InflaRx N.V. (IFRX) Earnings Call Transcript & Summary

Hello, thank you for joining us at our virtual R&D event, where we will discuss our Phase III program for vilobelimab, including our new primary endpoint called the modified HiSCR. A replay will also be available on our website following the live event. Before I begin, I'd like to point out that we'll be making forward-looking statements that are based on our current expectations and beliefs. These beliefs are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for more details. Today, our agenda will include an introduction by Niels, and HS disease overview presented by our special guest, Dr. Chris Sayed, review of vilobelimab and the mechanism of action, review of our Phase IIb SHINE study, along with key learnings. And finally, what we're all waiting for is our new Phase III program with the primary endpoint called modified HiSCR along with additional data post hoc from our SHINE study. We will also conclude the event with Q&A and allow those of you on the line to answer questions. I would also like to introduce briefly our guests today. And again, we have a very special guest, Dr. Chris Sayed from the University of North Carolina in Chapel Hill, and also my hometown here, who is a professor of dermatology and he is a disease expert and will be giving detailed overview of the disease. We also have our furious leader, Professor Niels Riedemann, our CEO, who will be going to details on everything we want to know about this new study. Myself, Jordan Zwick, the Chief Strategy Officer; Dr. Korinna Pilz, our Chief Clinical Development Officer; and Professor Hoda Tawfik, our Lead Director for Dermatology. So welcome, everyone, and I'm going to pass it to Niels.

Thank you, Jordan, for the introduction. I would like to welcome everyone, the entire audience here to our R&D event that we are excited to share with you. Before we go into the disease and the agenda, I would briefly summarize the R&D overall activities of our company. And InflaRx has developed a lead proprietary first-in-class technology targeting a very special part of the terminal complement space, the activation product, C5a. And we have various clinical trials running, which I will go through on the next slide in a second. And our proprietary technology is now accompanied by new technology, which we have very recently announced. Next slide, please. So we are focusing in the company currently on the immunodermatology area that we have explored as pioneer regarding the C5a role in this disease. Hidradenitis Suppurativa is our lead development and we have just initiated the Phase III development, and we are excited to share more on this today with you. But we also have another neutrophil-driven skin disease pyoderma gangrenosum, where we recently reported positive data on the Phase IIa open-label study, where we showed a dose-dependent effect on the healing in this very painful skin disease. Now these are both neutrophil-driven skin diseases, which is important in the context of our today's R&D event. We're also developing vilobelimab in other diseases. Some of them are under the life-threatening inflammatory arena. We have a global severe COVID-19 study in intubated COVID patients, which is coming to an end, and we expect data readout currently in this quarter. We have recently reported 2 positive ANCA vasculitis studies. This is a rheumatological autoimmune disease, as you may know. And we are planning to now orient it and get feedback from regulatory agencies to see how a future pivotal program could look like. We are also working in oncology. This is an exploratory approach here in the first Phase II trial in cutaneous squamous cell carcinoma, which we just recently initiated. Alongside vilobelimab, we have a follow-on C5a antibody, which binds to the same target called IFX-2. Still in preclinical development, this drug was modified to show different patterns, make it more applicable to chronic inflammatory indications. We also have recently announced the INF904 program in oral small molecule C5a receptor inhibitor. And we are very excited about this drug because it has best-in-class potential, which we have recently shown and announced. But today, next slide, please. We really want to talk about Hidradenitis Suppurativa, a development that has captured us, and we have gotten great support from the experts treating this disease, and it's really my privilege and honor to hand over to Chris Sayed, Dr. Sayed, he's one of the leading experts in this field and has been really instrumental helping us in the development of a new primary endpoint. So Chris, the floor is yours. I'm very thankful that we can hand over to you for this disease.

