients in Japan.
All the post-marketing data to date indicates that the rate of hepatotoxicity is low. We don't think this is a major issue unless, of course, you're the patient. We follow the guidance of the FDA, and even more so, which is to test every two weeks initially and then every month, and we continue to monitor. I think it is something that patients should be aware of. In terms of whether we would use it, obviously, if the drug's not available, we won't use it. If the InflaRx drug, obviously, it depends on the data. We are, in rheumatology especially, have been good at adapting to new drugs, both within class and between classes. We have multiple different drugs in different classes now that we use.
If InflaRx is able to run a trial that demonstrates, for example, preservation of renal disease in a solid fashion, that would be a major advance. If it was more convenient, if it did not have any signal of hepatotoxicity. It's really about the data. Does it work better, faster, longer, more patients go into remission? I think we learn from the data. We're good at interpreting that from the trials. I think people are open to using a new drug.
Got it. Then one very quick question, if I may. The company has outlined the phase II program, and obviously going after more renal impaired patients. How would you advise them, or what is your advice in terms of how they should enrich the patient population so that they get the robust treatment effect? There is some data that you just presented which shows that if you have significant renal impairment, you see a lot bigger effect from avacopan versus sort of other patients.
Well, first of all, to be very clear, I am advising the company. Second of all, just to clarify, it's not that you see a bigger effect if you have renal impairment. It's that those are the patients where you would see an effect. Yes, if you have a very low renal function, your delta can be a much higher percentage as you change. It's sort of a math issue. I've advised, if you want to, this sounds very silly, but if you want to look at a change in renal function, you need to have people who have renal disease. Renal disease is the majority of patients. I think the answer is to measure it carefully, regularly, and in more than one manner.
The serum creatinine leads to the measurement of eGFR, those proteinuria we can see, as well as hematuria, and even some of the biomarkers. I think all of those things hopefully will go in the same direction, give you more confidence in the results, and you can enrich by making sure the patients truly have active disease when they're enrolled. That's important. You also want to make sure patients aren't, unfortunately, have such a damaged disease that you're not going to be able to see an improvement. All of those things are built into the protocol. I think the right patients, especially for phase II, for all trials, the right patients that meet the eligibility criteria, and I think we'll be very careful about that.
Great.
Thank you.
Thanks, Doctor. Next question we have is with Steve Seedhouse from Cantor. Steve, can you unmute your line and ask your question?
Good morning. Good afternoon over in Europe. Thanks for taking the question. I actually have three I was hoping to walk through. The first one, just for the company, regarding the steroid taper in the randomized phase II in renal vasculitis. What specifically are you planning there? Is it the same as the avacopan or the control arm in ADVOCATE, or is it a different steroid taper regimen altogether?
Yeah, I am happy to take that question, Steve. Thanks so much. It is actually the standard today is derived from a study called PEXIVAS, which basically looked at outcomes in severely ill patients and found that a lower tapering or fast, a little bit, going off from a lower tapering to back then standard was yielding similar results. So, if you will, the current worldwide standard of care and guideline recommendation is used in this trial, right? It used to be even higher. It is still higher, but we are using the lowest recommended standard of care in all three arms, if that helps.
Very good. Okay.
Maybe just very quickly add, I was actually one of the three worldwide PIs for PEXIVAS. We definitely showed that. It is called a reduced dose, but it is certainly not low dose.
Appreciate that perspective. Thank you. The one slide you mentioned, the intention of demonstrating superiority, of course, again, in the renal vasculitis phase II. I was hoping you could just talk more about that, on which endpoints is that referring specifically to eGFR or also on BVAS or anything else?
Yeah, so I mean, very good question. Matter of fact, no one has done a prospective study in this patient population, so we're kind of breaking the grounds here. We need to see what we get, but clearly we want to see a trend, if not already a stronger signal in eGFR. This is not just based on the avacopan data, some of which were shared by Dr. Merkel today, but also based on the fact that we have a faster onset and maybe an earlier drug effect, and also very good signal control. So that's where one of our projections lie. Then there are repeated signals from other studies, not just from the avacopan studies, but also from the BDB-001 studies that make us hope that we see this consistent signal.
For example, proteinuria was shown in the avacopan studies to be significantly faster resolved in the treatment group. There's also studies that indicate that hematuria can be faster resolved. These are the three main parts that we're focusing on. We've also built some composite renal endpoints in the secondary exploratories that can give us an even better power than just looking at one signal, but that remains to be seen. Ultimately, this should inform us and enable the next stage of discussions with the regulators to really move forward with an adequately powered study that really demonstrates the superiority signal.
