InflaRx N.V. Aktie

Ladies and gentlemen, good morning, and thank you for standing by, and 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.

[Operator Instructions] Couple of things to note here. First, that today's call is being recorded. And 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. [Operator Instructions] So with that, I'd like to turn the call over to Niels Riedemann, CEO and Founder of Inflarex. Neils, 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 2 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 CRA in this disease. So it's really great to have Dr. Kohl with us. And 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 session here and also our development with your advice.

With me on the call, my teammates are Dr. Gabriela Alperovich, who just joined the team as Senior Vice President, Global Head of Clinical Development. Gabriela will be available for Q&A. Se's a trained nephrologist, extremely experienced in the renal disease space, development space. And of course, Tom Taapken, our Chief Financial Officer, who will be giving you some insights into external market research we very recently conducted.

Next slide, please. So we want to talk about izicopan today. The slide is not advancing. Could you advance to the next one, please? Thank you. So 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. And we are saying that because this drug has a very fast onset and a very high exposure with the potential for better efficacy. We have really within 1 week 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 this signal and in vivo head-to-head data with the marketed comparator where we show a clear increase, almost double 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. So 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, lower pill burden is what we believe we may achieve. We have a threefold increased drug strength, and that really allows us for less dosing. And on top of it, because we're not a CYP3A4 inhibitor, we may not have the same drug-drug interaction concerns, which may also have implications later.

Next slide, please. So today's takeaways upfront, we're really excited about the market opportunity. We just did external market research that indicates really a very nice $1.5 billion to $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 2 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's really something that we're honing in on and really looking for different efficacy signals, particularly in the kidney space. And then the second one that we just recently added an open-label study, an 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 aHUS, which is already in the making, where we believe we may have initial first data maybe already in 2027.

And this is exciting. We will show you some details later. And 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. And this is also expected to start and have initial readouts maybe in 2028. We do want to flag there's a Phase III study ongoing with our vilobelimab cell line-derived anti-C5a monoclonal antibody BDB-001 from our licensed 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'll 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.

And the next slide, please. So without further undo, we're excited to hear about the science behind ANCA vasculitis. And I turn this over to Professor Kohl, who is, as I mentioned, one of the key experts in the world in that. We're very excited to have you, Dr. Kohl, and please, the floor is yours.

Yes. So thank you very much, Niels. I'm 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're 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, the myeloperoxidase on the other.

And these ANCA activated neutrophils and the prime neutrophils promote eventually endothelial injury and organ inflammation. So the disease comes in different flavors. There are 3 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 about any 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. So it starts frequently with an infectious stimulus that can activate dendritic cells which 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 2 auto antigens, MPO and PR3 are -- 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. So 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.

Both 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's 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 ANCAs.

Next slide, please. So going directly into the role of complement. I want to show you today is that complement is involved in all different parts of the disease pathogenesis, priming, neutrophil activation with regards to ROS release, but also net formation and finally, also in the B cell response, which may surprise you.

Next slide. So I'm 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'm talking about human studies, you would see an icon for human. So the evidence from the animal models comes from an MPO-induced AAV model where, next please, where the [ office ] back in 2007 compared wild-type versus C5 deficient mice.

And after induction and after administration of MPO, the mice develop within a few days, [indiscernible] glomerulonephritis with albuminuria and leukocyturia and hematuria, but also with [indiscernible] nephrotic glomeruli, as you can see in the middle. But 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 and there is also deposition of C3 fragments such as [ BD ] and C3D in the glomeruli in the upper part, but not only there, but also in the small vessels in the endothelial cells.

And as you may notice on the very right, there is also some deposition of C5b29, sort 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, so 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?

So 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 very much preserved and looking almost healthy in the C5a receptor deficient mice. But you also can notice is that you see a massive influx of neutrophils and the 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, C5a receptor 1.

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. Then 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 crescentic glomerulonephritis development.

In contrast, when you look at the other C5a receptor, C5L2 or C5aR2, surprisingly, you see an opposing effect. So these mice that are lacking the second C5a receptor, they show a more severe phenotype with more -- with a higher frequency of crescentic glomeruli, showing you an opposing role of the 2 C5a receptors.

Next. So these data, clearly, demonstrate that C5a receptor to be important for the first step priming of neutrophils. But once these neutrophils are primed and the all antigens are exposed, the ANCAs drive the activation of these neutrophils. And 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. And what these also were able to show was that these ANCA IgG and only those ANCA IgG are driving ROS release or superoxide release and independent of whether you have an NPO ANCA or you have the PS3 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, and 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 1, 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 in the 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 anti-IgG and then you collect the supernatant and incubate them with normal serum, next, what you see is that only the ANCA IgG are activating complement. So what I've shown you in the cartoon above there.

And next, when you now use the serum and the supernatant from the cells stimulated with the anti-PS3 ANCAs in the presence or absence of the 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. And 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. And we and others have shown that C5a receptor itself is also able to drive [indiscernible] as we have shown, for example, in case of SARS-CoV-2 infection. Next. So in ANCA, there was an important study published in 2015, where the authors have shown that when an MPO ANCA serum is incubated with preactivated TNF preactivated neutrophils that they produce ANCA, 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 and neutralizing one, as you can see, that formation is almost completely inhibited. Next. So finally, I want to draw your attention to the B cells that produce the ANCAs. Next.

So 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 C5a receptor deficient mouse. So these naive B cells that express IgM were co-incubated with fibroblasts that were transfected with CD40 ligand and BAFF, which is soluble and survival factor to B cells. So 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.

And 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. And 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. And indeed, after 4 or 6 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. So 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. So it's not only restricted to the preclinical models, but I've also shown you some evidence for an intravenal complement-related transcriptional program in AAV patients with increased C5a receptor gene expression. And finally, for, 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, so 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, is able and drives acute kidney injury, as I have shown you. But the question is, is it also relevant for the transition to chronic kidney disease. Next. And in collaboration with colleagues in Minneapolis, we have recently figured out that in an ischemia reperfusion injury model, where you activate complement that the activation of renal tubular epithelial cells by the C5a receptor is critical for the autophagy 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 tubule-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. And now the signaling drives the macrophages more into a reparative M2 macrophage and you see a massively reduced fibrosis. Next, and finally, in collaboration with [indiscernible] in Charlesville, 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 paricytes 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, so 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 cells, tubular macrophage crosstalk under 4, which then promotes pro-fibrotic pathways and eventually results in tubular interstitial fibrosis, nephron [indiscernible] and so on.

As I've also shown you, there is a therapeutic implication because C5a receptor antagonist 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 linked tubular C5a to nephropathy and fibrosis. Next. So 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. 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.

So 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 cholangitis and microscopic cholangitis, 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, which have a whole group, a group of us internationally of how to name and define various forms of vasculitis. And today, we're talking about this group of vascular disease. But as you just heard from the previous speaker, ANCA-associated vasculitis as well includes 3 different diseases. We're going to concentrate on these 2 because EGPA or eosinophilic granulomatosis with polyangiitis really acts differently, and we're using different treatment regimens for that.

I 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'd like to talk about the big 3 or 4 that are the most common by far, and that includes the upper airway with 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. And glomerulonephritis, which is the inflammatory vasculitis in the kidneys. This is among the most feared complications, occurs in 70% to 80% of patients, and it can definitely lead to renal failure and death, and it's unfortunately very clinically silent, and so you have to be monitoring for it.

And neuropathy is very common, which leaves people with pain and dysfunction and that all of these other manifestations are present in many patients. Nobody has all of these, but most patients have several different manifestations. So what is 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.

They're still use of cyclophosphamide at times, especially for more resistant disease, and we need drugs that are safe and reduce infections. The biggest -- 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.

And 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. And 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. And 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 nondrug 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.

So new treatments are still needed. Let's talk about glucocorticoid sparing or steroid sparing. These are not the body builder steroids. This is the steroids that reduce inflammation. These are -- I refer to the -- 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. And so this is an example of a diseased kidney glomerulus is the individual units. You saw a few of these before. And what you -- 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. So renal disease or kidney disease in ANCA-associated vasculitis is a major source of morbidity and mortality. It is that what you 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 this is a very -- having -- 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, 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. So what's the standard of care? Well, 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 3 recent guidelines, the American College of Rheumatology, 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 said. We taper them down as fast as we can, but we still use moderate to high doses upfront. So I separate treatment to nonsevere and severe. Actually, most patients when they first present have severe manifestations. But there are some patients who have nonsevere, 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 know we try to get them off. It's not always possible. And we still use a drug called methotrexate, which we use a lot of in rheumatology is still the #1 drug for rheumatoid arthritis, and you can continue it. 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 in 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 3 to 6 months, and then we want to keep people there. And now that has gone on for years. And so 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 2 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 is used in some parts of the world more, it is followed by a less toxic form of immunosuppression, any of these drugs, but most of the trial data -- 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 remission and it is less toxic than cyclophosphamide. However, we certainly have patients on these other drugs for a variety of reasons. So rituximab is the mainstay of treatment. It was a major advance when we did our trials to the treatment. It is usually repeated every 6 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 6 months or 18 months or 4 years, the rate of relapse is quite high.

People relapse even on rituximab and only about 70% -- 65% to 70% of patients get into a glucocorticoid-free remission at 6 months. So 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. And so 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 2 academic leads in this program, and we voluntarily retracted the paper or asked the paper to be retracted from the New England Journal because there are some irregularities unknown to us that occurred.

There was a small number -- data from a small number of patients 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 a 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. And what we found was, again, at 26 weeks, the treatments were -- this is the [ 2019 adjudication of 2026 ]. On top, you can see that there was no difference between the 2 groups.

Now you say is that good? It is good because the patients with avacopan got no -- almost no glucocorticoids, actually, sorry, 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 glucocorticoid. Importantly, None of the secondary outcomes were affected by the problem that I agree with 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 GFR 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.

So they were -- and 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 2 of getting the complement inhibitor, the protein improved -- that protein is not good. You don't want to have protein in the urine. It improved more in the avacopan group than in the other group.

So it's a faster onset. Even more impressive was when we looked at the patients who had very severe kidney disease when they came into the trial, 50 patients, we're able to show that the patients -- both groups improved, but the group in red with the triangles was the avacopan group. They continue 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 United States, we do so with a markedly reduced dose of prednisone. And 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 United States.

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, there's -- 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 nerves or the airways, some airways get blocked off.

You want to allow for a more rapid or elimination -- rapid reduction or elimination of glucocorticoids. This is a major goal. We want to reduce hospitalization, length of stay and reduce costs. So 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 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 the cost of chronic immunosuppression for vaccine response, et cetera. Reduction or elimination of use of glucocorticoids. This is really another major goal I keep emphasizing, but especially preservation of organ function. So in summary, I'm not sure what's 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 remission of complement C5a and C5aR offers the potential for substantially improving treatment of AAV in 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 Jorg, for these great views into the disease, into the disease mechanisms and into the clinical features, but also into the role of complement, particularly C5aR. Next slide, please. So 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. So just in brief, we do -- we have already signaled that we achieved in week 1 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. So we see that very rapidly. I mentioned the type tenfold higher exposure. This is from Phase I data and compared to reported data, so not head-to-head studies. Please note.

I mentioned a very tight signal control already very early and over the first weeks of continuous dosing compared to reported data of a competitor. And then last but not least, I mentioned an animal model where we almost doubled efficacy at the same dose. So this is an interesting outlook, and we really believe we have really achieved a drug that works very fast and may provide for a 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. And even if you look in the later stage, the lower left red bars, it's still a 10x difference. I mentioned we are 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. And last but not least, we have over 197 patients and humans dosed in studies already with no real signals of safety concerns. So 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. And 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 some so far available data. We will have to test that in later-stage clinical development. I mentioned the CYP3A4 inhibitor that we are not. So 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 and the overall drug strength on the left-hand side, that shows you how much pills could be reduced in different scenarios.

So 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 when we leave the terminal pathway otherwise intact, we don't need vaccination. And that's -- and then also the projection of infection rates, which may be also, to some extent, linked to blocking the terminal pathway, which we're not blocking. So in that case, there could also be a difference.

Next slide, please. So there's an interesting modeling work that our team did that is a 3D modeling with the 2 molecules. You see in the center here, avacopan. On the right side, you see izicopan. And we introduced a trifluoromethyl group into the molecule that sounds pretrivial, if you will, but it's not. It was the basis of many years of work to lead to a 3-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 the are clashes at the part that would interact, for example, with CYP34/5 here with the heme part of that molecule. So in other words, with the structural changes in use, like 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 more metabolically stable and also have less metabolite formation in the GSH trapping assay. So next slide. Here, I would now like to hand over you for some external market considerations to our CFO, Tom. Tom, the floor is all yours.

Yes. 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 the development focus on renal vasculitis, we conducted a focused market research and interviewed 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 revolves around avacopan as a class effect that would paint 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 or 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 USD 1.65 billion according to our research. This base case is the 70% to 80% renal vasculitis population that Peter Merkel was just referring to. This will be also a base case in which we would not have any additional glucocorticoid sparing data available to show for.

And 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. Now if you translate this number of $1.65 billion, 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 $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. And we feel that with our profile, this would be still a possibility to command around $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 $1.5 billion. And 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 $1.8 billion, which, again, by adding markets like Japan and other countries would lead to a total global peak sales potential of about USD 2 billion.

So 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. So 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. So 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 like 70% to 80% of all patients anyways. And 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.