Yes. Thanks so much, and I'm very glad to be here. I could talk about Hidradenitis all day anytime. It's kind of a shame really that it's not a better known disease given how common it is and how severe it is. But because it's something, as we'll talk about, it's often hidden by patients that have a lot of stigma attached to it. It's unfortunately something that I feel like I always have to start with the basics. And so I'll kind of try to give a disease overview and talk a little bit about potential for why C5a is a relevant target in the disease. And as a disclosure like I've got partially selfish reasons for being here and why I've been involved in discussing things with InflaRx over time is because I see so many of these patients, 40 or 50 a week on Tuesday, I saw at least 20 patients with HS. And for so many of them, I am struggling to do better for them. As much as I try and I see so many of these patients, I need more tools to do better. And inflows been really passionate around HS and bringing a new therapy that can be helpful. So for that reason, I'm glad to be here and to be able to discuss a great potential future treatment option. We can head to the next slide. So again, starting with the basics, HS, this is -- again, I wish an image that everybody had some sense of existing in the world because this is much more common than people realize. But the disease is characterized by recurrent abscesses, painful nodules, these tunnels have developed a drain pus, in places like the armpits, under the breast and the groin area and on the buttocks, because it's again an area that patients can cover and they tend to sort of keep covering, want to hide and not have to talk about with other people. It's something that general public has no idea about. But I tell my patients all the time. You've worked with people with HS, you went to school with people that had HS. And just like you did, nobody knew it about you, the way you protect it and kept it from everybody else, they were doing the same. But there really are many, many patients out there that struggle with this disease. It is something that is recurrent over the course of a year, so much like people have rheumatoid arthritis or psoriasis things that flare up over the course of years and decades really. HS is similar in a lot of ways. It's a chronic inflammatory disease that mostly comes up and affects hair follicles. And so it is something that the patients deal with for a very long time. And it often comes up in adolescents kind of very early in life around the teens years or early 20s. It can come up at any time, though. Clinically, this is a good example here that we see in this photograph. There are 2 large abscesses here that you can see that would be exquisitely tender if you were to sort of push on these areas and any time the patient moves their arm, it's going to be very sensitive. You can also see there's areas where there's not necessarily a plus filled space like an abscess, but smaller kind of individual model where there's just firmness and tenderness and some swelling. And then you see these areas that are draining a little bit of pus just right if the bandages are moved in these other openings that you can't see active drainage at the moment. But with pushing and motion, you'd see pus kind of drain from those areas. So those are the openings of those tunnels that go into the surface of the skin that are -- that have such an impact and they're very long lasting. Down here, there's -- I feel like these 2 data points at the bottom about almost pretty much 1% of the patient -- or the U.S. population or European population likely having HS or symptoms that would match up with an HS diagnosis. And here is saying greater than 200,000 cases. So really, there's probably more than a couple of million cases if we think of 1% of the U.S. population. It used to be thought of as an orphan disease because it was just so underrecognized and misdiagnosed, but we're realizing there's a lot more of it out there than we initially thought. Next slide, please. And there's different thoughts about why this disease develops. And we know it's a chronic inflammatory condition, and it probably centers around hair follicles. People used to think it had to do more with more of a sweat glands. But it's really more follicular information. And people often think they just got a bad ingrown hair or bad shaving bumps for saving in these areas. But what likely starts this disease process off in our early disease is that you see inflammation that starts right around a normal hair follicle that maybe you just see a small pus will develop or some very subtle kind of redness around follicles. And you'll see this scattered within the sort of worse picture in patients with worse disease. Then for whatever reason over time, that follicle begins to dilate and become disrupted. And eventually, that rupture leads to the contents of the hair follicle, so the hair shaft, whatever bit of bacteria happen to live in that follicle, the other bit of sort of dead skin cell to breed that builds up in the follicle normally over time. As the follicle ruptures and breaks up under the surface, all of that spills in kind of underneath the skin. And then the body is so prime inflammation that reacts very strongly to it. And you form an abscess. That's where neutrophils and other inflammatory cells come in and form a pocket of pus that eventually hits the surface and ruptures. And because there is some disruptive regulation of the hair follicles or something with the wound healing that happens abnormally, sometimes these abscesses will rupture in the skin normally, but other times, it forms these chronic pockets where a pocket of sort of pus and inflammatory tissue kind of like a chronic wound healing base gets in trapped under the surface of the skin and has multiple connections that chronically drain pus. And so not every nodule becomes an abscess, not every abscess becomes a draining tunnel. But whatever, some percent of them do and become these chronic long-lasting lesions that last for much more than just a few days. Next slide, please. So -- and as we think about how this disease progresses, this Hurley staging system is what's commonly described and used to classify patients. And John Hurley was a surgeon who wrote a random textbook chapter about HS many years like –- no, decades ago. And [indiscernible] Hurley stage I disease. This is just the bumps that come and go, abscesses and nodules only. There's no scarring or minimal scarring and there's no tunnels present. So I don't need to do surgery on this patient. Hurley stage II patients need a little bit of surgery because they've got some of the scarring developing some of these kind of band or rope like scars. They've got areas that drain pus underneath those scars or where there were tunnels underneath these bands sometimes. And in Hurley stage III patient has a lot of these tunnels and a lot of scarring. So they need a lot of surgery. So this mostly came on from a surgical thinking of how to approach the disease, but it has to do with the damage that has developed over time. So we don't expect to make a Hurley stage III patient go back completely Hurley stage II with medication, but it gives us a sense of how much their disease has progressed over time and how much of a burden it tends to have on those patients. Next slide, please. Current treatment of HS is complicated, and there's not a straightforward algorithm. This diagram here is from management guidelines created in 2019. And as you can see here, across these Hurley stages, there's not one best fit or there's not a perfect step therapy that exists right now because patients respond very differently to different types of treatments. A lot of those treatments, especially then focused on antibiotics and they still do. Something about how the body reacts with no bacteria and HS is different. Like it senses normal bacteria as a threat. And so reducing and changing bacteria can be helpful, which is why we use antibiotics as often as we do, but they're not great long-term options. And at the time of these 2019 guidelines, the only medication that had a, let's call it, a category A recommendation, meaning there were large-scale randomized controlled trials with Humira, which we all know is approved now, and it can help a lot of patients, but there is still the gaping hold of need to treat patients who don't respond fully. We know that about 50% of patients sort of hit the primary endpoint, this HiSCR response that we focus on so much now. And about 25% in both of those studies is 26% to 28% and those Pioneer studies also hit that same response because the disease naturally waxes and wanes them over time. But that means that there's only about a 25% difference between placebo response rates with that medication. And in real life, I think that plays out where about 1/4 of patients love it. They have a great response. There's about 50% that are in the middle that are partially improved, but there's certainly more room for improvement and more that it would be nice to have more tools to try to do better. And about 1/4 of patients kind of get no response from it, which is always very frustrating. And so even though this was a helpful first step, we still need more options to treat this disease because many are still struggling terribly with it. And for some patients, the effect wanes over time. We don't have any sort of secondary backup approved therapy at this point. So for those that lose response or can't tolerate they have a side effect, we don't have an easy backup that's FDA approved. And we use other things that are off label, but that's always a fight. It's a major struggle for these patients kind of waiting and hoping to be able to get other therapies. Next slide, please. Next slide. So again, there are the 3 main lesions that we think about in HS, and I talked about this some earlier, a nodule tends to be transient there for a couple of weeks. It's tender painful, and it can certainly be disruptive. It's often on a bra line or long underwear line or bikini line where elastic pants rub. So something that's hard for patients not to think about and sort of plan their day around sometimes. But most of those lesions will improve over the course of a couple of weeks. And abscess is sort of an exaggeration of that. It's a nodule where pus starts to fill the space. And so you have a pus-filled. Sometimes it's the size of the grape, and sometimes it's the size of the grapefruit, it can vary a lot. These are exquisitely tender, very, very painful. But typically, they will drain over the course of a couple of weeks or patients have to go get them drained by having sort of a lancing or a incision and drainage procedure done to help relieve that pressure and pus and they get some relief. So these are worse, but they are at least typically transient and can resolve. Draining tunnels are what I kind of showed in some of those diagrams and the pictures of those openings that constantly drain pus. And so those can be chronically inflamed and very tender. They will drain pus every day, enough so that patients have to constantly change bandages sometimes once a day, sometimes many times a day. And so for a lot of patients, they have a constant -- they have tons of bandaging material around all the time. They are spending 20 minutes, 40 minutes, an hour every day just on bandaging before they can leave their house. And they constantly have a bag of bandaging material with them and a change of clothing because if something leaks around, if they've got to change their clothing. So these are a huge burden that patients have to take time and effort and there's a lot of discomfort associated with these lesions. And because they can last for months or years, they're much more stubborn than the transient inflammatory nodules and abscesses we see. And so I think you are going to have a sense that if you develop something like HS, the impact they would have on your life would be huge, right? It is clear from quality of life studies that has a bigger impact on things like atopic dermatitis and psoriasis, not that those things can be bad. But it's nearly as common as those things and much worse on average. And if we ask patients specifically, what -- how do these different lesions affect you in different ways? Or would you consider the impact of them? It's clear that it's not just intuition of physicians or experts that patients rate specific types of lesions is being worse. So inflammatory nodules clearly have an impact on this first column year. This is quite a burden to deal with. Abscesses are worse probably because the pain is increased because there's that worry about drainage spontaneously at any time. And then draining tunnels because they are so chronic, tend to be rated as the worst lesion because patients know that they've been dealing with it for a long time. And it's not something that -- where there's an easy light at the end of the tunnel for them. Non-draining tunnels, eventually, sometimes these areas do burn out or with treatment they compound. They stop draining, they become almost scar-like and they can reactivate at some point, but that is less of a burden at least. It can be a problem, the scar could be itchier kind of sore, but it's not the same as an area that's draining. So it's a major improvement when the disease transitions from lots of draining tunnels to non-draining tunnels and scar. And patients rate drainage as a hugely important aspect of impacting their life. Pain is most often the #1 problem that patients point out. But draining it is often that rated #1 also or as close behind it because again that burden of constant managing odor having to deal with the chronic sort of upkeep taking care of those areas. Next slide, please. And again, how this impacts patients' quality of life. Again, it's not hard to imagine that if you have areas that are always painful, if it's on the but people to sit at a desk for a long time. If you have a job that requires a lot of physical activity and using your arms where it rubs and causes pain out of the arm pits, it makes it very difficult to do certain types of work. So with it occurring early in life, often it affects patient's ability to attend school. And often, it tends to affect their ability to sort of keep and maintain jobs promote over time. And so in lots of studies that have evaluated these things, patients have more sort of -- they miss work more often, more school absenteeism, less likely to be promoted, feel like they've lost jobs over time because of it. And that becomes linked to things like lower socioeconomic status on average for these patients. So things like depression and anxiety and higher rates of suicide, which is tragic and unfortunate. And if you look at certain things like number of children that patients with HS have on average compared to the general population, it's clearly fewer partly because of the socioeconomic impact, or probably because of difficulties with intimacy. Again, most people have no idea what this disease is. And so for a patient in their teens, or 20s to explain to potential romantic partner. I get these boils that are in my groin area and all the scarring, this is a very difficult conversation for a lot of people to have and it takes a lot of trust. And so there are major barriers that it creates for these patients over time. Next slide, please. And so what does treatment mean for these patients? Sometimes we can do very well with the treatments we have. And so what that looks like is this patient that I showed earlier who has large abscesses here that are very painful, can transition over the course of months to having much less drainage. You can tell where this large abscesses kind of deflated. So this patient is definitely much less pain and much more functional. She's a patient who had 2 kids, she works a full-time job from home. She's in her 20s, like very active life, plenty to deal with already on top of all this. But we can kind of take her from having again or where there's less pain, less drainage, better quality of life. Here, we're planning out surgery because some of these tunnels just haven't completely resolved, and there is still some drainage and discharge. So it's still a fair bit to manage and surgery's going to get her even better, but she makes a big step forward medication. Next slide, please. And similar here, this is another patient consider as having a good response to current therapies, right? This first picture he can't even really lift that arm enough for me to get a good look. You can tell there's a lot of drainage. There's a lot of pain there, a lot of inflammation and ulceration. And after a few months of what I consider a pretty successful treatment, he's got very limited ulceration. He's got some remaining scars and a little bit of tunneling that's left behind with very stint drainage. But again, he's able to sort of work more successfully and sort of have much less impact on quality of life at this point. So it's a huge benefit to these patients in what they can do with their life, how they interact with other people, their families and their loved ones, when we can get them improvement. Next slide, please. And again, we're going to switch gears a little bit here. I'm going to try to not make the science kind of too complicated and not lose anybody here, but the general idea is that C5a is something that we've known for a long time is important inflammation. And we often think about the company and the pathway is important and bacterial responses to fight bacterial infections, but it's been known for nearly 50 years now that it's important for things like neutrophil activation, bringing this into neutrophils or disease inflammatory cells to the side of things like infection or to other sites of inflammation and creating a response to bacterial infection results and things like the pus that we see around infectious processes. So a lot of what's in pus are neutrophils. And you can see here that when neutrophils are activated, they start to form all these little blebs to the outside as they're attacking 4 pathogens like bacteria. So you can tell that in the presence of C5a, they go from being kind of calm here to sort of being really active with all of these blebs kind of you're off to the side. Next slide, please. And so they are clearly very important in HS. And with all the pus that's present in HS, it's no surprise that neutrophils have some active rolling disease. And it's kind of hard to explain. I think if you're not familiar, looking at skin that are histopathologic images. But here you can see the border, this kind of collection of cells that kind of looks like it's here to stripe on those. That's what borders, it looks like skin, but this is bordering one of these tunnels and this sort of white open space here is the middle of that tunnel. And so there's neutrophils inside that tunnel, all these little tiny blue cells around it. There's a lot of neutrophils mixed into those inflammatory cells. And so it's very clear that neutrophils are attracted to these locations. They're important in creating the pus and a lot of the information that we see. And there are also important in things like breaking down tissue that ultimately leads to things like scar formation as well, which is what we see later in disease. Next slide, please. I think in C5a it's important to rating lots of inflammatory processes. It's not purely just neutrophils. It has a lot to do with stimulating other types of cell growth. We know that all these inflammatory cytokines like TNF, which is targeted by currently available treatments as well as things like IL-1 and 17 that are important in lots of inflammatory processes like HS and psoriasis and Crohn's disease, that it plays a role in sort of stimulating further production of all these inflammatory cytokines. And again, other things that are important in HS were like vasodilation and edema that is redness and swelling of the tissue around those areas, and also production of things like matrix, metalloproteinases, NPs and fibrosis, which lead to the scarring process and contractor that we see in HS. So it really is at the center of a lot of the processes that are important in a lot of the misery that HS causes for patients. Next slide, please. And again, it's hard to get into the weeds too much sometimes in some of the scientific background. But I'll tell you that when I was in medical school, the main thing I was talking about complement was that it was important for killing bacteria. And so down here, we see things like C5b through C9b, which are all important in sort of attaching to bacteria and basically killing them off directly and C5a never got much credit when I was in medical school. But it was very clear at that time and just something where there was all the links aren't piped together, that when you have things like responses to bacterial infection, you need to pull in the other parts of the immune response, including neutrophils. And so C5a and C3a, other similar parts of the complement cascade work as those signal players and say, "Hey, there's danger here. There is infection. And we need to bring in things to attack it." And so again, that's how -- that's the way that initial bacterial response pathway recruits inflammation as part of that process. And if you have an aberrant response for all of a sudden, you're responding like those bacteria around that are dangerous even when there's not like we see in HS, you start to mimic these pathways to over express these pathways. And so when C5a is elevated, we get these exaggerated responses at inappropriate times. So even though there's not infection around, we see what it looks like a response to infection. These patients get misdiagnosed very often as having infections because that's what it looks like. Next slide, please. And so the sort of first proof of concept in HS really came with vilobelimab. It was described as IFX-1 at that time. But in this early pilot study with just 12 patients, there was a clear signal towards improvement. And obviously, early studies that are open label and unwind, it's very hard to read too much into them. But seeing the large majority of patients here seem to respond in a positive way was enough to spur on further study and further interest in targeting C5a as part of HS management. And so fortunately, there's a lot more to the story, which I'm not going to cover myself, but I'll be -- I'm always interested to hear it reviewed. But again, this was the first start towards really seeing C5a in action in HS. Next slide, please. So summarizing again, HS is a miserable disease, even though it's something that a lot of the audience may not have ever heard about before, they started looking into it, it is out there. Is it very common. And I am overwhelmed with the number of patients that I need to treat and under -- don't have the tools that I need to feel like do it the best that I could as much as I try. There is one treatment available. Again, that's been a huge paradigm shift in how we think about treating HS, but there are just too many caps and what we have available right now. And clearly, draining tunnels, which I mentioned is having the highest effect on quality of life, how we measure HS right now with highest HiSCR response. We're going to hear more about this. It really focuses mostly on abscesses and nodules. It makes draining tunnels very secondary. So there's a major need to rethink how we evaluate HS because these very high placebo response rates are difficult to explain and very difficult to interpret in trials. And so we need to really focus on tweaking them in some way to make training sinuses more important and to really be able to reliably tell when there's improvement. I mean C5a, I guess, based on these early studies, especially is a promising target to be able to do that. Hopefully, I've not taken up too much of my time slot here. So I will go ahead and pass on, but I'll be excited for any questions that come in like I said, I can talk about HS all day and we'll be happy to answer questions as we get to that section.