Very good. Last question, I'm curious for the company's view, also Dr. Merkel, if he has a strong view. The renal function benefit seen in ADVOCATE in those renal affected patients, do we know how much of that is attributable to an avacopan-specific benefit, let's say, versus how much is sort of indirectly from steroid sparing?
That's an interesting view. No one's asked me that. It's a good question. We don't think that glucocorticoids are toxic to the kidneys. They're toxic to lots of other things. We're actually pretty confident, very confident that it's very helpful in controlling kidney disease, but at a cost. The patients who got avacopan got much less glucocorticoids, so if anything, you expect their renal function to have not gotten better as quickly and to perhaps be worse. That's really why we're so pleased to see those results. The only difference between two groups is the glucocorticoid dosing and the use of avacopan. These data indicate that it was that strategy that allowed it. We can't be sure that glucocorticoid tapering doesn't help your kidneys, but it seems very unlikely pathophysiologically.
Perfect. Thank you.
That answers your question.
Yeah, very helpful. Thank you.
Yeah, and Steve, if I just as an add-on, this really is a good question, and one of the reasons why we're also designing the key study here on top of a GC taper, which is equal in all arms, is to not work against our advantage. This really optimizes our potential to see the delta, and that's really an important kind of learning that we had from not only interactions with regulators, but also a lot of interactions with experts such as Peter Merkel and others. This is one of the design element backgrounds. Yeah.
Yeah, that's precisely what I was getting at, and so glad to hear that answer from Dr. Merkel. Thank you.
I would add one other thing, if I may, is that the focus is on renal disease in the trial. All of the other manifestations will also be measured, as well as quality of life. And so, the company will be able to see if there are trends in other aspects of the disease as well, which we would expect.
Great. Thanks. All right, so just a reminder, if you can limit your questions to one so we can address as many folks as we can this morning. Next one is from Sam Slutsky at LifeSci Capital.
Hey, thanks for taking my questions, and thanks for the great presentation as well. On the study designs for AAV, could you just kind of remind us on the issues that the FDA previously had with the phase III avacopan design, just going back to their ADCOM, and then just kind of how your design itself addresses the issues?
Let me take that question. I think the first part was, what was the design issues? I think every design has certain strength and issues. But I think one of the requests of the FDA back then was that they show superiority, and the company, back then, ChemoCentryx, I think decided to test for superiority in a sequential manner. First test at non-inferiority at week 26 and then 52, and then test for superiority at week 52 and then back to 26. And they were required to have a superiority signal, but I think the FDA did not really agree to GC tapering schemes, and at least that's from the published materials for the avacopan approval, where there's a section on summary of interactions with the regulators.
We don't want to be guessing too much, but obviously there was a concern between what the FDA thought should be done and what the company thought should be done. And I think one of the issues, as far as we understand it, was here, that also led to the retraction of the data, was really that there was an unblinding happening, which led to a few patients, I think nine or so, were being asked to be readjudicated. And with that readjudication, there was just about a few patients helped to make that a positive superiority signal. But as Dr. Merkel said, and I think that's very important to reiterate, Sam, is that we have no evidence, and there's no claim also from the FDA, that any raw data or any data were altered in the trial.
And that's an important point that Dr. Merkel also made, that all the other data seen, and especially the renal signals, et cetera, they're fully valid. There's no reason to believe that anything was done to the raw data. That's the one thing. And you asked, how did this inform us? Well, one of the key issues that was brought up by the FDA is they want to see effects on top of standard of care. And this is something that I think is very clear from the published interactions, and this is also clear from our interactions back then when we started development with vilobelimab, that this is something regulators want to see.
I would say the trial design we are putting in front of you right now with a placebo-controlled study is clearly informed by initial additional interactions with the regulators and with their clear wish to say, "We want to see a drug effect, not just a GC replacement." That is something that was said before, so it is all public, it is all consistent, and in a way, our current design really caters to that.
Super helpful. Thank you.
Great. We are going to go for about 10 more minutes. Again, if anyone needs to drop off, we totally understand and appreciate the extra time you have given us already. With that, we will move along quickly to Mazi Alimohamed at Oppenheimer & Company. You are now live. Sorry, Mazi, you actually need to unmute your line if you can hear me.
Yeah. Hi. Can you hear me now?
Yes.