And at the same time, with B, we want to demonstrate the GC replacement opportunity with an additional Phase II open-label study. Here, we have tried to do a 2-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 BDV001, so a C5a monoclonal antibody that did just that, that could completely wait 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 are slightly different enrollment criteria. So 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. So this showcases the main the large study, the placebo-controlled study. As you can see, we have a 3-arm design, 2 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 the randomized placebo-controlled manner. And you see the darker red part is the standardized GC tapering, which will happen in all arms down to 0, in fact, we project currently about 35 patients per arm. Randomization ratio is 111. And obviously, these are patients with renal disease, renal involvement, so-called renal vasculitis. And the endpoints are -- while this is a primary safety endpoint, the key endpoints for us are B-VAS0, 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. And 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. And 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.

And you see here a 2-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 of Stage 2, where we really stop corticosteroids. Obviously, during screening, some patients are on steroids, you can stop them and enrollment in this case.

And this will be really informing us about the opportunity to reduce corticosteroids and 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 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.

So the highlights here, obviously, it's also that we are looking at endpoints. Safety is really here, including D-VA0 assessment, meaning remission. We want to reach remission rates, which are in line with expectations and with safety expectations in this area. And of course, that lays the ground for future work related to that medical need.

Next slide, please. So opportunities in additional renal disorders. Next slide, please. And yes, 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 are lots of complement inhibitors already tested. So complement plays a huge role in this chronic kidney disease.

We are envisaging here an open-label trial with Week 12 and Week 24 readouts. The dose would be izicopan 60 milligrams 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.

So this will be a key safety measure, 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. So 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 2 different -- focally for the 2 different groups. Next slide, please.

Now 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 all country of this diseases 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 this is 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. And what that is, means you want to see a normalization of the platelet count. You want to see a normalization of an enzyme or lactate dehydrogenase in plasma. This is usually released when cells are lyzed, 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, this is a primary endpoint in clinical studies that led to approval. And it means you're basically working on the disease control. And 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 don't know how much role the MAC formation plans, again, normally, our cells are protected from MAC lysis. So that shouldn't play a big role in our eyes, but we have to prove it, and we are looking forward to first results here.

So 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 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.

And 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 throwout of corticosteroids, so very meaningful for patients, and this could also inform further development for us.

Last but not least, I want to reiterate, this is our IP. This is a drug developed in-house owned by Inflarex. We have a strong balance sheet with EUR 153 million and a cash runway with all these 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. So yes, as Niels said, we can start the Q&A session. [Operator Instructions] With that said, just moving very quickly here. First question we have is with Yatin Suneja at Guggenheim.

Perfect. So this question is for Dr. Merkel, if he's still with us, so I'll ask it. So the question is around, number one, avacopan, have you -- or 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? And let's 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. But we are continuing to use avacopan. We believe not just me, but other members of our vasculitis center independently come to the same conclusion. We think the totality of the data still means -- guides us that this drug is effective and helpful for patients with ANCA-associated vasculitis. That being said, if it's taken off the market, we obviously won't be using it.

Hepatotoxicity issues are of concern. There are 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 2 weeks initially and then every month, and we continue to monitor.

So I think it is something that patients should be aware of. In terms of whether we would use it, obviously, if the drug is not available, we won't use it. If the InflaRx drug, obviously, it depends on the data. So we would -- 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 we -- 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 event if it was more convenient, if it was -- did not have any signal of hepatotoxicity. So it's really about the data. Does it work better, faster, longer, more patients on remission. So I think we learn from the data. We're good at interpreting that from the trials. So I think people are open to using a new drug.

Got it. And then one very quick question, if I may. So the company has outlined the Phase II program, 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 because 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, look, first of all, to be very clear, I am advising the company. And second of all, just to clarify, you don't -- it's not that you see a bigger effect that if you have renal impairment is that that's where those are the patients where you would see an effect. So yes, if you have a very low renal function, your delta can be a much higher percentage as you change 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.

And renal disease is the majority of patients. I think the answer is to measure it carefully, regularly and in more than one manner. So the serum creatinine leads to the measurement of eGFR, there was proteinuria, you can see as well as hematuria and even some of the biomarkers. So 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. And all of those things are built into the protocol. I think the right patients, especially for all trials, the right patients that meet the eligibility criteria, and I think we'll be very careful about that.

Next question we have is with Steve Seedhouse from Cantor.

I actually have 3. I was hoping to walk through. The first one just for the company. Regarding the steroid paper in the randomized Phase II in renal vasculitis. What specifically are you planning there? Is it the same as like the avacopan or the control arm in ADVOCATE? Or is it a different steroid taper regimen altogether?

Yes, I'm happy to take that question. Steve, thanks so much. It's actually like the standard today is derived from a study called PAxVUS, 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's still higher, but we're using the lowest recommended standard of care in all 3 arms, if that helps.

Let me just very quickly add, I was actually 1 of the 3 worldwide PIs for PEXAVAS. We definitely showed that. It's called a reduced dose, but it's certainly not low dose.

Appreciate that perspective. And 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, like on which endpoints? Is that referring specifically to EGFR or also on BVAS or anything else?

Yes. So I mean, very good question. A matter of fact, no one has done a prospective study in this patient population. So we're kind of breaking the ground here. So we need to see what we get. But clearly, we want to see a trend, if not already 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 like drug effect and also very good signal control.

So that's where one of our projections lie. And then there are repeated signals from other studies, not just from the avacopan studies, but also from the BBV1 studies that make us hope that we see this consistent signal. So 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. And so these are the 3 main parts that we are focusing on. We have 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. So 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, but also Dr. Merkel, has a strong view. So 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 that I like [indiscernible]. That's a good question. I don't think -- 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. So the patients who got avacopan got much less glucocorticoids. So if anything, you expect their renal function to have gotten -- not gotten better as quickly and to perhaps be worse.

So that's really why we're so pleased to see those results. So the only difference in 2 groups is the glucocorticoid dosing and the use of avacopan. So these data indicate that it was that strategy that allowed it. So we can't be sure that glucocorticoid tapering doesn't help your kidneys, but it seems very unlikely pathophysiologically. That answers your question?

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, right? 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. So this is one of the design element background.

Yes, that's precisely what I was getting at. And so glad to hear that answer from Dr. Merkel.

I would add one other thing, if I may, is that while 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 we will be able to see -- the company will be able to see if there are trends in other aspects of the disease as well, which we would expect.

Operator Instructions] Great. Next one is from Sam Slutsky at LifeSci Capital.

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?

Sure. I mean let me take that question. So 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 noninferiority 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 is a section on summary of interactions with the regulators. So 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 9 or so were being asked to be readjudicated. And with that readjudication, there was a -- just about a few patients helped to make that a positive p-value.

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, 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've 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. So I would say the trial design we're 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. And that's something that was said before. So it's all public, it's all consistent. And in a way, our current design really caters to that.

And so we're going to go for about 10 more minutes. Again, if anyone needs to drop off, we totally understand and appreciate the extra time you've given us already. So with that, we'll move along quickly to Mazahir Alimohamed at Oppenheimer & Company.

Okay. So thinking through the ADVOCATE renal subgroup, avacopan trailed prednisone for the first few weeks, which kind of fits with their profile, taking a few months to reach. So since kidney damage builds in those early weeks, how could izicopan ability to reach therapeutic exposure within a week potentially change renal outcomes?

Yes, I'd love to hear Peter Merkel's thoughts on that, too, but I'll give you mine first. So I mean, one thing we repeatedly hear from experts such as Peter Merkel and others is every day counts, like 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. So 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 you occur today, Professor Kohl 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 good kind of plasma presence, by the way, we also designed the trial in a way that we have a very fast enrollment. So we want the patients on the drug when they are screened and they're eligible as fast as possible. So the entire like design caters to this aspect, everyday counts, if you will. And I'm happy to hand over also to Peter to get his thoughts.

I think you put it well. I mean, yes, put the f out as fast as possible and keep it out. I would add this could be adjunctive even to whatever glucocorticoids are given as the standard of care. This is a different mechanism of action. So multiple mechanism 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 we have -- that's the goal of rapid therapy.

Let's go on to the next one. I think we have Ed Marks for Joey Stringer at Needham on.

This is [indiscernible] Stringer.

Just a follow-up on the endpoint success at week 24 in trial 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? And then in terms of the population for that trial, what are the -- can you disclose the eGFR and UACR entry cutoffs? And are you -- patients with an eGFR under, say, 20 enroll? And would you be stratifying patients across those arms?

Yes. So thanks so much. Very good question. So 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. And we believe actually those patients give us a very good delta. And so we don't have any safety concerns here treating on top of standard of care in any case.

So that's why we are 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. And when I say severe here, it's probably the wrong term. I mean very impacted renal patients versus less impacted renal patients. So we do allow some less impacted, but the majority will be heavily impacted renal patients.

If I may briefly add, Niels, sorry, is that all these patients have to have currently active disease to be enrolled. So we know this is a dynamic process, and therefore, it's more likely to respond to therapy.

Yes, very good point. And then 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 power 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 and this is 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 -- that drives the power. And so there will be not a huge difference from that. But that's something we're planning. So each group will be looked at separately. And yes, multiplicity is not on top of our mind because the first part here is exploratory.

Great. Okay. So we're going to going to cover 2 more remaining questions very quickly. First one is with Ryan Deschner at Raymond James.

Thanks for the question. For Dr. Merkel, which specific aspect of the izicopan's profile or early data sets do you find the most exciting in the context of becoming an efficacious AAV therapy and potentially a therapy that's differentiated versus avacopan? And then for Dr. Merkel and for Neils, how has FDA's view on the value of minimizing steroid usage in AAV evolved since the time of avacopan's approval?

I think I'll take the second one very brief and let Neil address that more, which is it's not clear if they 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'll let Niels answer that. In terms of what's 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 4 are great. Some combination of those would be good, especially with the right data that shows the outcomes. So there's potential for that here.

So yes, so to answer that 2, my take to the question, what is more important. Obviously, it's much more important what Peter said 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, don't have that concern, but we haven't done long-term dosing.

So the initial development was driven by the belief we can make a drug that is faster and maybe tighter controlling the C5aR signal. Yes. So that's kind of that part. Second part, like I think that the -- like with the FDA, I think there's -- right now, there's also like a political discussion between FDA and Amgen. We don't want to get in between that, right?

This is really something we don't want to guess about. I think it's all public, what's public. We don't have any other insights. This is just -- we just know exactly what you know about it. And so 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 patient's life is better with less corticosteroids.

My life has changed. I want to be on this drug. I want to remain on this drug. So I think the voices, they are so clear that it's hard for the FDA not to hear the importance. And the other part I want 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.

And I think we all think about corticosteroid sparing. I really learned that from Dr. Merkel and I really -- I'm a physician. As you know, I've treated patients with a vast amount of corticosteroids on the intensive care unit. That's 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's really great drugs, and it's also nightmare drugs at the same time, as Dr. Merkel alluded to.

And so I think the FDA has realized that because there's such a clear voice. The question is, are they accepting that as an efficacy outcome? I would say that's a matter of bringing them there and discussing with them. But 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's also a difficult situation because of the ongoing political discussions. So that's all I have here.

They haven't closed the door on it.

Great. Okay. One more question we have with Dev Prasad. [Operator Instructions]

So I noticed 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? And is there a scenario where Phase II is expanded into a seamless Phase II/III or a separate Phase III still a base case?

Yes, very good question, Dev. And I want to say, yes, the key readout is week 24, but we -- the study will be kept blinded. So study physicians and participating patients will not know which treatment arm they're in, while -- and by the time we have the data, maybe quite a number of them will have already reached week 48 years or 1 year. But yes, we're keeping that blinded on purpose to just increase the value of these data sets.

Obviously, study personnel that's involved in the study conduct cannot be or will not be unblinded either. And even the study sponsor, so we, the key people that are not involved in the conduct of the study will only get data as results and not a single patient data. So 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? So 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 are thinking of all, including, I would say, all reasonable ways to get to a registrational point as fast as possible. And we have, as I said, initiated actions, and we're still in ongoing discussions with the FDA. So 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 adviser here being Peter Merkel.

Great. Thanks, Niels. We are done with the Q&A. So Niels, I'll 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. Kohl and Dr. Merkel. I mean this was really outstanding insights into what's going on in the field. And 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.

Good morning, everyone. Thank you for standing by, and thank you for joining our conference call this morning to discuss our recently announced effort to pursue izicopan for AAV and other renal diseases. [Operator Instructions] Please note that today's call is also being recorded. [Operator Instructions] I would now like to turn the call over to Niels Riedemann, CEO and Founder of InflaRx. Niels, please go ahead.

Thank you, Jan. Ladies and gentlemen, good morning, and thanks for listening in. It is our pleasure to be sharing with you our recent prioritization here on the renal space, particularly in the ANCA-associated vasculitis. So may I please ask to forward to first slides. Please take note of the important notice and disclaimers. We will be making forward-looking statements. We are a public-listed company. So I appreciate your taking note.

Next slide, please. So we're excited about our new molecule izicopan which is an oral inhibitor of the C5a receptor Kibana really. It's a C5a/C5aR pathway is a critical driver of inflammatory cascade, both angles, C5a ligand and its main receptor C5aR, both validated targets from a clinical, both and the regulatory and commercial perspective also in ANCA-associated vasculitis. So there's promising clinical data with C5a antibodies, vilobelimab and [ PDB1 ] as well in the sense of ANCA-associated vasculitis that I want to flag here.

So this -- the recent regulatory scrutiny are related to a marketed comparator, our copartners provided InflaRx with a clear and present opportunity with its next-generation C5aR inhibitor, izicopan. So we believe that we have improved significantly on certain shortcomings, if you will, or certain areas where improvement could take place with our molecular, izicopan, and we believe it has best-in-class potential for mainly 3 reasons. We have a very fast onset of action, and that needs to coverage of the receptor right away as far as our PK/PD analysis goes in humans. So far, we have a very clean safety profile, no detected safety signals of concern, and we have properties that make drug-drug interactions and particularly potentially liver tox less likely, and we will go into this a little bit. And we also have potentially more convenient dosing, but also the possibility to still to go to once daily dosing.