Chris, thank you so much. This was a fantastic overview of what's going on with these patients and really illustrated the suffering that is related to Hidradenitis Suppurativa. So what we want to do now is zoom in a little bit on this potentially new treatment for these patients, vilobelimab's mode of action and go a bit deeper on the role of C5a before we come to the data and the new end point. So the terminal complement pathway is known for a long time, especially there were drugs available or one drug specifically that target C5. Now C5a, however, a is the key inflammatory, pro-inflammatory player that interacts with 2 receptors. The most well-known one is C5aR. And the other one that was later discovered and has some inflammatory role, pro-inflammatory role is the C5L2. Now the overall activation of these receptor leads into a strong pro-inflammatory response. There has been a lot of discussions on the role of C5L2. And the name is a little bit misleading because this is also a receptor for many other ligands like C3a, ASP, C4a. And so it's not surprising that it was discovered that this receptor has different pockets for these different ligands and actually causes different signaling with these ligands. And for C5a specifically, the signaling results ultimately in HMGB-1 induction, which has been indicated to play a real important role in the inflammasome disease, and therefore, also specifically in skin diseases. So overall speaking, C5a acts as 2 receptors, mostly through C5aR, which is also a lot more common on different cell types and causes a very pro-inflammatory response. Next slide, please. There's something very specific about C5a generation, which was really discovered by us, by InflaRx. You see on the right side, in blue, the complement pathways, they are very well known, 50 years of research. There are different ways, classical acting and alternative pathway to activate complement system, which ultimately leads into the generation of C5 upon rotations, which then cleave C5 into C5a, which I just described and C5b, which is an important part of our immune defense. However, it was also a long note, but really not really paid attention to that. There are other mechanisms that can cleave off C5a like the enzymatic cleavage, sometimes referred to as an extrinsic pathway. And that can be done to thrombin, trypsin, LSAs and other enzymes. They go to the so-called scissile and cleave off C5a and we have proven that this results in full length biologically active C5a. Now why is this important? Because the traditional C5 inhibitors, the antibodies available to block C5 could not prevent this type of activation. So in other words, if you do not target C5a specifically, you will not get the signaling of C5a that is caused through the receptors under control. Next slide, please. So our drug, vilobelimab is really a first-in-class drug that we believe we've been the first to introduce into humans for some years ago, while there were several other developments this is specifically difficult. Why? Because C5a when it's cleaved off from C5 may undergo a certain 3-dimensional change such that a new epitope or confirmational epitope is formed. And we discovered this epitope and the fact that vilobelimab binds to this epitope led to 2 very important key features. First of all, it gives us full control over the signaling. So we can really block signaling to receive -- have a very completely in human blood. Second interesting part of that epitope is, when we buy in there, we are very selective. That means we do not turn down or inhibit the other part of the complement system, the formation of the membrane attack complex, which is important for bacterial defense. So these are really unique features. And aside from the many known inflammatory actions that C5a causes, vilobelimab is truly able to inhibit them. Next slide, please. So this slide was already shown, and I'm showing it again because I wanted to drill a little bit deeper on that mechanism. Now we are here talking about the so-called neutrophilic skin disease. So this HS like pyoderma gangrenosum is believed to be driven by neutrophils that are abundantly present around the lesions. And therefore, there is an implied role that they may have in this disease. So C5a is really just chemo-attractant. That means without C5a, you don't even get these cells into the tissue and to the site of inflammation. Aside from the activating mechanisms that Dr. Sayed already alluded to, there's also recent research showing that C5a induces NETosis, which has been implicated to be important also in skin disease. Next slide, please. So when we talk about chemo-attractant, that means -- there is this factor that attracts the neutrophils into the tissue to the source of the site of inflammation. There is a great work from the Harvard Research Group from a group of Professor Andrew Luster that was published some years ago, which gave a lot of insight in the mechanism. Now this is a rheumatoid arthritis model in mind. However, what that study really worked out perfectly nicely was the role of C5a on how it attracts neutrophils into the tissue. And what you see in green, these small green dots are labeled neutrophils that have less left the grade blood vessels. So it's a live image in a model of inflammation of acute inflammation in the joints of these mice, so rheumatoid arthritis. And so they have left the blood vessel, and you see that magnified to the right side still here where these larger green neutrophils that have different shapes have left the blood vessel and are moving into the tissue. Now if you're working with the C5a receptor knockout and you can mimic that very likely also with antibodies. So when you are disabling the interaction of C5a to C5aR, you see in the same model, literally no neutrophils sticking or trans migrating into the tissue. So what this group has worked out in a beautiful way is that the initiating step of chemotaxis, the rolling and the sticking and the adherence to the endothelial cell war is solidly induced by C5a. So without C5a -- C5a-receptor into action, you do not get neutrophils into the tissue. C5a also induces LTB4 and BLT1 and engages then the next step, the transmigration process. And there are different chemokines which are differently important, and all of them are important to then further attract the neutrophils to the tissue. So again, without C5a, actually, you are not initiating the first step. Next slide, please. So how does it all tie together into HS? So we were the pioneers in looking into this disease because we got very interested because it's a neutrophilic disease, a neutrophil-driven skin disease. So the first thing we looked at is whether these patients have elevated C5a levels, and we have now shown that in different studies with validated ELISA assays in a controlled setting. So this you see on the left side here, the first publication that we worked on with the group in Europe, and we showed that C5a was clearly elevated in these patients, sometimes to a very high extent. Now another thing we showed, and I didn't want to repeat the data here in the middle, just mentioning them, is that C5a in the plasma of HS patients turned out to be the sole factor that immediately activated neutrophils in a setting that we call an ex vivo model. Now on the right side, it shows you that we were actually in patients, and this is the study that was quoted by Dr. Sayed. This was the first time we used it in an open-label study where we dosed patients with 800 milligram every week, and you see that C5a levels during dosing on day 22 and day 50 were very well controlled with 800 milligram of vilobelimab every week treatment. Now on day 50, we stopped the treatment and you see that C5a levels increased again. Next slide, please. So let's look into what we discovered and how we're moving forward. Next slide, please. So briefly, recall the SHINE study. This was a study where we treated and enrolled 179 patients and treated 177 of them in a 6-arm trial design, so placebo group and 5 -- sorry, 4 dosing groups of 5 [indiscernible] 4 dosing groups with increasing doses up to the high dose of 1,200 mgs every other week. At week 16, which was the primary endpoint readout, and until then, the study was placebo-controlled and double-blinded, we switched to an open-label long-term treatment of 5 months and we split the teams, so to speak, in 2 groups. All the patients that received a response score, a response on the original HiSCR were then treated with a pretty low dose that was 800 mgs every 4 weeks to see whether they keep their response. Now those patients that did not achieve the HiSCR, the traditional HiSCR response, they were treated on with what we call the medium dose, which was 800 mgs every other week. And so the goal of this study was to test whether we have a dose-dependent effect of vilobelimab on this score on the traditional HiSCR at week 16. And other goals were whether we could assess long-term safety of vilobelimab and test the durability of our response during the maintenance therapy when we switch into a lower dose. You may know the outcome of this study. We have published this extensively and also outlined that. The primary endpoint was not achieved. There was not a dose response. And we were very surprised that the placebo response rate was up to 47.1% at week 16. Now let's brief -- sorry, please go back to slide -- now let's briefly recap the HiSCR. The traditional score HiSCR means that you have to reduce the abscesses and nodules by 50%. So you count the total body abscesses and nodules, and you have to reduce them at least by 50% from baseline. While at the same time, there's 2 more requirements, you cannot have more baselines than you had -- sorry, more abscesses than you had at baseline. And you cannot have an increase of the number of draining fistula, which are now referred to as draining tunnels, also from baseline. Next slide, please. So when we look -- took a closer look, and I'm just going to give you 2 slides here, at what happened, otherwise, we saw that there was a somewhat dose trend -- dose response trend when we just look at the mean AN count on the left side here. And to our surprise, we saw a rather substantial decrease of draining tunnels in the high dose group, which you see on the right side, which post hoc resulted in a positive p value when compared to the placebo group. So there was a significant reduction in draining tunnels, and it looked like that there was also somewhat a dose effect on the reduction in the AN count. Next slide, please. So the logical thing was to look at that as combined total body inflammatory response, so to speak, so taking all inflammatory lesions, abscesses and nodules, and draining tunnels together and just counting the total body count of them. You see that, first of all, there is again a dose response pattern here at week 16, but there's also a fact that compared to the placebo group, there was a pretty substantial difference in the high dose group. Next slide, please. So the next thing we asked ourselves is when these lesions are reduced, how well does that correlate to what the patients report. Now as you know, patient reported outcomes are always varying a lot. It depends on the time of the day. So you usually need relatively high patient numbers to have a correlation. And on the left side, you see we correlated it to the Life Quality Index, the Dermatology Life Quality Index, but also to us asking the patients on their skin pain on the nominal skin pain scale and also on the drainage impact. And what we found out to our surprise is that the reduction of draining tunnels correlated significantly with improvement in these patient reported outcomes, but it was also correlating better than the other lesions. So in -- I would say, in concert to what Dr. Sayed had described, but the patients themselves voice about the impact these data on a relatively small data set, clearly indicated that the reduction of draining tunnel seems to be correlating well with improvement for the patient. Next slide, please. Another learning we made was related to the dose of vilobelimab. And this is really a new side that has not been previously published by us. This is the C5a concentrations in this trial from day 1, so pre-dose 2 week 16. And as you can see here, the white boxes are the placebo groups. And then the colors up to dark blue is the high dose group for each time point. And just visually, it's very nice to see that a day 4 date, so the first time post dosing at week 2, we had a relatively tight control, maybe also because there was an introduction of 3 doses of 800 milligram within the first 8 days before we went to the every other week dosing. However, at week 6 and week 16, it became apparent that only in the high dose group, we had a somewhat control over the C5a levels. And while they were being still somewhat in the normal range, they were not as tightly controlled as before. Next slide, please. So when we summarize our key learnings, we had to come -- we had to go through. We really had 3 main key learnings. So the first key learning is the reduction in draining tunnels is very important for patients suffering from draining tunnels, which is not really reflected in the HiSCR. So this was one important learning. The other one was the HiSCR has several short counts. There may be very high placebo rates. One of that is also supported by a recent trial readout with guselkumab, where there was also a relatively high placebo response rate with this score. And we know HiSCR does not take into account reduction of draining tunnels. It's not part of how this score was constructed, but draining tunnels are really impacting quality of life. And last but not least, we found that the score of the traditional HiSCR is very much driven by the end count reduction requirement. And that may be because abscesses and nodules are the most frequent lesions, but also the ones that fluctuate a lot. So last but not least, we feel that vilobelimab was under dosed even though we did see an effective dose, all the research work we did, and some of it we've shown here really indicated that we needed to do dose a bit higher. Next slide. So this really led us to searching for an endpoint that was really serving these patients that suffer from draining tunnels and really probably can alleviate some of the problems we detected. So the modified HiSCR considers reduction of all 3 inflammatory lesions, it emphasizes reduction of draining tunnels. It should anticipate to also help to control placebo response rates. And we were looking for a score that was dichotomous and non-weighted. So the FDA acknowledged that the draining tunnels are important for patients. And we suggested also adapt the HiSCR and also to include the improvement or the reduction in draining tunnels. And this was supported by the FDA within our Type A meeting, and this is how we came to the new response definition, modified HiSCR. Next slide, please. So this is the modified HiSCR as it has been constructed by us. And I'm going to walk you through this important slide. In the center of the slide, you see the 3 inflammatory lesions, nodules, abscesses and draining tunnels. On the left side, you see the traditional HiSCR, I'm not going to repeat the 3 requirements. On the right side, you see the modified HiSCR. So this score has 2 main requirements. The first one, you have to reduce the total body inflammatory lesion count, total ANdT count by 50% or more compared to baseline. But the second requirement of that score is, you have to also to be count responder reduce the draining tunnel count by at least 50% relative to baseline. So this was the new endpoint that we came up with, and it's my pleasure now to go into what that does to us and how this score looked like on the SHINE data. Next slide, please. So at week 16 when applying this new score to the data set of patients that had at least 1 draining tunnel at baseline, hence the slightly lower in size in numbers here, we saw that the placebo rate was well controlled with 26%, while the high risk group clearly showed an effect in this case, 54.5% response rate. Now please remember in the SHINE study, and we showed that slide earlier, there was a significant reduction in draining tunnels only achieved with a high dose score. The modified HiSCR response demands at least 50% reduction of training time count to baseline to be a responder. So it's not surprising that there was a significant improvement on the modified HiSCR only observed for the high-dose group. And since this was the only group that showed a significant reduction in draining tunnels. So this was a great sign for us that this score really reflects what we designed it for to be reflecting the important of trading tunnel reduction for patients suffering from that. Next slide, please. How did that work in the long-term phase? So when we treated the patients' open label. So here you see at week 16, we grouped the patients according to the new score, the modified HiSCR. So every responder was in the 100% responder group and the non-responders were 0 at week 16, of course. So keep in mind, these patients were dosed with a non-optimal dose. Most of the patients here that showed a modified HiSCR response were dosed down quite a bit. And most of the patients that showed no HiSCR response got a dose or a higher dose. So what that showed is that long-term treatment really led to improvement in the modified HiSCR in week 16 for those patients that didn't have a response. At the same time, not many patients, but some did dropped from the 100% response over time by having a suboptimal dose long term. Next slide, please. So another interesting way of looking at that is when you're looking at the original treatment group, placebo group versus the high-dose treatment group. So keep in mind, in the main phase of the study in the main period, these are the patients that were placebo patients the gray line or patients that were in the high dose group, which is the blue line. And you see that over time, the placebo patients, these patients did not know they were not retrospectively unblinded. When they were put on drug, over time, even though not an optimal dose of the drug, there was still a response detected leading up to over 40%. Next slide, please. So the next thing we wanted to ask is how does this new score correlates with some of the scores we had previously looked into and shown or existing scores and also to patient-reported outcome. So I'm going to walk you through this, some of the scores we have recently been speaking about a lot was the IHS-4 score. So clearly, there was a correlation, I would say, a good correlation to the IHS-4 score. Now keep in mind the IHS-4 score needs to go down in score, which shows improvement. So hence, there's this negative correlation. When we made out of the IHS-4 score, a dichotomous requirement after seeing how many patients achieved a 50% reduction of the IHS-4 score, we saw an even better correlation to the new modified HiSCR. However, that score also correlates well to the existing HiSCR, which is important. It also shows a significant correlation to some of the patient reported outcomes. So improvement in skin pain, improvement in the Life Quality Index, the lower the index, the better the patient and also improvement in the drainage. So the modified HiSCR really correlates with these endpoints and with patient reported outcomes. Next slide. Now this is an important slide for us, and I would like to take a couple of seconds here on that slide. So we tried to analyze in detail how the pharmacodynamic markers, so C5a levels of the patients correlated with response in this new modified HiSCR and also in draining tunnel reductions. Now -- when we did this analysis, we looked at different groups, and we found that there was a clear signal for patients that had a very tight control. So we looked at patients that showed C5a levels below 10 nanogram per ml with our validated ELISA. And even though these are low numbers, there seem to be a clear signal towards a correlation between patients achieving this high tight control load C5a levels and this response, which is here shown in dark blue in the modified HiSCR in this new HiSCR. Now we talked a lot about the correlation of that score to draining tunnel reduction. And on the right-hand side, we therefore conducted a similar analysis asking ourselves, is there a correlation in this pharmacodynamic parameter in C5a to draining tunnels. And not to a greatest surprise, but certainly to our pleasure, we found that there was a very similar correlation when we looked at patients that showed tight control of C5a levels, so below 10-nanogram per mL. So we believe this reflects nicely the trend and the signal that C5a levels are important and they correlate when they'll be tightly under control with this response in this new modified HiSCR. Next slide, please. So I just want to recap. The modified HiSCR is a new primary endpoint for patients suffering from active draining disease. So it does consider reduction of all 3 inflammatory lesions, it emphasizes the reduction of draining tunnels. There is, it's anticipated to help control placebo response rates, and it is a dichotomous non-weighted score. Next slide, please. I would also like to introduce to you a secondary endpoint, which we here introduced into the study, which we call extended modified HiSCR. Now the extended modified HiSCR is a very similar score, but it carries one additional requirement, which is the requirement that was originally also present in the traditional HiSCR. And that requirement is that you cannot have an increase in the abscesses count from baseline. Now why did we include this endpoint and call it extended modified HiSCR? Now this was an outcome of a discussion on the endpoints with the FDA, and it was recommended that we also include the aspect of no increase in absences from baseline in an efficacy endpoint. So I do want to share that when we're applying this extended modified HiSCR response to the SHINE data set that we saw relatively similar patterns with respect to response numbers, correlation to other endpoints and patient-reported outcomes. Now these are small numbers. And certainly, they have to be always taken in retrospect with a certain care. But we introduced the score as an outcome of the discussions with the FDA to also put this requirement in. Again, we do not believe this changes the modified HiSCR response a lot, but it is a requirement that we wanted to research in the secondary endpoint. Okay. With this, I am really at the end with the modified HiSCR as our new primary endpoint and related aspects. We hope that you are equally excited about this endpoint, which we took a lot of effort to develop, and it's my big pleasure to hand over to our Head of the Immunodermatology Development Franchise, which is Dr. Hoda Tawfik. Hoda, I'm very happy that you, who has been very instrumental in this development now take over and explain to us the currently initiated Phase III program. Hoda, the floor is yours.