Perfect. Thanks, Jan. Thanks for the great presentation. Okay. Thinking through the ADVOCATE renal subgroup, avacopan trailed prednisone for the first few weeks, which kind of fits with their profile of it taking a few months to reach steady state. Since kidney damage builds in those early weeks, how could izicopan's ability to reach therapeutic exposure within a week potentially change renal outcomes?
Yeah, I'd love to hear Peter Merkel's thoughts on that too, but I give you mine first. One thing we repeatedly hear from experts such as Peter Merkel and others is every day counts. Every day that you're not in remission, that the fire is not put out, you will lose nephrons in the kidney. You will probably cause damage to nerves and have other issues, like in the lungs, et cetera. If you think about a very slow-acting drug versus an extremely fast-acting drug, we would just principally predict that if you had therapeutic exposure already in the first days of pill intake, that if you believe in all the mechanisms that Professor Köhl so eloquently kind of alluded to play a role in this disease, we think that every day matters.
And that's why, Mazi, we did not only believe in our drug has a very fast onset and a good kind of plasma presence right away. We also designed the trial in a way that we have a very fast enrollment. We want the patients on the drug when they are screened and eligible as fast as possible. The entire design caters to this aspect, every day counts, if you will. And I'm happy to hand over also to Peter to-
Yeah.
I think you put it well. I mean, yeah, put the fire out as fast as possible and keep it out. I would add, this could be adjunctive even to whatever glucocorticoids are given as a standard of care. This is a different mechanism of action, so multiple mechanisms of action can be helpful. Additionally, this drug should work at the site of action, at the glomerulus or other parts of the disease outside. And that's different necessarily from how glucocorticoids work more systemically. So, I think it's really both additive and different and faster that can be very helpful. And then you maintain that. So, I think that's the goal of rapid therapy.
Thanks, Mazi. Let's go on to the next one. I think we have Ed Marks for Joey Stringer at Needham on. Joey, Ed, if you could unmute your line and ask your question.
Oh, hey, thanks. This is Joey Stringer. Thanks for taking our questions. Just to follow up on the endpoint success at week 24 in trial A. A technical question, how are you handling the multiplicity and the pooling of the 30 mg and the 60 mg dose in terms of efficacy endpoint success? Then in terms of the population for that trial, can you disclose the eGFR and UACR entry cutoffs, and can patients with an eGFR under, say, 20 enroll? Would you be stratifying patients across those arms? Thanks for taking our questions.
Yes, so thanks so much. Very good question. I'll start with the second first. Yes, we do allow very sick patients significantly under 20. So we are basically enriching by really allowing very sick patients. That is informed by some study sites where they have very severe MPA patients that we would lose if we don't allow that. We believe actually those patients give us a very good delta, so we don't have any safety concerns here treating on top of standard of care in any case, so that's why we're allowing that.
Stratification, well, there are built-in measures to allow some patients with less severe disease, but the majority will be driven by severe disease. When I say severe here, it's probably the wrong term. I mean very impacted renal patients versus less impacted renal patients. We do allow some less impacted, but the majority will be heavily impacted renal patients.
If I may just briefly add, Niels, I'm sorry, is that all these patients have to have currently active disease to be enrolled. We know that it's a dynamic process, and therefore it's more likely to respond to therapy.
Yeah. Very good point. The first part of the question was, how do we control for multiplicity? Again, this is not a fully powered study yet because we have to first understand the signal to fully power it. But we do test both groups versus placebo. So the testing regimen there, again, that's exploratory, but we'll be testing each group versus placebo, and obviously there's sensitivity analysis when you can also test both groups if both are equally. But that doesn't usually, as you know, the smaller group drives more like that drives your power. There will be not a huge difference from that, but that's something we're planning. So each group will be looked at separately. Multiplicity is not on top of our mind because the first part here is exploratory.
Great. Okay, so we're going to cover two more remaining questions very quickly. First one is with Ryan Deschner at Raymond James. Ryan, if you could unmute your line and start your question.
Hi, thanks for the question. For Dr. Merkel, which specific aspect of izicopan's profile or early datasets do you find the most exciting in the context of becoming an efficacious AAV therapy and potentially a therapy that's differentiated versus avacopan? Then for Dr. Merkel, and for Niels, how has FDA's view on the value of minimizing steroid usage in AAV evolved since the time of avacopan's approval? Thanks.