So we're excited because this molecule can address different markets and potentially here, first, the ANCA-associated vasculitis market, which is currently believed to be $1.3 billion peak sales estimate and given our properties, maybe we can expand on this market even. We see use of this particular molecule across the broader I&I space, but particularly also in the renal arena particularly in aHUS, IgAN, C3 glomerulopathy and some others. And we are also intending to provide first proof of concept in due course here in these indications. So we have a strong IP position. This is our molecule, composition matter is issued, and we have really an issue situation already in various jurisdictions, particularly in the U.S. and Europe and other areas.

Next slide, please. So before we go into it, just as a short reminder, because we oftentimes get the question, why don't we just take upstream complement inhibitors. You are all well aware that there are very successful molecules in the complement world on the level of C5 inhibitors, C3 inhibitors, factor B and others. And one of the reasons really is that there's different ways to generate C5a. There is a path from the complement pathways, but there's also a direct leverage mechanism through all sorts of enzymes that are present in various inflammatory diseases. And that these envelopes directly outside the reach of the mechanisms of these other drugs. So you can generate full-length biologically active C5a to large amount even in the presence of these inhibitors in human blood. We've shown and in published this. Therefore, if you believe the great body of work of over 6,000 publications on clinical -- preclinical research around the C5a receptor and the ligand C5a to be meaningful in the I&I space, you may appreciate that a target inhibition is really what you need to control the pathway.

That brings us to izicopan, our oral C5aR inhibitor, which may be applicable in multiple inflammatory indications and which has shown a very good control over the signaling pathway here in its first Phase I studies and also in the Phase IIa study.

Next slide, please. So I want to come back to the point of the best-in-class -- potential best-in-class properties of izicopan. And I want to slot this into 3 areas, particularly. So we designed this molecule to give us a different plasma presence from the one reported for the marketed comparator. You see on the upper right side, our -- in blue, our human PK data from the Phase I study. And please note, it's not a head-to-head study with avacopan. This is just a reported Phase I data from a plotted in this graph, but it gives you a visual that at 30 mg, which is the approved dose BID for avacopan, if you take a single shot of 30 mg and compare it to izicopan 30 mg, you see this as the order line above it, you already have a 10x area under the curve increase in PK and a higher peak, 3x higher peak and just a very different plasma presence.

And why is this important? Because we believe this reads through to receptor coverage and speed of onset of action, and we have various data to support this belief. And particularly, we also are able with our formulation to updose very highly up to 240 mg, you see here, safely without safety signals of concern. And that may be important to explore the full bandwidth of efficacy if you think of tissue presence of this because remember, PK and PD so far in complements mostly measured in the plasma influx.

So that was our starting point, but we quickly learn that our molecule is very differentiated on other areas as well, particularly potentially to improve safety profile. So far, we have over 180 humans exposed and a very clean GLP toxicology study package, including 9 months nonhuman primates. We also have done studies to further characterize the molecule in seen that deliver enzyme CYP3A4, which is important to clear and metabolize chemical drugs like avacopan and our own drug, but also like other drugs, including corticosteroids, may be inhibited by certain drugs particularly within the label of avacopan as a time-dependent inhibitor. And we have recently shown that we are not a time-dependent inhibitor, in fact, we have explored this to very high concentrations and believe that we are not inhibitor of this mechanism.

We also show a differentiated profile in metabolic stability. So all these indicates that we have a molecule that may not have the liver tox issues that are in the label in our market comparative. And we also may have a dosing advantage. We have 30 mg per capsule as opposed to 10 mg for the comparator. And we still see the potential for once-daily dosing according to our current modeling of our Phase IIa data that we recently got. So we're really excited about this differentiation last but not least, from a patient's perspective on the lower right corner, you see again, this was not a head-to-head study. This is just plotted in the graph. These are the data that avacopan approval data in ANCA-associated vasculitis, where it's mentioned that it takes 30 weeks to reach steady state. And you see here some data from our early Phase IIa study, different diseases in HS, hidradenitis suppurativa and in CSU, chronic spontaneous urticaria. But you see that we tested 60 mg BID, 90 and 120 in these studies. And already at 60 mg BID, we have a multiple of that plasma presence right off the bat. So we believe that we may have a faster onset of action with our drug.

Next slide, please. So I want to speak now a bit about ANCA-associated vasculitis. Next slide, please. This is a rare disease that typically is an auto inflammatory -- autoimmune style disease. There are certain antibodies directed against neutrophil features that excite these cells and other cells, but particularly when finding these neutrophils, they involve various orders because they involve the endothelial cells in the vasculature which can affect all organs on the right side you see typically most affected all in the renal is the kidney. So you see here that the glomeruli in the row A, B, C and also the small vessels G, H and F for complement factors. So complement is activated in the kidney and that drives, but also in the vasculature of all organs and that can drive damage.

The [ orphan drug ] market. I mentioned already that it has a large market potential. We also want to just mention that there are different subtypes that tax that usually studied in multicenter studies are called MPA and GPA. There are certain differences between these 2, but I want to -- in the interest of time, not go into that detail right now. However, the current treatment medical needs are clear, there is an induction of remission treatment that usually entails either [ psychophosphamide or rituximab ] in combination with very high-dose corticosteroid treatment. This is a very toxic treatment for the patients. The patients suffered dramatically from the corticosteroid use, and there is a high unmet need to get the patients as fast as possible in remission and of the rather toxic high-dose corticosteroid drugs. And then there's also a remission or a maintenance therapy, which is usually done with rituximab and which is unit then initiated. There are also some other drugs that are usable according to standard of care that is usually initiated after you achieve remission.

Next slide, please. So the next slide, please. The mechanism just one back, please. Thank you. So the mechanism here is very interesting and included both C5 and C5a receptor. I mentioned these antibodies you see there on the right lower corner, that are directed against features of the neutrophil and actually excite complement right on the surface of the neutrophil, which is covered with C5a receptors and get that immediately excited puts out oxilate [ radicals ] enzymes undergoes [ nephrosis ], induces vascular damage really that can enter a vicious circle because with the damage, there's a lot of coagulation initiated and microangiopathy happens so to speak, and more C5a is released because of these mechanisms and because of these enzymatic activations that I mentioned earlier. So that's the vicious cycle. And clearly, C5a and C5aR are believed to be drivers of the disease.

Next slide, please. So let's look at the market a little bit together. Indeed, I mentioned that the global market for [ TAVNEOS ], avacopan, our marketed comparator have been suggested to be roughly $1.3 billion at peak sales. You see a graph on the right side. And I want to mention that the mechanism of action has been well established in major markets. When you think about what U.S. physicians think there was a recent survey about from 21 U.S. treating physicians that treat a lot of ANCA patients in -- they typically like the C5aR inhibition and initiated treatment during the major flare phase and then continue treatment for 6 to up to 48 months. And the real reason why they give the drug according to the survey is almost all of them say for glucocorticoid reduction, I mentioned that need already, but also some mention for renal function preservation and generally for all in preservation.

There are concerns about the tox profile and some recent reported liver tox issues. But also physicians say that they monitor for it, and it is decently under control, at least comes from the U.S., and we've heard similar from European physicians. When asked for product X with our profile, they see a potential strong share from new AAV patients, but also some switching promoted in the year that they believe that currently, they treat roughly about 15% and mean it could go up to 55% and then up to almost half, 45% here may also switch over.

So this is highly encouraging for our product development and next slide, please. So how do we get there? What's the -- we call it the rock to boat scenario. So how would the label look like? Ideally, you would like to have a steroid reducing a rapid taper enable. So that's part of your label, which is not currently the case for our competitor. And ideally, you demonstrate early benefit, early reduction of proteinuria and improvements in eGFR, both signals were present for avacopan I should mention and then also potentially improve the time to remission. That's something that we believe our drug may show. Additionally, of course, ideally, a clean label, ideally no liver tox on the label. And then last but not least, convenience, lower capture intake or even once daily dosing. You see corn here how important steroids reduction is for certain physicians.

This was an interview from an external research we conducted. On the right side, so the overall development role is like trying to increase the signal data to placebo, especially during the early major flare phase. Now how do you get that done from a study design aspect? You want to enroll patients fast. You don't want to mandatorily taper them down to a certain level, which was previously done in studies, which kind of preselected a bit better patients because they were already out of the out of maybe out of -- or to a certain extent, already doing better. And then you can enrich for patients that have severe renal impairment. We got that recommendation from various experts in the field. They believe that you can go early and go to very severely real impaired patients. Obviously, another idea would be to fix the remission induction to rituximab in combination with corticosteroids. And I mentioned also, of course, you would like to have an aggressive rapid steroid taper paper in your treatment arms to demonstrate that you can do that.

Next slide, please. This is really presumably the current planning stage of a Phase II trial. We have a base case scenario in which we do a Phase II or we call it Phase IIb trial, but the 2 trial followed by a Phase II much like the development path that [ ChemoCentryx ] back then did with avacopan, however, we are putting the studies, if you will, together, but we're also trying to rein some of the feedback that we gathered from earlier interactions between [ ChemoCentryx ] and the agencies, particularly the FDA, as this was published in the approval documents.

So you see here placebo standard of care arm with a general standard GC tapering approach, GC stands for glucocorticoids and then a drug approach instead of placebo with the exact same underlying treatment to establish signals of efficacy. And then the third arm would then just go to rapid taper to say that when you're at the taper, you do not differentiate from the signal that you have detected in arm 2. Now this will be a 26-month week readout because we won a 6-month endpoint for the renal endpoint of eGFR. We may or may not go to 52 weeks and to treat out to get more data, but the unblinding would take place after week 26.

As far as endpoints, the first Phase II is a safety endpoint descriptive nonpriority for BVAS 0, BVAS the score used, Birmingham vasculitis activity score, used to see if you get into remission and when it's at 0. But we also want to really focus our secondary efficacy on the early criteria. We believe there's good reasons to believe that there's a good delta early. This was visible with treatments on C5a reduction inhibition just as much as the avacopan at week 4. We will look at eGFR, a signal of renal function at week 26, and we also invested time to remission time to BVAS 0, amongst other secondary incomes.

Next slide, please. So once we selected that and assuming that the efficacy determined comes with or without the rapid steroid tapering, we would then go to Phase III approach just very similar to what you would be familiar with from the approval trial, except again, we would probably adjust according to the signals detected in the first trial. So there's a scenario on where we go to a noninferiority on BVAS, paired with a superiority, which could be different. In this case, for example, eGFR be it 26 or 52 or time to BVAS 0. And scenario 2 would be to directly power for superiority if any of the end points allowed to do so. So that will be determined only when we have the data. Currently, the planning is that will be roughly 150 to 170 patients per arm. Obviously, that needs to be adjusted once we have data and do a statistical planning.

Just as a rough idea, the Phase II study is what we have here currently fully financed. We see the financing reading through 2029 right now. So we believe we cover -- we will cover the readout of that Phase II study that I introduced to you in the slide before.

Next slide, please. So there's also an aggressive approach, if you will. We also plan to go to the FDA given the recent environment, regulatory environment to see if there is a more expedited path with this new drug. Now we can't promise, but we certainly want to make a push. We have certain ideas how to do a seamless Phase II/III registrational trial approach. Obviously, that would entail going back with some data after the Phase II part to the FDA. But if the FDA, the agency was amenable to it, we would certainly try to discuss this with them and potentially that could reduce the time to commercial market significantly.

Next slide, please. So last but not least, I want to share with you a bit of the excitement around the real indications that we will also investigate in a more open label fast fashion so that we have data to come as early maybe as next year and in the next couple of years before the ANCA vasculitis readout.

Next slide, please. We are particularly focused on 3 renal indications, and we have a network that includes center s that are very, very familiar with these indications and with complement inhibitors in this indication. I want to speak very briefly. You don't have to go to go through the entire slide, but why have we selected aHUS, IgAN and C3G. Now all 3 have in common that there is an approvable accepted endpoint, which is more or less a biomarker endpoint. I will explain to you the TMA response for aHUS in a second. But you probably are familiar with the surrogate marker protein urea reduction in IgAN as well as in C3G, both will be then followed by -- with an eGFR stabilization as confirmatory endpoint. So that's an interesting environment because proteinuria reduction is something that was seen in these indications also with avacopan before, and I will show you the data in a minute. And in aHUS, that is actually a relatively rapid response that you could already men early and we sure that, too.

So all 3 indications have an interesting biomarker approval that has been at least in IgAN and C3G have shown to be present in early studies with avacopan. And in all 3 indications, there are complement inhibitors already improved. However, we may see a big advantage to have a drug that you don't need vaccination with because we don't inhibit the membrane a tech complex, the arm of the component system that if you block it, can cause serious infections, including meningococcal and meningitis. And we have an oral drug that may be an advantage on some of these indications. And so let's look into it real quick together.

The next slide, please. So aHUS, atypical hemolytic uremic syndrome. Next slide please, is an interesting indication. You know that this was one of the first indications were Alexion's drugs, [ Soliris and now Ultomiris ] have seeked approval with this TMA response, you find that definition below that, that means you normalize the platelet count, you normalize the serum LDH levels and you improved the serum creatinine by 25%. If you reach all 3, you call the TMA responder, and these are small open-label trials that have led to approval based on this end point of these complement inhibitors. Now some say, okay, is there really -- these are actually pretty interesting large markets, given the high price in this real life threatening disease.

