InflaRx N.V. Aktie

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.