Thank you very much, Niels. I'm really very happy to introduce to you our Phase III program initiated in January this year. So last year, in November, we submitted the study protocol to the FDA for approval. And we did not receive any comments from the FDA within the 30-day and the 60-day review period. Therefore, we do not expect any critical protocol review issues pending with the FDA. Accordingly, we initiated the trial activities for the pivotal Phase III study with a newly designed primary endpoint, the modified HiSCR as explained by Niels. We expect, of course, to continue our interaction with the FDA, with respect to the trial protocol. If you look to the study details, the study population still in the same -- yes, exactly, thank you. If you -- we look to the study population, the study population is the moderate-to-severe Hurley stage II to III HS patients with at least 1 active training tunnel, which is estimated to be approximately 70% to 75% of the moderate-to-severe patient population. The patient enrollment in the study is projected to start in the second quarter this year and about 60 centers are planned to participate in the study in the U.S.A., Canada and Europe. Next slide, please. On this slide, you can see an illustration summarizing the study design of our randomized double-blind placebo-controlled multi-center pivotal study to determine the efficacy and safety of vilobelimab in patients with moderate-to-severe HS with at least 1 actively draining tunnel. After randomization -- after a screening period, the patient will be randomized in the blinded main period into 2 arms, placebo or vilobelimab, 1,600 milligram every second week in each arm, 143 patients will be enrolled. After 16 weeks of treatment, the primary endpoint, the modified HiSCR will be assessed at the end of week 16, then the patients will enter into an open label extension period. All the patients here will get vilobelimab, 1,600-milligram every second week. After additional 16 weeks, that means at end of the week 32, the second assessment will be done. And then the next assessment will be done at the end of treatment means at the end of week 50, followed by 4 weeks observation till the end of study at end of week 54. Next slide, please. And here are the endpoints of the study. As you heard by Niels, that the primary endpoint is the newly developed, modified Hidradenitis Suppurativa clinical response M HiSCR. And the response of this score is defined as the proportion of patients achieving both total body inflammatory lesion count ANdT reduction from baseline for at least 50%, and draining tunnel count reduction from baseline of at least 50%. The secondary endpoints will be measured or assessed at week 16, and in long-term. We have the extended modified HiSCR, the traditional HiSCR, and the IHS-4. The modified HiSCR again in the long-term as well as patient-reported outcomes and safety endpoints. The next slide, please, shows us the key inclusion criteria for the study. So the patient population of the study must have moderate-to-severe HS disease, Hurley stage II to III, and AN count at least 3 as well as at least 1 draining tunnel at screening and at baseline. This disease should be diagnosed for at least 1 year, and has to be stable for at least 2 months before screening. The patients must have an inadequate response to at least 3-month treatment with oral antibiotics for treatment of HS or demonstrated intolerance or contraindication to this treatment. Next slide, please. Here you can see the summary of the key exclusion criteria. Any other skin diseases or conditions that may interfere with the assessment of HS or uncontrolled active infections. This is an exclusion criteria. Treatment with intravenously administered anti-infectives or oral anti-infectives, other than tetracycline within the 4 weeks prior to baseline is an exclusive criteria as well as any systemic medical treatment for HS within the 4 weeks prior to baseline as well. Other therapies, which interferes with the response measurement in the study or chronic systemic corticosteroid therapy within 3 weeks prior to baseline or deroofing surgery for HS within 6 weeks prior to baseline. And any history of certain preconditions related to other inflammatory diseases is also an exclusion criteria. Next slide. So on this slide, let me please summarize where we are standing now. InflaRx conducted and completed the SHINE study some time ago, and out of which we extracted several learnings. The main and key 3 learnings out of the SHINE studies are related to the pitfalls and limitations of the traditional HiSCR. The importance of the draining tunnel in HS as well as the information we got about the dosing of vilobelimab in HS. Taking all these learnings in consideration and adjusting the outcome of the SHINE study as well as the outcome of other studies with other drugs, InflaRx developed the new primary endpoint, the modified HiSCR to address the needs of patients with actively draining disease. I'm excited that we are currently starting the conduct of the Phase III program with this new endpoint the modified HiSCR. InflaRx went through several stages of the development to understand and work out the role of complement C5a in immuno-dermatology. We learned a lot, and I'm honored to participate in this program and to be a part of the team of InflaRx, the pioneer in the field of complement C5a, and we will continue building out our expertise and our stronghold in this interesting area. Thank you very much.