However, next slide, please, you may argue, well, isn't that a MEK-driven disease, which is in the front of minds of some people we've spoken to. However, Well, the answer from us is, well, that's not really entirely clear if it's a MEK or a C5a-driven disease or if it's maybe even predominantly see C5a-driven disease. Why are we saying that? Now there experiments done with avacopan on the right side, you see that they use treated patients with aHUS and use the serum before treatment and after to excite platelet endothelial cells. And then they saw when you excite these cells and then you let blood flow over, you all a sudden see platelet aggregation, which is one of the hallmarks of the disease. Except when you do that with the treated serum, you see that also below in the graph, you're almost back to normal levels. So the red bar is basically control where you don't excite these cells. The bar in the middle is the one where you give the serum of the sick patients that actually leads to platelet aggregation and then the one with the treated serum. Now we have -- and on the right side, sorry, I should have said that, the MAC formation is not affected.

Now we have confirmed this with very similar experiments with our antibody, vilobelimab that blocks the ligand C5a and with our new molecule, izicopan, the oral C5a/C5aR inhibitor. And so we believe that C5a/C5aR seasonal may actually be 1 of the key drivers of vascular damage in this disease. And we would love to test this because we can test as relatively early. And if successful, we could potentially introduce later an oral drug into this space, which doesn't need vaccination.

Next slide, please. IgAN, next slide, please, is rare or a pretty large rare disease, if you will. So there are quite a few patients for being a rare disease. It's one of the larger renal diseases. And this is also a disease which involves the kidney and complement activation, in this case, also an antibody-mediated industry. So without going into all details, there are complement inhibitors, one is approved, which is the factor B inhibitor. It's an oral inhibitor, which has shown proteinuria reduction followed by eGFR improvement. And very recently, just a couple of weeks ago, Alexion's trial, AstraZeneca trial, the readout with [ ULTOMIRIS ] with the anti-C5 antibody and also shows a significant proteinuria reduction, which was a Phase III clinical study.

Next slide. Now with our drug work, we believe there's a good chance. Why would we believe that? Because avacopan was tested in this disease. You see here, these are just 7 patients preselected went into the short-term treatment of only 3 months, but you see in the center graph that proteinuria measured by urinary protein creatinine ratio greatly reduced for being such a small patient group. So certainly, they look like a signal that's kicking in after about 8 weeks of treatment, and also, there were signals of less inflammatory markers in the kidney in the urine, I should say. So clearly, early signals, but in line with the role of complement and very encouraging to test this further.

Next slide, please. So we come to the last indication, with C3 glomerulopathy. C3G, nex slide, clearly another complement-driven renal disease. In this case, slightly different mechanism, like predominantly involving the alternative parts, but in the end, usually, all parties are excited through that. And again, an interesting case, this is a more rare but also very interesting disease with a very high unmet medical need. And here, you know that the former [indiscernible] drug, [indiscernible], was approved for proteinuria reduction followed by eGFR improvement. So also the role of complement well established.

The next slide, please. Now would the C5aR inhibitor approach work? There are early signals of efficacy, again, generated back then with avacopan. This was a trial of actually 22 patients for each group, so not even that small for being such a rare disease. And again, you see a nice separation between the placebo and the treatment curve on UPCR, so on proteinuria. And also you see the eGFR differentiation after time of treatment, which is typically 26 weeks. The first time where you see it better.

So there is a common thread, next slide, please. There's a common thread in these indications where complement inibitors are improved, where the regulatory pathway is clearly established on signals that have been seen with C5aR inhibition. So we're very excited to test this and to put up a study in which we can improve early growth concept to maybe then roll out into more serious development should we see a good signal. We think that can be done relatively fast and cost efficient, and this is what we are planning here to do going forward. Again, I mentioned we have an expertise in that work last but not least with these clear endpoints and the differentiation of our molecule, this could be a very interesting expansion into the renal disease.

So last but not least, next slide, I want to also talk about hidradenitis suppurativa. I'm excited. We have guided the market that we would have interesting discussions with the FDA, and I'm happy to say that because we had an interesting Phase II readout that we hold a biological like activity just in 4 weeks of treatment, the pretty deep reduction of draining tunnels and significant improvement in pain. We went back to the FDA and concluded our discussions, and we think we majorly move with the agency over the years. So they acknowledge the importance of draining tunnel as a major contributor to HS disease, which is really a big thing that changed the position there and is supportive of a new endpoint in HS, the so-called hidradenitis clinical response score, which could be validated in the Phase IIb trial and potentially used as a new primary endpoint of pivotal trials.

Now why do we suggest that this would be the first endpoint that actually includes in a meaningful manner, the DT reduction, draining tunnel reduction into an endpoint and thereby we hope and we believe it may help to control placebo response rates much better than the old endpoint, given you need, of course, have a drug that meaningfully moves all lesions, including particularly the draining tunnels. And you can see the details. So we see this as a potential great potential for the future. We would, at this point, only develop this further with the collaborator. But we believe that this field needs new drugs with new mechanisms and we believe that could be an interesting path forward. So we wanted to not withhold this from you guys to make sure that we did progress that quite well. So this remains a potential future upside but cannot be our current focus of development.

With that, I'm really thankful for your attention. We conclude the presentation session, and I will hand over now to Jan for the Q&A session. Thank you.

Thanks, Niels. So yes, we'll have about 15 minutes here for the Q&A session. [Operator Instructions] So we have our first question from Yatin Suneja at Guggenheim.

Yes, can you guys hear me?

Yes.

Perfect. Guys, thank you so much for taking the question, very nice presentation and the overview. So I have a couple, if you could sort of address them. So number one, on avacopan front, right? So there are basically 2 debates. One is on the safety. The second one is on the efficacy. So the question, and I know now you sort of touched on it, but if you can maybe frame for us what gives you confidence that the talks that avacopan has is a compound-specific issue not a class-specific issue, and you do not get that, right? So that's one part. The second part is also on the efficacy. And I think there is some debate if we read a little bit about it that maybe the efficacy is under question. So can you maybe put in perspective in terms of what we have seen on the efficacy front with this mechanism across a number of renal indication like what exactly, because when we talk to nephrologists or rheumatology, the reason they really like avacopan is the data on kidney protection or organ protection, which we don't see it on the label. So I'd love for you to sort of put these things in perspective. And then I have a follow-up after that.

All right. Thanks. Very, very good questions. Thanks, Yatin. We appreciate that. Yes. So let me start with your liver tox question. So we've done a lot of work on our molecule and try to understand where the differences lie. I Mentioned the CYP3A4 inhibition which were not a time-dependent inhibitor. We believe this is very important because this pathway metabolizes a lot of drugs, including our drug, and it's also one of the metabolic pathways on how avacopan and its potential metabolized may get to metabolized. So in a way, if you time dependently start inhibiting this mechanism, you may slow down the metabolization of certain drugs, but also maybe of your own metabolize.

So we -- aside from this clear differentiation on CYP3A4, we also looked at metabolic stability. Obviously, these are all preclinical assays that are managed to scout, whether you fall into certain higher or lower level of concern, so to speak, and all chemical drugs can be in these categories. And we've seen a very strong difference in metabolic stability in, for example, the GSH [ trapping ] studies that we recently done had ahead with avacopan's molecule. So there's really an initial big differentiation, which stays over time and like in several orders at the beginning and over the entire time in an order of magnitude when it comes to, like, in this case, the active metabolite formation in this assay. We've done also other metabolic assays in liver microsomes to understand this depreciation. So we came out with the conclusion that our drug, which is very different on the 3-dimensional layer. It has 3 [indiscernible] centers. It is -- it is an amorphous drug and not crystal in a steady state. So it is quite a differentiated drug, but particularly, it's pretty stable in these metabolic assays.

So this, including that we have over 108 patients already with very high doses tested, granted only up to 4 weeks, but without any signals of safety concern with no enzyme and GOG GPT elevations in the liver that were AEs or [indiscernible] none of this occurred, plus the fact that we have all this differentiating mechanistic data in the preclinical studies and a very clean overall tox package. We can only say that until today, we have no reasons to believe that we have this concern. That's where our confidence comes from.

Now there's no reason to believe that this is an effect of C5a/C5aR pathway inhibition. We have never seen this with our highly potent antibody blocking the ligand. There is like a myriad of research on different C5aR blocking molecules preclinically that actually have been shown to be all in protective in certain diseases, particularly also the liver. So really, there is no reason to believe there's a class effect. We rather believe that this has to do with the molecules themselves and they go into a liver tox signal. So I hope that covers it from all angles that we can cover today.

To your second question, is the efficacy question. Yes, there were some questions around that. So I would like to start by the data that I showed you here at the end of my presentation. So very consistently avacopan has shown that it had effect on proteinuria on eGFR improvement on the renal side of the game. So I would argue that this was also present, by the way, in the ANCA vasculitis study. And even though there is regulatory scrutiny around the molecule, and we cannot speak about the details of these ongoing scrutiny situation with the FDA. But from all we understand is that these efficacy signals, they're all there and they're all real, right?

Our understanding is that there is a debate around how BVAS was adjudicated at the end of the 52 weeks. So from our understanding, there are various efficacy signals that came out of the study with avacopan. Now we believe we can build on them. We may be able to engage patients earlier, go to more severe renal patients to make these efficacy signals with a faster, potentially faster acting drug more visible. So I hope that covers it. Would we necessarily power for superiority on BVAS at week 52? That's a very tough game as far as we believe that avacopan was tested but not powered for superiority [ as ] that endpoint. So that's a matter of finding the right angle with the FDA how to approach this. But we do believe there are various signals, valid signals of efficacy of avacopan in ANCA vasculitis, and we want to build on them. it.

And then just a quick one. How could you use China as a region to generate data maybe on a faster pace across the indications that you're pursuing?

Yes, thank you very much. That's a very good question. So in the recent years, there are certain areas that have been explored by larger companies like companies like Novartis, AstraZeneca, Alexion and others in the renal space as far as I believe also Roche and others that involve the renal space in China, there is a network that we know very well. We're very well connected to that network and to Professor Zhou, Z-H-O-U, that runs this network in Beijing and Shanghai that can lead to very fast enrollment. The reason why we're knowing so well through our contact there, but we also we developed our BDD001 license molecule that is the vilobelimab IV antibody targeting the ligand licensed to a Chinese partner. And they are in Phase III development. They did a very rapid 100-patient Phase II development within this network. So we know that the enrollment speed can be dramatic there. which we believe we can explore.

Obviously, we would not just enroll patients in China, but we could certainly make like benefit from this amazing network that has ample experience not just in ANCA vasculitis ancovusculitis, but also the 3 other indications we mentioned here. So we really try to exploit that speed factor to get faster to data. But I mentioned, we cannot just go to China, so we'll also want to look at Caucasian patients, of course, in other regions.

Great. And then I think just reiterate a bit on the other renal indications we talked about, we think we can start showing some data next year on the IgAN, aHUS and CG3 [ in ] one or more of those next year.

Okay. So in the -- moving on quickly, I want a couple of questions we have that were submitted to us in writing. The first one is from Sam Slutsky at LifeSci Capital asking that based on your PK/PD data, what go-forward dose do you envision using for AAV?

Yes. Thanks for this question. So Sam, good question. So we have not fully concluded this. So this has been taken with a certain care. We have explored so far 60, 90 and 120 mg BID in other indications, right? 120 mg is a bit on the high side, but we tested the drug in the skin disease hidradenitis suppurativa, which usually like meets a lot of truck levels to show these lesions improve. So our current data model suggests that we could move with 60 mg BID. Again, we cannot finally fix it today because we also are looking into switching this to cut and how we best switch it. Our modeling data suggests we can do that. not right off the bat. So expect us to have, at least maybe during the early treatment in the remission phase to the BID, but then potentially switching to [ QD ].

Great. We have another question that was submitted early on, just wanting you to talk about -- also talk about the market potential we see for izicopan in AAV and perhaps also in these other renal diseases that we'll be looking at.

Yes. So I'll start with AAV. I mentioned there are 2 reports. One is actually from Yatin Suneja and then the other one, I showed the market research suggesting that the peak sales of [ TAVNEOS' ] avacopan could be clearly north of $1 billion, maybe up to $1.3 billion. Now we are very encouraged by talking to physicians, and you saw the survey from Sam Slutsky from LifeSci of U.S. physics that currently, they don't have the majority of paints are not on these drugs. So there's a large potential to either put them on the drugs more with maybe a differentiated label or less concerns. So we think that with the profile our drug has, this opportunity could be expanded beyond the $1.3 billion. We can't say how much. We're just saying the initial research suggests that there's space to really expand on it. And that's what excites us.

Now on the other renal indications, these are all interesting indications. IgAN is a relatively competitive field, but pretty large markets. So these are certainly really interesting indications as well. aHUS is at a high price point, but it is also in a very large selling indication for rare disease last. And then I think C3G is not fully built out yet. So we don't fully know how large it is. But all of these are believed to be up to above $1 billion by various players. So we're excited because of the profile, and we'll try to capitalize on building it out in the renal space here.

Great. We have 3 questions in the line. I think if we then pretty quickly, we can do them before the time. First one is from Timur at Cantor.

This is Timur on for Steve. So just to follow up on something you mentioned earlier about Phase III design I think the FDA was previously fairly insistent on superiority on sustained remission of sustained remission. So why do you think the FDA would think different by now? And when do you expect to discuss this design with the FDA?

Yes. Thank you, Timur. Yes, absolutely. We want to discuss this relatively soon also to maybe ask for, as I mentioned, for a more seamless approach. We'll see how flexible FDA will be. But just to correct you slightly, they did not insist on that endpoint. They made several suggestions for alternative endpoints, at least from the published documents, including, for example, time to BVAS 0, time to remission and others. So I don't think they were insisting on it, but this is the -- what -- in my understanding, back then, ChemoCentryx came back with to say this is a noninferiority study, but we will test for superiority at week 52. At least this is the order of events that I recall from reading through this very carefully. So there was space to discuss different end points with the FDA.