I think I will take the second one very briefly and let Niels address that more, which is, it is not clear if they have evolved. We believe glucocorticoid sparing is incredibly important and beneficial to patients. We need to work with them, the FDA, the agency, to come up with a plan where they will accept that as an outcome. Certainly, it would always be part of a trial anyway, and so you have those data to bring to the package, but I will let Niels answer that. In terms of what is hopefully better for this product or any product, I would add, is that, I mean, again, I believe in avacopan, but faster, stronger, easier, safer. I mean, all four is great. Some combination of those would be good, especially with the right data that shows the outcomes. There is potential for that here.
Yeah. To answer that too, my take to the question, what is more important? Obviously, it is much more important what Peter says than what I say because perception beats a lot. But I think the reason why we developed izicopan was that we saw that potential to have a more tightly and faster controlling, C5a receptor controlling signal. The safety was a signal that popped up later, and we just found out by doing a lot of work that we, at this point, do not have that concern, but we have not done long-term dosing. The initial development was driven by the belief we can make a drug that is faster and maybe tighter controlling the C5aR signal. Yeah. That is kind of that part. Second part, I think that with the FDA, I think right now there is also a political discussion between FDA and Amgen.
We do not want to get in between that, right? This is really something we do not want to guess about. I think it is all public, what is public. We do not have any other insights. We just know exactly what you know about it. For us, what we see is that a lot of patients and a lot of physicians hand in remarks or have handed in remarks that are public, and a lot of them, if not all of them, are saying, "My life is better, my patients' lives is better with less corticosteroids. My life has changed. I want to be on this drug. I want to remain on this drug." I think the voices, they are so clear that it is hard for the FDA not to hear the importance.
The other part I wanted to reiterate, when you think about back then, there was this legendary ad board that led in the end to the approval of the drug. Already there were very strong voices, particularly from patients, how important that is. I think we all think about, oh, well, corticosteroid sparing. I really learned that from Dr. Merkel, and I am a physician. As you know, I have treated patients with vast amount of corticosteroids on the intensive care unit. That is nothing new, and I never felt afraid about that. But when you talk to patients, which we did extensively lately from the Vasculitis Foundation, you understand the nightmare. It is really great drugs, and it is also nightmare drugs at the same time, as Dr. Merkel alluded to. I think the FDA has realized that because there is such a clear voice.
The question is, are they accepting that as an efficacy outcome? I would say that is a matter of bringing them there and discussing with them. Have they understood that this is important? I think they do, but those things take a bit of time, and maybe right now for them it is also a difficult situation because of the ongoing political discussion. That is all I have here.
They have not closed the door on it.
Yeah.
Great. Okay, one more question we have with Dev Prasad. Dev, if you could unmute your line, and we can address that very quickly.
Yes. Thank you for taking the question. I noticed the key readouts are at 24 weeks, but the treatment runs 12 months. Is the back half there to make the study registrational ready? For example, like capturing the sustained remission, relapse, and steroid exposure? Is there a scenario where phase II is expanded into a seamless phase II/III or a separate phase III still a base case? Thank you.
Yeah, very good question, Dev. I want to say yes, the key readout is week 24, but the study will be kept blinded. Study physicians and participating patients will not know which treatment arm they're in. By the time we have the data, maybe quite a number of them will have already reached week 48 here, so one year. But yeah, we're keeping that blinded on purpose to just increase the value of these datasets. Obviously, study personnel that's involved in the study conduct cannot be or will not be unblinded either, and even the study sponsor. We, the key people that are not involved in the conduct of the study, will only get data as results, and not the single patient data.
We're not unblinding on the patient level side, but certainly to a certain extent on the results side at that week 24 point, if that makes any sense. Your question was, do we do that to have a study registrational? I would say we do that to increase the quality of the overall data package, and anything else is a matter of discussion with regulators. Can we roll this over into a faster approach? I think we press released today that we're really making all efforts to think into how we can be fastest to market. We can't speak for what the FDA will or will not allow in due course. All we can say, we promise you that we're on it, and we're thinking of all, including, I would say, all reasonable ways to get to a registrational point as fast as possible.
We have, as I said, initiated interactions, and we're still in ongoing discussions with the FDA. This will be a path, but I think we feel very blessed because we see a lot of support for what we're doing with people like Dr. Merkel and globally recognized leaders in the field, with the key advisor here being Peter Merkel.
Great. Thanks, Niels. We are done with the Q&A. Niels, I'll just hand it back to you for closing remarks.
Well, all I have to say is thank you so much for listening in to our audience, and thank you so much again to our great speakers, Dr. Köhl and Dr. Merkel. I mean, this was really outstanding insights into what is going on in the field. Thank you everyone, and also for the entire team to be involved. A lot of work went into this, and I thank everyone. Have a great rest of the day.