Thank you, Hoda, and thank you, everyone, for joining us for today's event. As a reminder, a replay will be available on our website under the Events and Presentations part of our website, so that will be available. This now concludes the formal presentation, and we're now opening the call up for questions.

[Operator Instructions] Great. Our first question comes from Steve Seedhouse, Raymond James, who wants to ask a question.

Yes. Are you able to hear me, okay?

Perfect.

Great. With respect to the C5a level data that you presented, this is on Slide 45. So the less than 10-nanogram per ml. Obviously, you mentioned you underdosed. Now it's pretty clear in the SHINE study, and it looked like there was like, I don't know, something less than 10% of patients that retain that level of C5a control at week 16. So I'm curious with the new dose now, 1,600 milligrams in the upcoming Phase III study. What level of control -- like what proportion of patients with that level of C5a control, have you modeled, or do you predict, you'll get relative to the 1,200 mg?

Right, Niels, why don't you answer that question for Steve?

Yes. Happy to do so. So thanks, Steve, for this very important question. Now you picked it out absolutely correctly, at this level at week 16 and looking at patients with C5a levels below 10, this was only a smaller fraction of the patients. Now this is a post hoc done effect. But keep in mind, we did a lot more modeling on physiological-based PK modeling, tissue penetration, estimation, et cetera. And without being able to go into all these details, it was very surprising to us that the slightly higher dose, which is 1,600 showed a very, very different coverage of the interaction with the receptor, especially in the skin. So there was -- I would say, a surprising difference. Now we are not necessarily saying it has to be under 10, because we grow when we did this correlation analysis, patients below 10, and then 10 to 20, 20 above, et cetera. So we didn't go into that granularity. So the data should not necessarily suggest that 10 is the number you need to reach. However, in our modeling, we also took into consideration the Phase II data where we dosed with 800 mgs every week. And so we do have that comparison. And we do know that this dosing led to a very tight control granted that we didn't dose as long with that. So all the modeling really suggests that even though the dose increases only from 1,200 to 1,600, that there will be a great difference in the patients with low C5a levels. Last but not least, I want to say that the modeling was really geared towards attaining a certain level of vilobelimab. This is how we set the model up. And also with that model, we showed that, that dose really led to an almost complete coverage of the level we set for vilobelimab to be present. So we feel relatively confident that this dose is the ideal dose for us moving forward.