Great. Let's go quickly to Ryan Deschner. Ryan?

Two questions from me. One, how big of a factor at this point is the potential for avacopan to be forced from the market by regulators? Is it more nice to have or critical? How are you thinking about that as a base case?

Ryan, I may have misunderstood you what potential did you completely refer to? Sorry.

The potential of avacopan being forced [ out of the ] market by regulators?

Okay. Sorry. Yes, it's hard for me to speak. I don't want to speak on behalf of another company. I mean, they made a huge effort to bring this mechanism to ANCA vasculitis patients that really, as far as we understand, suffer dramatically from the current induction remission therapy. I think the language that the FDA used was very harsh. And for all we understand is that what may have happened is according to what was filed by the FDA is that there was no raw data manipulation, but a change on how the BVAS 0 was assessed. Now from my understanding is that had occurred before unblinding that would have probably been okay. but it didn't. So that's probably where the FDA hung up. But again, that's purely my interpretation. I don't want to speak on behalf of any other companies. So I can't say how the likely it is. We just noticed that the language is very harsh.

Is there a program that you're launching is contingent upon avacopan being pulled from the market?

That's a really good question, Ryan. Thanks for that -- definitely not. We discussed this at length with our experts, and we looked at market research. We conducted market research previously ourselves. We are only moving here because we see such a competitive advantage, whether or not the other drug gets pulled, right? We see the drug being decently differentiated. We have an idea how to work this out in clinical trials. And we think we can excite people that are even used to the mechanism with this drug. So we are not contingent on that decision.

Got it. And what gives you the most confidence, I guess, on the efficacy side that you were discussing read-through in terms of avacopan is it what was seen in the clinical trials from that developer? Or is it more the real-world sort of uptake and response from physicians on avacopan?

I think really good question. I think really both, but I want to reiterate that the signal that was there, particularly on proteinuria in the early time point, the reversal of the kidney injury that occurs in a major fare was present also in the Phase II study and in the Phase II whenever the drug was in there. So it's a very consistent signal and I've shown you that is a signal presence in other diseases as well. So the organ preservation by coming in early and helping the patients with this mechanism is a signal that is pretty valid followed by EGFR also in the ADVOCATE study. So I would actually argue that the drug shows efficacy in the disease, clearly, maybe we can improve on it. That's our goal with a potentially better profile block. But we are encouraged by this.

Secondly, when we speak to experts and also the research I mentioned, there's really excitement around the mechanism. It's well established. Yes, of course, no one wants to see any tox signals, no one -- ideally, you always have everything clean, but the people use the drug. Nevertheless, they want to reduce corticosteroids even though that's not in the label, but the trial showed that they reduced the intake at least. And so we are encouraged by both, really. We think there are clear efficacy signals that we can potentially improve on. And we believe there is excitement and acceptance of the mechanism in the market already established. So this really prompted us to switch and to really focus on this development here with this opportunity.

And Niels, I think we have time for one more question from Mazahir at Oppenheimer.

So I guess just to -- the first one was really kind of around the opportunity. So kind of given that the agencies proposed withdrawal of avacopan, and I guess, obviously, the clear unmet need that would create. Do you believe that there could be like a credible case here for breakthrough therapy designation? And also, I guess, secondly, like in terms of the FDA interactions and the expedited time line, could you kind of just help us understand what we could expect an update on that conversation? And then secondly is kind of thinking about trial enrollment. And so given -- this is -- regardless of whether avacopan was pulled or not, but just given the uncertainty created, do you think that -- or I guess, maybe refresh, are you seeing any early signals from any nephrologists, rheumatologists about an increased willingness to enroll patients? Have you had any preliminary site activation conversations? and I guess lastly, do you anticipate the current competitive vacuum, I guess, accelerating your enrollment time line? Or could potentially accelerate your enrollment time line?

Yes. Great question. So I'll start with the second first, Mazahir. We think that because the mechanism is so well accepted and not every patient is eligible. This is also an expensive drug. Obviously, you need coverage so. I think that, in and of itself, helps our enrollment. We are not at enrollment stage just to be clear, right? We've just announced the switch here, so we're not there. But of course, if the other drugs got pulled from the market that may create a certain, let's call it, a void for the lack of a better term, that may even put more patients into trials with the exact same mechanism that people feel is active in the disease. So I think it helps us that it is an accepted mechanism in the very first place. And obviously, there may be an additive effect in certain areas of the world.

And yes, the other question, when can we expect FDA interactions? Obviously, we're interested to do that as fast as possible, but we also want to do it as smart as possible to maybe having a chance to maybe ignite a discussion on an expedited path. Usually, it takes 3 months to schedule from submitting the request and you need to be having your documents and your ducks in a row that takes a couple of months to work up to. So I don't want to give a concrete month guidance, but it will be a second half of the year endeavor where we are talking to the FDA, as early as 4 maybe as long as 6, 7 months from now is kind of where the current estimate lands, but we want to prepare that well.

And then last one, not least, breakthrough. I think for breakthrough designation, you need to have data that show that you're better than a comparator. We don't have data yet with this molecule, so we can technically not file for breakthrough until we have the data. If we had the data, for example, from a Phase II trial, that is the route we could explore.

Thanks, Mazi. So we are at our time unfortunately. I think we will be available over the coming days if anyone has any follow-up. So Q&A session is now over. Niels,, just want to hand it back to you for just a quick concluding remarks.

No, just thanks for listening in. We're really excited as our team, Tom, our CFO, together with Jan, me, will be here available for you guys in the coming days. If you had to follow up questions, we are certainly excited I hope you see the excitement from us. And yes, we will be in touch, and thank you so much for listening, and I appreciate it. Thank you.

Great. We are now done. The conference call is over. Everyone, have a good weekend and a Happy Mother's Day for those who are celebrating.

Thank you.

Good morning and good afternoon, everyone. Thank you for standing by, and thank you for joining our conference call to discuss our top line data for INF904 in HS and CSU. [Operator Instructions] And please note that today's call is being recorded. [Operator Instructions]

I would like to now turn the call over to Niels Riedemann, CEO and Founder of InflaRx. Niels, please go ahead.

Good morning, everyone. It's my pleasure to welcome you as well to our conference call this morning on our top line Phase IIa data. We're thrilled to share these data with you, and we're very happy that we got to this point. So we will dive right in. Before we do so, just 2 notes here. I will be joined by our Chief Medical Officer, Dr. Camilla Chong. Dr. Chong will present the data in chronic spontaneous urticaria, and I will present the data on hidradenitis suppurativa.

We're also thrilled to have with us for the Q&A session, Professor John Ingram. Professor Ingram is not just a treating physician that is passionate about HS treatments and knows a lot about that, but he's also one of the key opinion leaders and really key scientists driving the field forward in HS as a former Editor and Chief of the British Journal of Dermatology, also very well versed in the scene, and we're really thrilled to have him with us for the Q&A session. So with that, we'll dive right back -- right into the presentation. So please, next slide.

So we'll be making forward-looking statements today. Next slide, please. And please take note of the disclaimers. These are important disclaimers on the forward-looking statements. We will also be showing you for comparative illustration only some data that were presented by -- and reported by other companies. So this is for illustrating purposes and comparative analysis only.

Next slide, please. So just on the mechanism, as a reminder, we have a small oral compound inhibitor of the C5a receptor, sometimes referred to as C5aR1. The C5a receptor is a known and validated target in immuno-inflammation field. And obviously, it's part of the complement system, and a small inhibitor of this receptor has certain advantages. It has a deep tissue penetration potential, which acts then in the site of where the inflammation really takes place, in this case, the skin. And also, it's not really dependent on how much C5a is being produced. With that in mind, it's important to know that you cannot simply block the C5a receptor with upstream inhibitors because C5a can be produced by various pathways, particularly through enzymatic cleavage on the cellular level in the skin, but also in different tissues and also in the blood. So to block this pathway, you need a targeted inhibitor.

Next slide, please. We have previously shown data, and this is from our Phase I study here that indicated that INF904 has best-in-class potential. And this is really based on a very differentiated PK profile next to the reported comparator, which is a marketed drug avacopan, and. You see the data here, as a reminder, on the upper right corner. So at the same dose already, we reached a tenfold area under the curve increase and a very differentiated ability to block the receptor and really have a tighter control over the signal.

Why is this important? Because ultimately, we believe and some of the data today shown will hopefully make that point again that with that, we can explore efficacy to a much higher extent and eventually, this will lead to higher efficacy signals in clinical studies and in clinical application. I just also want to remind you that by now, we have, including the data we will present today, about 180 human subjects exposed to the drug with no signals of safety concern.

Next slide, please. So this was a PK and safety study. So we will start with PK and safety. PK at this point is very preliminary. You see that on the right side, we plotted a compiled PK data in green HS and in blue from the CSU study. But the illustration here is not complete. You see the number of subjects are indicated underneath the figure. The point we are trying to make is it's very differentiated from the marketed comparator. Already at week 1, we have a multiple higher exposure for both indications across the 3 tested doses in HS and the 2 tested doses in CSU.

And even if you see the plotted line here from avacopan from its approval data in ANCA vasculitis reaching at 13 weeks steady state, even if you compare that, we clearly exceed that sometimes by a multiple. And so we just wanted to also let you know, we started with 60 mg BID, and that was based on the knowledge that 60 mg BID is actually covering the signal quite well in our Phase I studies, we've been able to demonstrate that. So we believe 60 mg is a clearly active dose, but we wanted to explore efficacy upwards, which in skin disease is particularly important as oftentimes when first tested drugs are underdosed in this.

Next slide, please. So safety, very high level, you'll find more details in the appendix with the concrete listings. There are no signals of safety concern detected in either of the arms. There is no reported SAEs in either of the arms, so no severe adverse events. And there is just 3 adverse events of mild grade 1 nature reported in 2 patients in the HS cohort and 1 particularly also mild grade in the CSU cohort. So very, very clean safety profile so far, and we're really happy to report that we have no signals of safety concern.

Next slide, please. So with that, we jump into the HS data set, and I'm thrilled to be able to be presenting this for you today. We have 29 patients as depicted here below that we will be showing you today that have reached the end of treatment at week 4. And out of these 29, 25 have already reach the end of study, which is week 8, so 4 weeks later without dosing and without additional visits. The other 4 remain and have not reached that endpoint yet, but are in the study. Please also take note there's 1 patient in the low dose group, 60 mg and 1 patient in the medium group, 90 mg that is still finishing up treatment and data entry. So they are not included in this. The high dose group, therefore, is complete, but the other 2 dose groups, each missing 1 patient that is still -- that are still in the treatment phase.

Next slide, please. So just as an indicator, again, this is the setup. The color coding will be consistent throughout the deck. So yellow will be the 60 mg BID group, pink is the 90 mg and red the 120 mg. You see here the 4-week dosing intervals, again, dosing is every day BID with 4 visits after the baseline visit. And then another 4 weeks, as I mentioned, no dosing and no visits where the patients are just coming back one more time for safety and efficacy analysis at so-called end of study week 8.

Next slide, please. So with that, we are showing you here the baseline of the 3 groups, 60, 90 and 120 mg and below that is the combined data of all 3 dose groups. You will see that they're overall pretty balanced and in line with previously reported and conducted HS studies, maybe highlighting that on the AN count, which drives an important regulatory endpoint, the so-called HiSCR, the end count is the highest in the 120 milligrams dose group and the lowest in the low dose group. There's a difference that is noticeable. The DG count is between 3.5 roughly and 4.5, in line with other studies. Also, the severity score indicates that the high dose group is the most severe, the so-called IHS-4 score. And then maybe also noteworthy that we have a few prior biologic experienced patients and a slightly higher BMI, body mass index on the upper right in the low dose group.

Next slide, please. So we will now show you the lesions first and then the scores, and we'll start with the driver of the HiSCR, the so-called AN count. So just as a reminder, abscesses and nodules are 2 of the inflammatory lesions. The third one is the draining tunnel. Abscesses and nodules come and go all the time, so they fluctuate a lot in the patients. So they can go up and down by over 50% in lower count patients, and that's very normal. And you see on the upper left side here how the average in each dose group is composed with respect to the nodules and the abscesses, making the AN count altogether.

And as you can see, the high dose group is the most severe one. I should mention that in green, we always depict the compiled data of all 3 dose groups. So when looking at that, we would like you to appreciate first that you see a very consistent overall reduction, and this is week-by-week data, so high granularity in the absolute reduction of these counts. Now you see that oftentimes, there's a lot of zigzagging, there's flaring patients. So just one flaring patient can cause a lot of zigzagging in this curve. So we were very happy to see a very consistent move. And you can see this is exceeding 8 total abscesses and nodule counts already at week 4 in the high dose group.

So why is this important? How does it come? Next slide, please. We have done a lot of comparative analysis that we will share with you in which we compiled the data that have been reported for successful drugs and created the average of that. And you will always find in blue completed and successfully conducted Phase III data sets that are averaged and in gray Phase II. In this case, for example, it was just one drug in Phase II povorcitinib, and we then report the best reported dose. And in Phase III, of course, the doses that have eventually then also led to an approval. And you can see the corresponding placebos are always in the dotted lines. So blue is Phase III, gray is Phase II.

So you see that the green line of all doses here compiled is just on par with the reported successful drugs here, but the red line is clearly exceeding this. And the other thing that we can learn from this orientational comparison is that the placebo ability to reduce the AN count is across the different studies that we looked at, always in the range of minus 2.5 and minus 3.5. Now that is not unimportant because they drive the HiSCR. As a reminder, the key criteria is a 50% reduction of the AN count from baseline.

So if you have a baseline of 6 counts, you need to lose, for example, 3 nodules, and you reach that criteria, a 50% reduction. But if you're coming from 30%, you would have to go down to 15%. And if you see that the average placebo makes about 2.5 to 3.5 points, you can already kind of see from that, that this is oftentimes driven and drives response in the low count patients. So the low count patients provide a lot of noise, and they can drive placebo response rates in that score.

Next slide, please. So looking at draining tunnels, we had mentioned previously and guided the markets that draining tunnels are an interesting lesion as we can see them as an indicator lesion. Why? Because historically, they are very low responders -- response rates for placebo trials. So the draining tunnels are more consistent, less fluctuating. One draining tunnel can produce up to 1 liter pus per day. Just want to let you know that draining tunnel is what you see to the outside, but this usually means if you, for example, draining large milliliters of -- up to a liter of pus from one draining tunnel that there's a big underlying large inflammatory lesion in the deep skin that produces -- an inflammatory lesion that produces this pus.

And so reducing draining tunnels is a remaining unmet medical need, but it's not easy, and it's usually not done by placebo responses. So here you see the same picture, different doses, different -- again, the high dose performs the best. And on the right side, you see something that was created recently by calling dT 100, meaning how many patients that have draining tunnels at baseline are now completely draining tunnel free. I just want to remind everyone, we're talking about 4 weeks of treatment. So at 4 weeks in the high dose, we have half of the patients already draining free and the average around 30%.

Next slide, please. How does it compare? Pretty impressive in my eyes. As you can see, the placebo from the Phase III trials -- by the way, I should have mentioned, always underneath, you find all the trials, all the data that went into the curves. In this case, it's adalimumab, secukinumab, bimekizumab, povorcitinib. So everything that was recently reported here is in there. And you see placebo has very little reduction of the draining tunnels. And you see that the compiled successful drug data here, they reach about 1 -- a bit over 1.3 point reductions overall. And you see no matter whether you report on all patients or only on those that have draining tunnels at baseline, which in this case, makes the difference between dotted red to dotted -- solid red and green, there's a very steep initial decrease that we can note here for our drug, INF904.

So next slide, please. So how does that funnel into the HiSCR. We now looked at the lesions. The lesions are part of HiSCR. I should mention, reduction of draining tunnels is not rewarded and not looked at in the HiSCR, you should just not have increases. So as we explained, there's a lot of noise in the HiSCR, there's ups and downs. And usually, you don't get granular weekly data as we can show here. But again, we're very happy to report that this is moving upwards step by step,with reaching about 38% in the higher dose group already at week 4.

And then remarkably, when we took the patients off drug, those 25 that reached the end of the study, the additional 4 weeks of drug, the responses steepened. Now obviously, the denominator is just 25, not 29 here, but the high dose group is complete. So that 63% you see there is not changing anymore. The other 2 groups have still a few patients coming in, so they could still change to a higher or a little bit lower level. But the point is that response is deepening. And we, of course, looked into how can that be explained. First of all, we can confirm that the preliminary PK data at the end of the study, so 4 weeks off drug, do still show active drug levels in the range above the IC50 of the drug. So where there can be a blocking ability still from the plasma levels being estimated.

So that's one thing we want to note, but also the mechanism does provide for a change in the inflammatory environment in the skin, meaning you will have less of certain immune cells moving into the skin over time and being activated in the skin, and that can also have a carryforward effect. On the right side, you see something that we created to illustrate how HiSCR moves overall. And so for this -- it's the pool data, and we set out knowing about the variability in small data sets, how can we depict and create confidence that there is a movement towards a higher HiSCR rate. And the way we did that is we created the stacked bars here. We're looking at HiSCR 30, then HiSCR 40, HiSCR 50 and HiSCR 74.

And we said, look, if without the -- with knowing about the variability over time, these stacked bars should get higher as more patients move into the next response level. And obviously, if you're at HiSCR 40, maybe you need to lose just one nodule or one abscess and you're already in HiSCR 50. And this is exactly what we see here. These stacked bars, they extend, they get larger, and we're at a HiSCR 75, then at 24% at week 8, which again is something that we wanted to depict.

So next slide shows you then how that compares. So again, depicting the Phase III studies. First of all, you see visually that placebo is not so much differentiated, and we know about that problem. Very recently, we got reminded again that placebo response rates do play a role. I want to mention again that can be mitigated when looking at the baselines in different ways and how you control not to have too many low AN count patients in your placebo group. But we are right on the blue trajectory line, obviously, with some variability and obviously, with the high dose, again, performing better. But I would say, clearly, we are in the range that we can check the box in HiSCR, and have the fantasy that, that may even move higher over time and that needs to be proven out in future studies.

Next slide, please. So the last remarkable point here in the HS data set is really the pain scores. NRS30 meaning on the pain scale from 0 to 10, you get a ground score. You will notice in the baseline that this was roughly between 6 and 7. So these patients are highly impacted by pretty intense pains. And it's rare that you have a consistency in small data sets because this individual score, which is a patient-reported outcome has a lot of variability. But you see a consistent improvement alongside the lesion improvements that we've been showing you in the pain up to a pretty remarkable level in average over 65% and 75% in the high dose group.

Now that is important. We define high NRS30 as having at least a 30% reduction from your base score and at least a 2-point reduction, which is a bit more stringent than some others use. A recent competitor read out a different way by saying we just want to show you patients that have at least a 3-point reduction. So the NRS30 was not part of that, but we also applied that logic and the lines did not change by chance. So no matter how you look at the data, they're really in the comp -- it's shown they really kind of stand out in as much as they are very consistent, and they're showing a very, very large improvement in -- very early in the first 4 weeks. And that's maybe in line again with treating the inflammation in the skin.

Next slide, please. So this is less of an efficacy demonstration, more of a comparator slide. We've mentioned that we think we have a best-in-class potential drug that is shown and supported by our Phase I data. And I think this supports it again because avacopan was used in HS in a pretty sizable study, roughly 120 patients per arm. And you see this is the data that are reported on clinicaltrials.gov about this study. And you see that for dT, draining tunnel, this was plotted out over the time phase of 12 weeks. And you see how we compare next to their approved dose 30 mg, which did not really separate from placebo.

And on the right side, you see a bit of an apple and pear comparison, our data at week 4 and their data at week 12. And when looking at AN count that drives HiSCR, you see that there is a signal in avacopan, maybe even a dose response. Again, you see that placebo is within the range I mentioned to all of you between 2.5 and 3.5. But there is a signal in avacopan, maybe not as strong as a signal as bimekizumab can do maybe up to 7 or so at that time point or even over 7. But it's just reaching this very late, and it's not very impressive, but we have reached this already in average at week 4 and clearly exceeding with our best reported dose at week 4. Similarly, the pain scores that I already illustrated, there's a clear difference. So we believe this is another good indicator that the drug is very differentiated and has activity away from the marketed comparator.

Next slide, please. So with that, we conclude here. So we believe that this data here show a biologic-like efficacy in the first 4 weeks with AN counts and HiSCR responses. We see the HiSCR responses deepening 4 weeks off drug, and we have an explanation for that, and that's a very encouraging signal. We see fast and deep reductions in dT and that really is very differentiated from reported placebo and also compares favorably to the Phase III drugs. And also, we showed you a very consistent reduction in pain. In the backup, you will also find data on Dermatology Life Quality Index, which are equally impressively like improved already at week 4. So that's in line with the lesion reductions. And I mentioned safety that we don't have a safety signal of concern. And with that, we think we delivered to the market here a very interesting, a very differentiated mechanism of action that is an oral, and we are very excited to take this drug further in this indication.

With that, I'm done with my part. I'm happy to hand over now for the CSU part, which also shows clearly very interesting signals and an active drug. And I would like to hand over to my colleague, Camilla, would you be so kind and take it from here. Thank you.

Thank you, Niels. I'd be delighted to take the CSU part of our presentation. But before I present results from our CSU study, I would like to take the opportunity to acknowledge the late Professor Prof. Dr. Marcus Maurer from Charit Berlin, who really persuaded and collaborated with us in this to embark on the CSU study because he really believed in the crucial role that C5a plays on not just the mast cell, but also the underlying inflammation. and we are grateful that his hospital continue to work with us and is, in fact, one of the sites in this particular study.

So for the purpose of today, I will be presenting 30 evaluable patients who have completed treatment up to week 4. And out of those, we have 23 right now who are -- have data at end of study. The remaining 7 are still ongoing, and we also have an ongoing arm 3.

Next slide, please. As Niels have shown you, the study design is fairly similar, except for CSU. We do not have the 90 milligrams group. We have the 60 and 120 milligrams BID. We also have arm 3, of which we try to enrich the 120 milligrams dose group with patients who have previously been treated with anti-IgE and who have either had incomplete or no response and also those who present with low IgE, more indicative of the type 2b endotype. These patients have 4 weeks of treatment and then from end of treatment to end of study, no drugs are dosed. So basically, they have a dosing-free period, but we follow them up.

With that in mind, I'd like to show you in the next slide, the UAS -- first of all, baseline characteristics. So as you can see, the mean age of these patients are around 44 years old, predominantly female with quite severe moderate to severe CSU at baseline and also poorly controlled disease. On average, they have had CSU for at least 3.5 years. We have a group of patients who are anti-IgE experienced, but predominantly anti-IgE naive.

In the next slide, please, I will share with you the UAS7 results at week 4 of both doses, 60 milligrams achieving a UAS7 reduction of just under minus 14 and the 120 milligrams group at minus 8. On average, we achieved an end of treatment results of around minus 10.4. And I've mentioned earlier to you, from week 4 to end of study treatment where they have no drug being dosed, the effect on the 60 milligrams group continues to deepen down to minus 16.3 with a more modest decrease overall on average between the 2 doses.

Next slide, please. Now how does this compare with other Phase II studies that we are aware of who have progressed from Phase II to Phase III. And here, we took on average the placebo rate, which is around minus 6.3. But if you look across the active treatment, whether it's omalizumab, remi, rilza or barzo, the clinical activity range that you see here is from minus 9.1 all the way to minus 20. So clearly, we do achieve with the 60-milligram group UAS7 reduction which is within the range of therapies that have moved into Phase III and is differentiated from placebo.

How does this compare with Phase III data in the next slide, please? We also see fairly similar placebo range, which is perhaps slightly more at minus 7, but a clinical range, which is also interesting, that starts from minus 8.5 all the way down to minus 19. Now those of you may remember that dupilumab at week 4 do not achieve substantial reduction in UAS7, but takes just that little bit longer to get to the clinically impactful UAS7 later on at week 24.

So in the next slide, what I hope to show you are the UAS7 reduction in some of the subpopulations that we've looked at. So on the left-hand side, you will see patients who have more severe CSU at baseline. So in other words, CSU patients who have UAS7 score of 28 and above. And here, you do see that the 60 milligrams group have a much deeper reduction of UAS7 at minus 15.4 and also a little bit more with 120 milligrams group at just under 9. In addition to that, we looked at a group of patients, albeit the numbers are very small, we have 3 patients who presented with angioedema at baseline -- very severe angioedema at baseline. And here, you can see that the reduction is around minus 18.7.

In addition to these 2 subgroups in the next slide, please, we also have patients who have low IgE baseline. And those of you may remember that some of these patients are more indicative of the type 2b endotype and they're more difficult to treat. Here, the UAS7 reduction is around minus 12. But bear in mind that the placebo rate taken from remi and barzo data, Phase II data at week 12, placebo average is around minus 3.8. So it's a lot more differentiated here in this particular group of patients.

Next slide, please. And this is disease control as measured by UCT7. I'm pleased to say that all 3 doses achieved a 4-point improvement or more in UCT score. And those of you may know that a UCT score that is minimally clinically impactful difference is 2 points and above. And here, all -- both doses achieved more than 4 points. And on the right-hand side, you will see that UCT indicates at least 30% of patients achieved good disease control at week 4.

So next slide, please. So in summary, I hope I've shown you that our 60 milligrams dose clearly achieved efficacy within the clinical activity range observed from Phase II and Phase III studies. And in some subpopulations, particularly those with more severe disease at baseline, those with angioedema and low IgE patients, the reductions are more substantial. INF904 also shows good improvement in disease control, and I'm also pleased to say that the drug was well tolerated and did not result in signals of safety concerns.

So we are also grateful for the continual support that we're getting from Professor Martin Metz, successor to Marcus Maurer, and further exploration into potential CSU program will be discussed and provided at a future R&D event together with and also HS.

So with that in mind, we would like to also now -- we are thrilled to have with us Professor John Ingram that I hope have joined us to start our Q&A session.

And in order to do that, perhaps we can kick off by asking Professor John Ingram that in his view, in your view, as an expert and treating physician in HS, what is your impression of the data? And perhaps related to that first question, what do you believe matters to your patients and to you as prescribing physician when it comes to measuring progress and/or improvement? So those are the 2 questions -- I don't know whether John...

Yes, we're still waiting for John. So what I can do is if you could just hold that, Camilla, going through some of the questions we have -- we received and then address them when he gets on board. So just quickly, at this time, we'll start the Q&A session as we wait for John Ingram. You may ask a question a few ways. One is you can raise your hand using the icon below the presentation window and then we'll get people individually. You can also use the chat, the Q&A button below the presentation. And I'll read those questions out loud. So with that, we've got the first question from Steve Seedhouse at Cantor.

Congrats, obviously, on the really encouraging data here. I wanted to ask a few questions. First, I believe this study according to the clinicaltrials.gov entry enrolled across quite a lot of sites in the U.S. and Europe. Just hoping you could comment on maybe the distribution of enrollment across those sites, particularly in the HS study. I'll start with that question.

Niels, I think you could take that. I think you need to unmute perhaps or no.