And a question for either you or Hoda, just on the powering assumptions for the Phase III study, that the kind of 143 per arm, given the new endpoint, what are you assuming for just placebo response and effect size. If you'd be willing to share.

Yes, Neils, why don't you take and Hoda, can jump in as well.

Yes. I'm happy to start and then pass it over to Hoda. Maybe just one thing. We have not disclosed yet the powering of the study. However, I mentioned during this presentation already that we geared that new endpoint to have a good control over the placebo response. And you know that we had a 47.1% placebo response in the traditional HiSCR. So in that same study, we -- in all time points, we circled around 25%, plus/minus 5% or so percent. And we do believe that at least in this SHINE data set, we had a very good control. The reason why I'm saying is, because we had, as you know, the minimal dose group, which didn't get induction therapy and was 400 on every 4 weeks. And we've seen the exact same circling around the 25%, maybe up to 30%. So we do also expect that when we drive this higher in half, maybe certain other effects under control that we haven't spoken about today, but had another occasion, that we would not exceed that 25% a lot. So this is kind of the range that I would like to give you. I pass on to Hoda, as again, we haven't disclosed it, but certainly, maybe Hoda, you can remind again the primary endpoint and that's we did a statistical set up for that endpoint. Yes.

Yes. Actually, we use the data of the SHINE study to give us the confidence about this new endpoint. So we made some post hoc analysis, which also Niels showed in some slides, how it looks like with this newly generated or newly developed endpoint the modified HiSCR, how it would look like, if we apply it for the SHINE study data. And we got by this confidence that even with the dose, the 1,200 milligram, we could show a really good result compared to placebo within the data of the SHINE study. So we are really very confident that even when we are going to 1,600-milligram vilobelimab, that the significance would be even better.

Maybe lastly, I just wanted to ask Dr. Sayed couple of questions. You noted some treatments that you use some treatments off-label. I'd be curious if you could expand just on what you typically use off label after Humira? And then also, when you think about vilobelimab and the new endpoint modified HiSCR hypothetically -- so if this drug came to market having succeeded on the modified HiSCR, and particularly if that's driven by the draining fistula improvement, hypothetically, how would you envision fitting a drug like that and amongst other drugs that might have worked on the old HiSCR endpoint?

Sure. All great questions. So first, I guess, I'll tackle common off-label therapies. Adalimumab coming to market sort of really highlighted the TNFs. And there was some old data on Remicade, which is infliximab, at lower doses at 5 milligrams per kilogram kind of like used for psoriasis. That never works well enough for HS. You have to dose, double that, closer to Crohn's disease dosing and then usually double dose twice as often, which goes to show again. Even if you think you're dosing aggressively to start within the trial, the patients often need more. There's just something so [indiscernible] you need more. So if you do some very aggressive dosing with Remicade tends to be sort of next line after Adalimumab sales. And then other TNF inhibitors like Simponi Aria, or the Simponi is a subcutaneous dose, sometimes will also use -- those drugs are kind of hitting the end of their protective life. And so there's no way -- and there's already biosimilars for Remicade now. So there's no way those drugs everything get approved. So we fight for those all the time off label. After that, it is kind of all over the place. I think what people actually use next. I was using IL-23 agents like Skyrizi from AbbVie for a while or guselkumab or just Tremfya from Janssen. But they both -- Janssen just published secukinumab, it was really just like not helpful. And so that's not going to be pursued. And then like the risankizumab trials, those just kind of stopped early. So IL-23s are looking like a dead and in practice like I never felt like those are doing what I hoped they would. They weren't the step-up that we saw in psoriasis when going from TNF to IL-23s. IL-17s, I try to use they're very hard to get at this point to get approval, but those are sometimes used off-label. But really just kind of throw the kitchen sink at it sometimes. JAK inhibitors, IL-1 antagonist, there is a long list of off-label biologics that we try to use and that are sometimes moderately effective, but there is no like clear path. It's always a struggle to get drugs like that approved. And then we use things like antibiotics, there's like IV or the tandem, which we use as sort of a rescue therapy. But again, the algorithm from the management guidelines is all over the places, because the evidence is very limited still and accessing a lot of those drugs is a big challenge. So hopefully, that answers that one, but I'm happy to clarify some things. I think the next question was it breaches this meets criteria with this new modified HiSCR. How does that fit with the algorithm? And part of that is going to depend on exactly how robust the responses are, but it's like we're not going to have comparative data from, say, like the pioneer study is working to a direct comparison. But if placebo response rates, you're going to hang out of that 20%, 25% mark, and we're going to see treatment responses of 45%, 50% like we saw in the pioneer study. So I think people will read that in a very similar way. I don't think most people are going to make too much differentiation where they say, it's not the same measurement, they love HiSCR so much, because the HiSCR is not -- it was -- it's a great first way that we measure disease. As a step forward because there weren't validated measures, but nobody is like a level that is super strongly tied to it, I think where they're going to say, I don't believe a modified HiSCR all of a sudden, especially if we can kind of show that it is tied very closely to things like quality of life and other measures being approved. So if it has a similar -- it's similar kind of levels of improvement and differentiation from placebo. I think it will be very well accepted is something that is likely to help a lot of patients. If it surpasses that, it's going to potentially be able to margin as you know more often -- more commonly used first-line drug too. So yes, I don't see -- I think people are ready to see the HiSCR, either be modified or other treatment measures we put into play that, that feel more reliable because people are seeing this trend of high placebo response rates and trying to figure out what to make of it. So hopefully those answers the 2 questions. Happy to expand a bit more to sort of, if I missed something there to go a little further.

No, that was terrific.

Thank you, Steve. Our next question on the line comes from Evan Taddeo at Guggenheim. And Evan, I know you had a number of questions in the chat. So maybe you can give us everything you need live. You should be good to go now. Can you hear us, Evan? Well, Evan recovers, I will -- I'll ask his question that he posted in the chat. One of his questions is -- one of his questions, I think for you, Dr. Sayed is, how many abscesses go on to form draining tunnels? And how variable is this across the HS patient population?

Yes. That's a great question. And like the more I've sort of looked through this data and thought about that, I discussed with the FDA about the importance of an abscesses versus the tunnel. I don't think anybody knows the answer to that question. Like I see plenty of abscesses that you drain it, it gets better, and it does all right, but nobody has done stays, I think where they've tracked abscesses and seeing how many turn into tunnels and how many don't. I think it's probably a minority, because I see a lot of patients that, that have especially smaller abscesses that heal up fine and tunnels, certainly do not result in patients can have 50 apps as is over time and develop 2 tunnels, right? So there is -- it's clearly a minority, all those -- I think it varies patient to patient, like some patients that feels like almost everything that pops up, leads to scarring and tunnels is just how their disease kind of varies from others. So I think there's a lot of variation amongst patients, but it's probably a relatively small minority of assets that actually become a tunnel over time. But it would be an interesting study to try to do where we follow that over time, but that's more of my curiosity. So I think it's -- I would say it's generally a minority though. And in abscesses it's form within chronic tunnels, what often happens is that there it is chronically draining tunnels that they try to sort of scar over and seal at their drainage point. And because they can't drain any more, and abscesses builds up within that. And so a lot of abscesses are actually sort of a temporary flare or a temporary change in a chronically draining tunnel. And those are sometimes the worst, because there's already this big pocket that's there for the pus to fill. So those abscesses isn't get really huge sometimes. But then that abscesses comes down, and it goes back to what the baseline was.

That's great. Hopefully, it's good for Evan. And maybe hoping me if he has a follow-up. Another one of his questions for you Neils and Hoda. Is what has to be done in the eyes of the FDA for the modified HiSCR to be validated? Do you perform any additional analyses? Or is this validation already built into your Phase III program?

Yes. Maybe I'll start and Hoda, if you want to add, please feel free at any time. So...

Go ahead.

It's really difficult for us, and we should probably not try to speak for the FDA. So I would say there is definitely general guidance, and we have discussed on principles how to fully validate -- you know that the traditional HiSCR was also borne out of, I wouldn't say a failure, but a not so easy readout of a Phase II study back then from adalimumab. And similarly, this was borne out of Phase II study, the new HiSCR, new modified HiSCR. So the traditional HiSCR is modified in Phase III. That's the same thing we have to do. There are ways you are validating such a score. There are guidelines as to how to do that, and we have gotten also experts, U.S., experts on how to do that to incorporate that, and we have shared that with the FDA. So there are tools that relate to patient-reported and physician-reported tools that you use as an anchor, in order to validate the outcome. Obviously, one of the work that's always interesting is to see and we showed some of that, how does it correlate to existing scores that are either accepted or used in the past. Hoda, I don't know, if you have much to add, please feel free.

I can't agree more. Just to add that, if you remember what I showed in my slide with the endpoints that we are including in the secondary endpoints, patient-reported outcome, but also physician global assessments, which will help us in the validation of the -- of our primary endpoint. As Niels said, as discussed with the experts, with U.S., experts and also discussed with the FDA. So these are well-known tools, and we will get advantage of it.