Yes. I'm unmuted. And Camilla, you correct me if I say something wrong. But we had -- that's right, we had a bit below 30 study centers. So I think 28 actively recruiting in the 2 arms. Not every center recruited in both -- in each arm, obviously, but we had a good distribution. The -- like roughly 40% of the patients in the HS arm came from the U.S. And then I think the largest site recruited 4 patients. So there was no single center that recruited like a majority of patients or so. So very well distributed over maybe like a total of maybe in the range of 13 to 15 sites in HS and similar site like level in CSU. I'm assuming you were most interested in where HS was recruited, but happy to give you more color on CSU as well. Camilla, I don't know if you could speak to the site distribution in CSU.

Yes, absolutely. So similar, we have U.S. sites as well as Western European sites coming from Bulgaria, Germany, Poland, Greece and also Georgia.

Great. Just mechanistically, also, Niels, I mean, nobody has been studying complement longer than you and also HS. Curious if you could comment on the -- like the draining tunnel data, the pain data and maybe also the DLQI data are sort of where the most profound effect you see is. Is that what you expect with the mechanism here? Like how is that fitting into the sort of hypothesis of this mechanism in HS?

Yes, absolutely. Great question. Thanks, Steve. So maybe noteworthy before I go into answering directly that the C5a receptor expression has been found to be increased in various immune cells around all 3 types of lesions, abscess, nodules and draining tunnels and in all stages of the disease, like in early Stage I, II and III. Now you know Hurley system is more like a chronicity kind of thing rather than a severity thing. But what I'm trying to say is the receptor expression is up regulated in different cell types. Now we've always been pronouncing the role of neutrophils in this disease as it's clustered into the so-called neutrophilic skin disease bucket.

And obviously, they do play a big role, particularly in draining tunnel and abscess formation. And and why is that? Because C5a induces NETosis in these cells and the production of granular enzymes and also of oxidative radical. So if you think about the impact of NETosis has been implicated in the last few years more and more by the experts, the HS experts to be driving and also not just driving like draining tunnel existence and pus formation, but also the actual development of draining tunnels. So the NETosis angle is an interesting one, and we really cater to that.

On the other hand, there are different other cells, like immune cells, like monocytic cells, histiocytes that show strong expression, and they also modulate the inflammatory environment. So when thinking into pain, if you change the inflammatory environment, you may work on like 2 different angles. I mean, there's certainly the pathogenic pain, if you will, like the destructive -- the tissue destructive angle of neutrophils and other cells that will cause certain dendritic cells or certain receptor like just to be damaged and causing pain. And then there's also a potential direct angle into the [ no reception ] of pain that has been described in the literature.

But on a more kind of high level, if you do change the cellular component and the activation status of these cells in the skin, you -- actually, what you are expecting is not just to be active on draining tunnels or their formation, but to over time, particularly also move abscess and nodule counts further down, further down, further down because you're kind of taking away one of the driving factors of the disease, which is really the immune cell-driven inflammation in the skin. So that's why we are so encouraged, and we do believe it works on all 3 lesions. There's data in the appendix as well on the total inflammatory burden of disease, which is the AN DT count. And also there, clearly a differentiated movement from any placebo ever reported.

So I would say the pain is the most impressive one because it's an integral part of the disease that is oftentimes not well addressed. But at the same time, I would not focus that we're just working on draining tunnels. I mean, we're really working on all 3 lesions. And that was the belief that drove us back into the disease. We all had made our experience, like we recently all made experience again through another big readout that HiSCR can be very difficult because particularly controlling placebo responses, and we have a good idea now why that is. We've done a lot of modeling. So I pause here. I could go on and on, as you can see, but I hope I addressed part of it by really the immune cell composition in the skin.

Yes. I appreciate that perspective, Niels. Just one last quick one for me. The IgE experienced arm 3 of the CSU trial, just an update on the status and the timing maybe of when you might have data from that.

Yes, absolutely. I will hand this over to Camilla. Camilla, do you want to take the CSU part?

Absolutely. Arm 3 is challenging, as you know, with this particular patient group. So we would like to take a review by the end of November to see how far we have got with that, but those numbers are difficult to come by. We will announce the progress in due course.

So no clear guidance yet when we expect that to be fully closed out. But yes, it's been proven very different. As you can probably appreciate, Steve, one of the challenges in these smaller trials is if you provide like a 4-week treatment outlook for patients with a chronic disease, it's not necessarily appealing for many of them. So it's not so easy to get patients on board. But yes, we don't want to create excuses either. This arm is recruiting slower. And that's probably why it's usually just looked at retrospectively in the larger studies, but we're doing our best on that one.

Great. Thanks, Steve. So we do have John Ingram, but I do want to have one question for Camilla, a very important one, and I think in our case, a very easy and fast answer. So that's related to the use of antibiotics in the HS study. If you could give us a sense of how that was used?

Absolutely. I'd be happy to take that. So first of all, patients are not allowed to have systemic antibiotics during the course of the study. And I'm pleased to say that no patients actually took it. So therefore, we didn't have any patients who were on systemic antibiotics. We did allow any patients who were previously stabilized on tetracycline-like drugs to come into the study, but I'm once again pleased to announce that we didn't have any such patients either.

Great. And Camilla, if you want to address John and get our insight from him.

Absolutely. So Professor John Ingram, thank you very much for joining, and we are delighted to be able to have you here to perhaps give your perspective as an expert and treating clinician in HS, your first impression of the data that we presented so far and then also a leading on kind of next level of question is, what do you believe matters to your patients and to you as a prescribing physician when it comes to measuring progress and/or improvement?

Thanks, Camilla. And yes, it's a pleasure to join you. It's -- for me, I'm a clinical academic. So I have 2 clinics a week, and I do HS surgery. And those key issues for our patients, I think the early data is addressing. It's -- we have, of course, these 3-lesion concepts around nodule inflammatory abscess and draining tunnel and all 3 are important. The -- probably the lesion type that's been the most difficult to treat has been draining tunnels, and that's where I think some of the additional focus is at the moment. And one of the issues there is that they can drain continuously for weeks or months. So an abscess might last 10 days and be acutely painful. It may give a pain score that's gone from 0 or 1 out of 10 to 10 out of 10 for that 10-day period, but then it will resolve.

A draining tunnel will carry inflammation typically for a very long term, as I mentioned, months quite routinely. And that produces drainage and odor and stains clothing and limits a person and will be painful. So they'll have that pain continuously. So I thought it's very encouraging to see the data that you have around within 4 weeks. I think we should be mindful that this is very short-term data in that we have seen in treating our patients that if a targeted therapy is going to work, it often works quite swiftly. So this data probably does represent a demonstration of the mode of action being pretty effective in targeting HS inflammation. And that's not a surprise to us in HS.

We've always felt that complement was an extremely good target for HS therapy. The innate immune system is such a big component of HS. And we've seen, as Niels has already mentioned, that there's links with neutrophil biology, for example, where it's all part of that pathway and interleukin 1 and so on. So this is very congruent with our thinking. We've been looking for a molecule that is effective against this target. And the early data is encouraging. And I think we look at the overall lesion counts, and they are greatly reduced. And I think importantly, the draining tunnel count in particular. And that then is complemented by the patient-reported outcomes in terms of pain is the key symptom of HS. It's followed by drainage and fatigue. Those are the 3 actually that patients most value in terms of improvement. And then the overall concept of quality of life comes in. So that's the DLQI.

You've seen here some substantial changes from baseline. The DLQI minimum important difference of 4 points is probably a bit low in HS to be very direct about this, that our patients need more than a 4-point decrease, but it's a pretty good start to at least attain that. And we can see here that, for example, on the high dose we, get a DLQI mean score reduction of 10 points. And that's the -- those are the kind of figures that we really have been looking for in HS because if you have a DLQI score of between 20 and 30, you're going to need it below 10 to really demonstrate that clinically meaningful change as well as the minimal important difference.

So the data is, of course, week 4. We would anticipate deepening of response going to week 12 or 16, primary endpoints of most Phase III trials. But beyond that as well, although often it's observed case data, you'll see at least maintained, if not deepening of response beyond week 16 up to the sort of 1-year mark. So this is encouraging, very encouraging early data.

Great. Thanks, Professor Ingram. So we do have a few other questions. [Operator Instructions] We also have now Ryan at RayJ.

Congrats on the data. Question for me is, is the 120 mg dose looking like the go-forward dose given the safety and efficacy data so far? And are you thinking about less frequent dosing cadences given the magnitude of the continued HiSCR 50 response that you saw? I have a follow-up.

Yes. Niels, I think we can [indiscernible] you and Camilla.

Yes, happy to take that. Certainly, we -- that's one route we are contemplating right now, just given that it's performing the best on every angle of the data set. But we are still doing some PK work. We have not yet gotten all samples in, as you can see. And we will also do simulations that will further inform us. Now what -- to your second part of your question, yes, we do see potential ability to maybe move this to once daily dosing, but not -- maybe not right away. We're trying to assess this right now because we've seen, as you know, like when we take patients off drug after we've loaded them for full 4 weeks that we saw quite a good continued response after we've taken them off drug.

And the preliminary levels we see at week 8, 4 weeks after stopping of dosing are encouraging. So maybe we can, after full loading, like also look into once-daily dosing. So that's something that will come out of the simulation work. So we can't fully answer it. But certainly, we're not currently planning to go higher than 120 mg. That's clear, but we're also trying to assess the abilities in between 60 and 120 for sure.

Got it. And then regarding potential prioritization, how are you thinking about prioritizing upcoming clinical studies and clinical progression for HS and CSU based on this data set? And do you anticipate a meaningful target dosing difference between these 2 indications at this point?

Yes, very good question as well. I'll just take it in the interest of time. Certainly, there -- like we judge both data sets as warranting to forward the development. Our key interest is in probably also a market that is very interesting just from the medical need, which is HS. And I think the data clearly warrant that. So there will be an initial focus here to move forward with HS. But that is not to say that we've looked at the CSU data a lot, and we feel there's a clear differentiation to placebo, obviously. There is the ability to move forward into a deeper response with also targeting not just the histamine/mast cell angle, but also the angle in like tissue inflammation, which is going on in that disease as well.

So there is this clear wish to further progress it. And we think this is a pipeline and a product potential that we have in our hands. So while we focus maybe initially to drive start in HS, there's clear, I would say, support internally and also clear wish to move it forward in CSU, but also beyond in some other indications. We mentioned previously the renal space, peripheral neurological space. And as you probably appreciate, there's renewed interest here in the area through recent deal, but also through a marketed drug that's bringing real sales. So from that angle, we clearly see this potential.

Thanks, Niels. And then for those that are queued up, we do offer Professor John Ingram to answer your questions in HS, if that's of interest to you. So let me -- so Camilla, this one is for you. It's regarding the data we saw in the CSU arms. I'm wondering if you can give us your thinking on what we might be seeing there in the context of other successful drugs and target coverage and things like that.

So I think what's encouraging about CSU data is that the 60 milligrams group, a bit like in HS as well, you see efficacy with 60 milligrams. We cannot fully explain why we see the modest decrease with the 120 milligrams in CSU. We do know that there are a couple of patients who seem to skew the results because of flare in one particular patient in particular. But I guess I'd like to bring your attention back to the development in omalizumab, right? The 600 milligrams group actually ended up having worse UAS7 reduction than the 300 milligrams. Now it's early days. And as Niels mentioned, we will be doing further PK analyses as well as PK simulation to really try and understand the efficacy that we should be focusing on. But I think we come away being very encouraged that 60 milligrams show good efficacy.

But if I may add, Camilla, and also to the earlier question of Ryan, the 60-milligram group, particularly also in CSU provides for -- I mean, it's preliminary PK data, but it provides for a real good and high exposure as well. So from that end, it's like just like to basically reiterate what you just said, that promotes that 60 milligram is a viable way forward too, right? And you just basically also said, in other words, we don't fully know yet whether there's an inverse dose response here or whether that is just a matter of sometimes in small trials, you may have a few patients having a large impact. And when you look at larger data sets, that may not be the case anymore. But yes, that being said, like 60 is viable from an early PK look, right?

Exactly.

Great. We've got one question from Katherine Dellorusso from LifeSci.

Katherine, I think you might be live. Go ahead.

Okay. So we'll go next to Andreas at Op Co.

A couple of technical difficulties here. Congrats on these results. Two questions for us. Thinking about the Phase IIb in HS, would you be interested in including an active comparator in that study? And maybe some of the additional comments around potential dosing arms there, duration, primary endpoint. I know you showed a couple of very interesting data points there. And then just in CSU, you saw consistent responses across low IgE, Ig patients and also strong effects in severe and angioedema subsets. So do you plan on kind of enriching the Phase IIb/III study for a subset of those patients? And could you use a baseline Ig as a predictive biomarker. That's for us.

Okay. Maybe I'll jump in first and then Camilla can jump in. Thanks, Andreas, lots of really important question, clearly. I think for the HS part, we haven't yet fully done the simulations on PK, but we anticipate maybe at least 2, maybe 3 doses moving forward with placebo. Your question was, do you want to put in -- or do we plan to put in like an active comparator? I know that has been, I think, once or twice been done before. But if we do so, we haven't fully excluded this possibility.

What I don't necessarily like if you have a certain power assumption and if you like to do like a certain study just to put a smaller arm in because I want to come back, like a lot of people judge like efficacy on HiSCR and in small data sets that can be very deceiving, right? The problem with that is, again, if you have 2 data sets that look in mean baseline AN count the same, they can be very differently distributed in terms of -- the question is how many low AN count patients you have. When I say low is maybe below 10 in the placebo arm. And if you, by chance, are in that noise, those types of things can screw results. And so if you have 2 noncomparable data sets, that's something we would want to avoid.