Great. Thank you, Hoda. So Evan's last question, he is having some microphone issues. But I think his last question is, how will the modified HiSCR be reflected in the label? Would this ultimately narrow your label on HS, specifically to moderate-to-severe acting draining disease? And so I think from our perspective, that is our proposed indication. I don't know if Niels has any comments, but maybe what we can ask is, which is important here. We've seen approximately 70%, 75% of the Hurley II and III HS patients in our data have active draining tunnels. But maybe Dr. Sayed can see what he sees in the physician community in terms of that proportion?

Sure. So on -- yes, Hurley II disease is defined by at least scar being present, and then typically there are tunnels that are present. And if I'm thinking about using a biologic drug or a patient who's going to potentially do home injections or infusions, they're often going to have draining tunnels that are active more so than just old scars that are present. So I don't think it's going to be a huge limitation. I think the large -- the very large majority of patients that we put on biologics already, probably have draining tunnels when it comes down to it in real life. And again, the labeled indication is what's there. I don't think it's going to limit how I use it. I think if there are patients where they've got Hurley II disease, it's very active in some way like in reality. And I don't want to like -- I know there's regulation about, so I can say, but in real life, like I am sure that I will try to fight to use that drug even like slightly off label in patients who feel like they need it. Again, it may be something where I've got to argue it and appeal it. But if I know that it's likely to be helpful, in my mind, I'm going to sometimes be fighting for in that way, too. But I think, again, the majority of patients I already treat have draining tunnels that it is going to be a minimal limitation in my mind.

That's great. Thank you, Dr. Sayed. So we also have -- we do have some more written questions. We have similar via questions, but I'm just going to answer, I think, readout some written questions that I think are important here that have been asked by Joe Schwartz from Leerink. And one of his questions he's asked with the divergence between the Phase IIa and Phase IIb data, how are you thinking about trial sites in the Phase III? What steps InflaRx taking to ensure proper clinical trial conduct? What's the expected mix between ex-U.S. and U.S. sites? And I think this is a good question for Hoda and Korinna Pilz, who was also on the line, if they want to enter those questions.

So Korinna, you would like to start and then I can continue.

Not necessarily, just go on.

So in the Phase III study, we have, as you said, a mix of U.S., Canada and Europe to be able to cover all the international region. And we have a good relationship to lot of sites in the U.S., and also in Europe. And as I said, we will have about 60 sites enrolled in the first study. And how we will put waiting in one or the other region, I would like to wait with this information until we start the study, and then I can give this information later. But generally, we would like to have information from the 2 areas, U.S., and from the other side on the above the Atlantic.

Maybe if I may, I will also add to it. Hoda, I think, Joe, me also reflect a little bit to the question how do we control trial conduct. And I may be able to say a few words and please feel free to add. But the SHINE study really taught us a lot. And of course, you need to make sure that you don't have side effects, so you don't want to have 1 site enrolling 1/3 of the patients. So this is something we can -- we are definitely installing. But there's also other things you can install in a way you stratify, and this is something where even though we have not made that public, we put a lot of thinking into how to stratify, how to make sure that we balance what we get. Also, if you think about with the emphasis on draining tunnels you also want to know, you want to know, is this balanced in the groups. And so I think we have really put a lot of thoughts even though not all of this is in the public domain for various reasons, also for competitive reasons. We've put a lot of thoughts on how to control that. I would just like to add, like, ultimately, next to these very important control mechanisms, which really relate to having similar routes in placebo versus placebo -- versus drug, because that happened in the past in some trials. Next to that, I would like to say that we really put emphasis on controlling the placebo response. And we believe that looking back at our data, with that endpoint, they have the most important way to control placebo response. I think together with the mechanism of install that I kind of hinted to, that should give us a really good handle. It's not an easy disease. There's fluctuation. The reason guselkumab data show that people struggle with a traditional score, and Dr. Sayed also alluded to that, there is certainly the need for more control. And with our post hoc analysis, we believe we will get that. Now we don't know, if that's case looking forward, but the data we have show that.

And maybe I can add also one sentence also from the operational point of view. Of course, the study will be conducted or will be managed by a CRO. However, we have a strong team at InflaRx, where we will continue having an interaction with the experts in the U.S., and in Europe, always interacting with them and getting a feeling from the field how -- what is going on in the study in the different areas to keep the control in our hands and don't allow any deviation. So -- from the operational point of view, a strong CRO and a strong team in-house.

That's great. Thanks, Hoda. So more questions coming from Joe, in terms of the trial itself. And I think this is an interesting one is, how many patients are projected of active draining tunnels? Can they resolve spontaneously, or do all patients have active tunnels? I think this is more of a [indiscernible] question. And then kind of digging into that a little bit clear is, is how are these tunnels going to be characterized by investigators? What is the evidence to support that a patient actually has one? Are these patients that have active draining tunnels always considered Hurley stage III? Or is clinicians do they have a different rubric to apply a via response. So Neils, maybe I don't know, if you want to take the first crack at this.

Yes, I can give it a first step. And I'm sure Dr. Sayed is probably the most appropriate person to answer to that to certain aspects of that. But I do think that Hurley stage, as Dr. Sayed explained, is not necessarily reflecting always like a clinical trial setting. But it was rather a surgeon view on the disease. However, and I think, Chris, you already mentioned that, that a lot of the Hurley stage II patients have active draining internals. So I would not kind of narrow this to 2 or 3. I think the patient population we chose in general is the patient population that carries these lesions. Now not everyone has a draining tunnel. I think Jordan mentioned 70%, 75% in our setting had draining tunnels in the SHINE study. That may be different if you go to different regions in the world. But I think also, I heard Dr. Sayed already say that there seems to be a majority of the patients that he sees that actually are considered for biologic, which I would assume would then also be potentially considered for a trial with a biologic would have draining tunnels. So the last part of that question was also to the spontaneously resolve. That's not, to me, to my understanding, maybe not the easiest question, because I do understand that there are some spontaneous or long-term true resolutions that last. But there's always this grey zone like with all these lesions, there's always an interrater and intrarater variability. I don't think that anything can take that away. So the way that the draining tunnel was diagnosed in our trend before is really -- there has to be a physical examination and also applying gentle pressure on pulp patient in the area around joining tunnel to see whether that provokes the discharge of liquid cost. If it is completely dry, it's certainly not a draining tunnel. And as you can imagine, if a draining tunnel is on the path of getting better, you may still see it in a patient today, you may see the patient then in 4 weeks or 2 weeks down the line may no longer be diagnosed at draining tunnel. So I can confirm there are a few patients where within a trial, you will have what you may call spontaneous, which is difficult to prove, but we'll have a draining tunnel at one point without interfering with the drug and that no longer be a draining tunnel next time. But I don't think it's a large amount of patients, at least not in our data. But I pass it over to Dr. Sayed, because I think he may have a much better view with his expertise background than I do for my trials, right.

Yes. So evaluating HS from a clinical standpoint, whether it's AN counts or being able to say with complete certainty that something is -- there's a time at a [indiscernible] there is a grey area there, it's imperfect. But usually, again, like if there is drainage, and it's been occurring for the day, and when the patient takes their advantage off, you're going to see some drainage that's kind of collected around whatever drainage point there is, this tends to be kind of a constant process. And so on the vantage you're going to tell that there's no yellow discharge that's been there, because it's been draining through the day or when they left their arm, you're going to see you can work some passes kind of sitting on the skin irritating it near those openings. So it's usually relatively straightforward. As the disease improves, or is it waxes and wanes and comms, there may be less drainage where again, it takes some dental how patient to have a small amount of plus come to the surface. But generally, patients -- we're talking to the patients asking them too, are you seeing drainage from anywhere. It's something where it's -- there's some back and forth that goes into it to of trying to ask them if they're noticing it or not, either through the course of a day. So you can generally assess how much drainage there is, and have appropriate suspicion that you need to kind of look harder and sort of find where it's coming from. You asked a lot about like natural history like kind of tunnel that's draining spontaneously go to non-draining over time. And yes, there are times where the disease can wax and wane, and somebody can have 4 or 5 draining tunnels at one point and the next time 3 by chance because one is [ calmer ] or I mentioned how they can try to sort of seal over and form an abscesses over time. And if it does that, it's not actively draining. It's non-draining. There's an abscesses there instead. So there is this possibility of some waxing and waning. But the chance that somebody has got 10 draining tunnels going down to 5 draining tunnels spontaneously. That is pretty unusual to see that big of a shift over to a shift over time, whereas individual tunnels can vary some over that period of time. It'd be more unusual to see globally a patient improved to that level. And I tell patients all the time, yes, if there are draining tunnels or even kind of non-draining tunnels that are active from time-to-time, for me, I can't predict if it's going to be active for 6 months or 6 years or 16 years with this back and forth all the time. And that's where we start thinking about surgery over time for a lot of these patients, too, because it's just impossible to predict. But there are certainly patients who they've got some tunnels in their 20s and they've lived with the disease for a long time. They can form scar in a way that the tunnels stop draining over time. It is just -- there's just too much uncertainty, and it's a lot of suffering to have to wait that long. So where there is, again, some very -- like some variability over time to see a major global shifts in them over the course of 16 weeks is atypical, which is why I think we see the modified HiSCR perform better from a placebo response standpoint. Is that you're not going to see that happen quite as often, especially in patients with more draining tunnels to get that [indiscernible] shift over time.