So if we did put in, and it's not finally excluded that we will put in a comparator, it's just maybe less likely in my eyes, but it's possible. We also do work with experts to discuss that. We would then put it in at the same size and not as a small arm, if that makes sense. And so to the other questions, I think in CSU, I'll definitely hand over to Camilla here in a second. But yes, I mean, we -- like we are very encouraged by some of the findings in the more severe subgroup. Why? Because when we discussed this with our expert, Professor Metz at the Charit , he mentioned this angle that I mentioned before, if you're not just treating histamine from mast cells and clearly, the receptor is expressed on mast cells. But if you are also changing the environment, that may have a different impact longer lasting.

And he reiterated 2 things. The one thing is if you treat that tissue inflammation, that may be particularly important for those that have a very inflammatory phenotype. And talking about angioedema, if you think about how many patients have angioedema history, it's roughly 40% according to literature. So it is a sizable subgroup that could be of interest. But we haven't like made that decision yet, but I hand over to Camilla to give more color or her thoughts on moving forward in CSU.

Yes, sure. I mean currently, lots of great ideas coming our way and also in discussion with Professor Martin Metz. I mean I think we would look at the group with so-called who have more inflammation and those who are indicative of Type 2b endotype low IgE. But I would say we still have Arm 3 ongoing. And I think results from that would also help inform in our planning for Phase IIa. So I think we could potentially enrich but enriching this group with low IgE will also take longer, and that's been our experience. So it's possible, but also in terms of timing, it will take potentially longer.

Using baseline IgE as a potential biomarker, I mean, I think baseline IgE is informative, but I'm not sure if it's a perfect biomarker because, as you know, if we wanted to go fully for type 2b endotype CSU population, we also need to think about potential other tests like basophil stimulation test, [indiscernible] and so on. These are not commonly done in a lot of hospitals. So it's possible that we may want to think about substudies to really see where else we can enrich, right, and how else we can enrich the population. So all things are possible, and it's still ongoing. So hopefully, more to come at a future R&D Day.

We do have a question in the chat. Niels, this is for you related to some interest, right, in the C5aR mechanism in recent weeks and given where we are with the product profile, where you see -- where we see potential avenues of further development outside of HS and CSU, some -- perhaps some low-hanging fruit on that.

Yes, great question. So first of all, I want to reiterate, I think these data further support that we may have a best-in-class asset here in our hands, just upfront. The C5aR as a target is really well researched. There's a lot of studies, c5a, C5aR over 6,000 publications in PAMED. And the target is really indicated in many inflammatory diseases, particularly many autoimmune and autoinflammatory diseases. There have been over the last couple of decades, lots of efforts to drug this target, but it's a tricky target. C5a, we know really well as a tricky target, but C5aR is also not easy because that's the big contribution back then from ChemoCentryx, who got acquired by Amgen for $3.7 billion some years ago is they found that allosteric binding site inside the pocket of the receptor that when you target that and your drug gets in there, then you can really evoke a complete blockade of the signal.

So that discovery was important. The cyclic peptides in previous history, they all had toxic side effects. They were good blockers, but toxic. And so the chemical ones, it was difficult to target, as I mentioned. However, targeting that allosteric binding site means your drug is very lipophilic to get in there and then becomes a formulation issue. And that's really where we worked like several years on, can we find an angle to get to that same allosteric binding site, but with a formulation and a drug that has a better PK and therefore, like blocks that much better in the human system, in the in vivo system. And that's where our drug is differentiated. So recent activities. There was a recent Biogen, I think, agreement with a small company that has a -- that's very early. We don't know much about that product. That's been about I think it's a couple of years away from even IND filing.

So we can't really say too much about it, but I think that further indicates there's interest. So long story short, target is well known. If you can drug it and you have a drug that fulfills all requirements, I think it's a very interesting pipeline and a product potential. And I come back to my first sentence, I think we now have a best-in-class drug in our hands, and we're really excited to move it forward.

Great. Thanks, Niels. Katherine, if you can hear me, we'll try you again. I think your mic should be working.

Yes. And I apologize for the technical difficulty here. This is Kate on for Sam Slutsky. I'll be quick here. Did you happen to measure C5a levels in the studies? And was there any correlation between patients who responded better to those with higher C5a baseline levels?

Katherine, really good question. I just jump in. We don't have this data yet. We have, though, in previous times, not seen that the baseline C5a levels, which are elevated in HS, for example, clearly, and also have been reported to be elevated in CSU. They're not necessarily a good patient-by-patient like indicator whether your drug works or not. And that has to do with a lot of intraday variability about how much C5a is produced, but also with a simple fact. If you have low -- if you have very high C5a levels, you know there's complement activation going on. There's no other way.

But if you have low or not elevated C5a levels, that can be just because you can't exclude that complement activations going on because there are so many receptors around that you may just not see the elevation yet because they are soaked up by the so-called big [ sink. ] So our historic experience is that C5a levels are not necessarily a good initial guidance. And obviously, this drug, just reiterating, it doesn't block C5a. It goes to the receptor. So it wouldn't be a PD marker for our drug either. But we don't have the data in yet. We do measure C5a levels, and we can probably say more at a later time point.

Also, we now have Will at Leerink. Will, you can ask your questions.

Congrats on the data today. Really great to see. So just one question on the pain data for NRS30. It seems like there was a flattening of response between week 3 and 4. But then on HiSCR and some of the other endpoints, even draining tunnels, we see a really nice improvement between week 3 and 4 still. So I guess, just curious what you make of this dynamic? And is there anything here that we should appreciate as we dig into these data a bit more? And then I have a quick follow-up for Professor Ingram.

Yes, absolutely good question. I mean, for the 75-milligram group, it looks like this, but I want to reiterate, 75% NRS30 and a 2-point reduction, no one has delivered that at week 12 or 16 ever. So maybe it is real that we don't see much more than we see already between week 3 and 4. So we will get more granularity on week 8 data to make that point. We don't have that yet. But if you look at the dose groups below the 120 mg, they seem to be still moving. So is the 75% NRS30 response the highest we can get to? I cannot answer that yet. But if it was, it would still be, at least to me, pretty impressive and very differentiated from the rest. So sorry, I can't give you more at this point in time, but we may have more over time. Yes, I think yo also had a question for Professor Ingram.

Yes. Great. I appreciate it. And yes, just for you, Professor Ingram, I appreciate your time today. I guess just quickly thinking about the evolving treatment paradigm in HS. It's seen a lot of recent data sets over the past 12 months or so. But when we think about INF, I mean, I could see it being a very valuable second-line option for people who failed biologic therapy, but then with this really rapid onset of action here, it seems like it could be a very valuable first-line option as well. So just curious to get your preliminary thoughts on how it might fit into the treatment landscape, assuming these data are replicated in future studies.

Will, yes, I think I was also going to comment on your pain question as well because some of that flattening until week 3 to 4 may in part reflects that you have to attain that at least 3-point reduction in pain and when baseline means are around 6 or so. There may be that, to some extent, you kind of produce that rapid improvement. Then there's a bit of residual pain, for example, from chronic scarring as well in HS. So maybe that some patients, it's quite hard to get their pain scores down to complete sort of low levels because of that scarring too.

But in terms of where INF might sit in terms of the treatment pathway in HS, some of this will depend on the delta really in terms of comparison with, for example, anti-TNF biosimilars, the payer will be mindful of that. If we -- there's a demonstration of improved efficacy beyond those biosimilars, then the cost benefit equation may allow to be the first targeted therapy. What we've seen, of course, in recent times is that Phase III results, there's nothing that's a substantial improvement above, say, adalimumab biosimilar -- adalimumab in the PIONEER studies in terms of its HiSCR 50 attainment. And so there's probably then payers might consider this subsequent target therapy to be second line after the biosimilar on cost grounds.

What we look for now is for a targeted therapy that performs substantially above those levels so that we can advocate that they should be first line as a targeted therapy. And that's where I think there's an opportunity because HiSCR 50 is not a very high bar. Someone might have 20 inflammatory lesions to have that reduced down to, say, 9 or 8 is not remission. It's not even minimal disease activity. It's still ongoing active disease. So we're now looking to see if we can get high efficacy bars and get increased attainment. And then we could ideally look for those new therapies to be positioned potentially even first line in the targeted therapy pathway.

I think we'll have a couple more questions. I know we're a little bit over time, but trying to cover as much as we can. Our next question is from Dev Prasad at Lucid.

Congrats on the data. And just one question from me. So now you have dosed several patients with INF904. What's the emerging safety narrative for regulator? And are you -- any class-related concern you are proactively monitoring?

Absolutely. I may take a first step here. So yes, you're right. At this point in time, we have no safety concerns that emerged from all the -- and remember, we tested very high doses up to 240 mg in the Phase I study. So I think from that end, we're good. We have a preclinical package up to 9 months nonhuman -- GLP nonhuman primate tox studies and also no safety signals of concern and no real dose-limiting toxicity detected. And so from that angle, we see an interesting opportunity for a safe oral in the future. Obviously, we have to still prove it. But so far, it looks like that.

Now what are we monitoring? There's no class effect known. So I think generally blocking the pathway is -- can be considered very safe. There have been -- there was one liver-induced toxicity in the avacopan approvals, and there have been some signals since, but that's related to avacopan in our eyes. It's a very decent inhibitor of the CYP3A4/5 liver detoxifying machine, as I call it. And we have shown preclinically that we are 36-fold less engaging with that enzymatic apparatus. So very likely, we don't have that problem, which would be great. Are we monitoring anything to -- I mean, we are always monitoring safety, obviously. And one thing for any immunomodulator is always, generally speaking, if you have like an infection risk, for example, over time, and that's also expected by regulators to monitor that. Now that will be only looked at in like controlled studies that are longer-term dosing. But really, yes, from that angle, I think that covers the question. I don't know, Camilla, if you had additional thoughts on that one.

No, you've covered it. Thank you.

Great. So one more question, I think, Niels's, and I think, Professor Ingram, I think a good question for you regarding just thinking about potential synergies with other mechanisms in HS, for instance, IL-17s. Clearly, it's early days, but we like to speculate on things like that. So Niels, I don't know if you have any idea or Professor Ingram...

I would really, really defer here to Professor Ingram. First line, John, I think you're much more positioned to really -- I have my biological ideas about that, but I think you as a treating physician with so much expertise in HS, I think I'd like to kick that question over to you.

No problem, Niels. And I think it's a great question because we've seen so far that monotherapy is almost a luxury in HS that we've yet to really see a single agent provide us with a universal minimal disease activity state in our patient cohort. So we're already using co-treatments routinely in terms of a targeted therapy plus, say, an antibiotic or an antiandrogen therapy. And certainly, I'm aware of case reports and colleagues who are using 2 targeted therapy agents to manage their most challenging patients with the highest inflammatory burden.

So it's very much the case that we have these multiple pathways in the HS pathophysiology, the inflammatory soup that exists in the dermis of HS lesions. And so -- of course, there'll be safety considerations. There will be cost considerations when we combine more than one targeted therapy. But in terms of reaching those higher efficacy bars, that's certainly a possibility that is already in use. And we're also familiar with bispecific options and so on. So I think that it's a compelling option. But I think, of course, it's quite a fair way down the road in terms of current development of INF and others.

Thank you, Professor Ingram. So one more question. Neils, this one is for you since you pointed on this last one. It's regarding just giving a little more color on what you think we're seeing with the PK data and what we're thinking about the end of study portion where we saw continued efficacy in many patients even 4 weeks after dosing has stopped.

Yes. So maybe I start with -- I mentioned that we have like levels detected. That's preliminary. So we don't have all the samples in, but the preliminary one suggesting a range of plasma presence in the range of, let's say, 50 to 200 nanomolar. And that's about where -- like that's the range to where avacopan accumulates at week 13. So that's why we're saying we still have drug levels that are able to block. How much? I couldn't tell, and that depends like patient by patient. We also want to see if this is like more pronounced in 120 group versus the others. We have to still see this data to be more granular and get more data in.

Our IC50 of the drug is around 25 nanomolar, which is pretty much exactly the same like avacopan, but our ability to reach a blocking level in plasma and in human tissue is clearly higher with our differentiated PK and formulation. So that also illustrates that these levels are over the IC50. So from that angle, we are confident that what we see still provides some blocking. Now clearly, not the same level as during full dosing. And the idea is now to do simulation work to understand what made the half-life look after we loaded the tissue after week 4, can that be simulated? Can we -- like how long will we have full coverage of those 4 weeks? And maybe if after loading is a less high coverage enough to continue an improvement, right? These are the questions we right now have. We can't address them all with PK simulations, but maybe some of them. But I hope I could give you a bit more color on why we believe there are still active drug levels at the end. Yes.

Great. Thanks. So we are out of time. Niels and Camilla, obviously, thanks for joining us. Professor Ingram, thanks for joining us as well. For those listening in, you know where to find us, you can reach out to us if you have any questions or need any follow-ups. We are available via e-mail. So again, thanks to everybody. We're free to drop off.

Thank you.

Thank you.

I think there are still 90 participants. I'm not sure if we're off or not.

Yes. I was wondering that, too. Anyways, for everyone who's still on, I wanted to say a big thanks for all the contributions, all the work, all particularly for John Ingram, I know he had clinics this morning. So he was like hard pressed to get in, and he's been very patient with us. So thanks so much, everyone and the entire team for making this happen. MC service team, you did a great job. I think this went all smoothly. And yes, I hope we could cover some analyst questions. Obviously, there's only that much time, but hopefully, we can have discussions now with them after the release here. All right. Big thanks to everyone. I will jump off as well in case you still hear me. Hopefully, you got the thanks, and we'll be in touch shortly. Thank you. Bye.