Thank you, Dr. Sayed. Another question coming from Joe Schwartz is based on the regulatory pathway. And wanted to understand what the agency is looking for at approval that they have provided any other guidance what a successful trial would look like? And secondarily, while we're answering this as well is trying to understand how long full enrollment would take. And so maybe, Niels, you can begin and pass it to Hoda with additional commentary.

Sure. Happy to do so. First of all, thinking maybe listening thanks, Joe, for these great questions. So my general, I would say, if I review our interactions with agencies, different agencies, usually they don't tell you how to do the trial, generally speaking, right? You have to propose something and they may reject or comment or guide sometimes. So I cannot really comment to how the FDA sees every detail. Usually, you had relatively general guidance. That's my, I would say -- well, it's my experience. So it's difficult to make like a broader disclosure here what the FDA would concretely look for approval, because as you may see in the very recent past, we've seen approval where all the experts say, we don't see a drug effect. and drugs pretty much get roof. And then we've seen vice versa. So I think that's very difficult. So I hope you understand that it is really difficult for me to comment. And you know that we had, I would say, a not so easy path to get to a type A resolution meeting. This meeting, I think, was really bringing a breakthrough for us, because we brought experts. We brought patients, patient advocacy group leader for that matter. We -- it took a lot of energy and conviction that we are on the right path to make our arguments. And I do believe they've been hurt, which is reflected. Whether that leads to approval, I have to be really cautious on that. But I do believe 1 thing pretty strongly that we've listened to experts like Dr. Sayed and others, that if you have a response and show a substantial reduction of draining tunnels. And that's why I put the slide in it. It's always derived from the 3 same lesions. And from all of our post hoc correlation work, achieving that score is more difficult than the traditional HiSCR, and is more meaningful, likely looking forward. The post update will show that. Looking forward after being very careful making statements. But that's where the company has the conviction that this -- what we show here should be meaningful. FDA approval predictions, I would rather abstain from for that matter. And I pass on to Hoda for the second part of the question.

Enrollment.

So the enrollment, could you please repeat the second part, the enrollment...

Yes, Joe, and some others also ask some more questions in terms of enrollment time lines, when would we expect enrollment to be reached?

Okay. So what we can say that the enrollment start is projected for the second quarter this year. We have our forecast for the conduct of the study, and we have our projection when the enrollment is -- will be finalized. However, this is not yet communicated and please understand that I don't want to communicate it here until we make it public, but we have our plans. I would say, the realistic plans and promising plans and projections when we can finalize the enrollment in the study.

Thank you, Hoda, and I will concur -- once we have an idea...

Exactly.

Concrete time lines, we certainly would educate the public on where that may land. Once we've started enrollment and see how that's progressing.

Correct.

Thank you, Hoda, and thank you, Joe. Hopefully, we answered all your questions. If you have any additional ones, feel free to e-mail me. Our next question is coming from Anupam Rama for JPMorgan, and he had a few questions, I think we answered, but one is for you Dr. Sayed. What is clinically meaningful change in your view in the proportion of total inflammatory lesion count draining tunnels (the M HiSCR) relative to placebo. What is the minimal delta that would get you excited, that you may see in our pivotal study?

Yes, purely looking at change in AN count is going to be -- that will be a secondary endpoint potentially. And I don't know -- I'll be interested to see like some groups have started reporting things like a HiSCR75s, looking at a 75% versus a 50% reduction. I mean hitting a HiSCR50% right now is still kind of the gold standard as far as like a disease reduction, which is important to tell you that you're shutting down certain aspects of the disease, you're hopefully for any progression, meaning there's not as many new leases coming up anymore. So 50% is good. Obviously, I love better, seeing a 75% reduction is a big fleet for most patients. And especially that's an average because I mean some patients are at the 50% mark and somewhere at the 90% and 95% mark. If I could -- if there was -- if it was like psoriasis, where I expect 90% and 100% improvement scores to be reported, that would be -- that's the dream, right? But I think right now, 50% is where people feel like happy from a comparative standpoint that if we can hit that mark in a significant number of patients, that's a clear win compared to what I have to use right now. And if we had 75% that is at the same rate that other drugs at a 50% mark that is clearly a big leap forward. And so I mean, I think, at least having what we have now and having a backup option of some kind, would be very, very helpful. something that surpasses that would be even more valuable.

Great. Thank you, Dr. Sayed. He does have, Anupam has one more question. How do you think about the positioning of our study versus other studies that may be focusing on just Hurley stage III patients? And how that -- how you view that kind of trial design versus how we're focusing on the Hurley stage II and III with active draining -- with patients who have [ acting ] draining tunnels, -- how do you view that in terms of clinically?

I mean, I don't know, these studies that are only looking at Hurley stage III. Most of them -- like the most common criteria is Hurley stage II or III disease, but some minimal number of AN count, like 3 or 5, depending on like the pioneer studies had a minimal of 3, some use a minimal of 5, for an ANdT count for inclusion criteria. But there aren't many that are looking at only Hurley stage III. And in my mind, like I need to prevent patients from getting the Hurley stage III, I'd much rather have a drug that is applicable to both Hurley stage II and III patients. And in a perfect world, even Hurley stage I patients, if we could show some way that, that were blocking progression. But yes, Hurley stage -- I don't want to have to display catch up when a patient is already at Hurley stage III. I want something to use earlier. So much more important tool to have and will apply to many more patients. We can show that in Hurley stage II, we're howling people to.

Great. I think another one of his questions, Dr. Sayed was in terms of the route of administration, vilobelimab as an IV. And there are other products like in the market that are either subcutaneous injection, or I think some of the other JAKs or orals, and as well as there is a C5r AR inhibitor in development for HS is oral. So how do you feel about the route of administration in terms of this patient population and their ability to easily receive infusions of this nature?

Yes. So I mean, for some patients, it's a challenge, having the time and transportation to go somewhere frequently to receive a drug, but there are many patients who prefer that. A lot of patients are needle flow became the idea of injecting something at home is terrifying, but they don't mind somebody starting an IV for them. And some patients have -- like a lot more nausea, where they're kind of leery of oral drugs. And so the idea of something where they can go get it. They don't have to worry about remembering to take it, they schedule their appointments, they show up and they get it done. Some patients actually prefer that, believe it or not, which for me, I feel like it would be hard for me to do that on a regular basis. But for patients who have flexible scheduling, it is often very appealing. And right now, like again, I use a lot of infliximab and a fair bit of Simponi Aria. So those things require infusions that are often much longer. I mean those computes can take 2.5, 3 hours sometimes for Remicade. And patients with HS like they are willing to do it, if they know it's going to help, and they are scared to stop it, if they -- once it starts to work. So that with the disease this bad, patients are willing to do it. One barrier is going to be making sure more and more providers get comfortable with it. [indiscernible] centers across the state and have a good network that I know how to use. Some providers don't do that as often as prescribing subcu drugs. So there will be some -- but more coming back to it, I think, especially around HS, knowing that, that Remicade ends up being sort of a second-line therapy for a lot of patients. So -- and with a lot of other IV drugs kind of coming into for things like Lupus, there are more and more routes for patients to be able to get infusion medications. So there will be some challenges there. But again, I have had at least a few 100 patients on Remicade over the last few years. So as much as it's a barrier for some, it's not going to keep people from wanting this drug if it works well.

Thank you, Dr. Sayed. Our next question comes from Ed White. I saw he has a question in the chat, but he also started putting in the -– raise his hand. So I will ask him from the chat, Ed White at H.C. Wainwright, our analyst. With the higher dose, any comments on the expected side effect profile? Maybe I'll hand this over to you, Korinna, to answer, Ed.

Happy to do. Not sure.

Yes, we can hear you.

Yes, with regard to the safety with 1,600 mg every 2 weeks, I would like to refer also to our PG data that we recently published, where we administered an even higher dose of 2,400 milligram every 2 weeks. And in one of these studies where we used 800 milligram every week, 1,600 milligram -- or 2,400 milligram average 2-week and PG as high as dose, we saw a safety profile or safety findings that we were new with -- compared to the lower doses. So expectations on the 1,600 milligram dose is that it will be most likely could show a good safety profile, and we will see what we have seen before, but we will never know what the expectations are that in this direction.

Thank you, Korinna. Ed's next question comes around the anticipated cost of the trial and how other studies may be impacted by the focus of HS. And I can certainly answer this, and Niels can chime in. Certainly, we have voiced to the market that we have the appropriate capital to start this Phase III program. The program that we were addressing here is the first study that is initiating now that will start enrolling in Q2. There was another question asking about the second study. There will be a second study. In our view 2 studies are needed for approval in this indication. We have not disclosed how much those would cost and we wouldn't quite yet. I think in terms of other programs, we are fully prepared to continue on this immunodermatology focus. What we didn't talk about today, which is extremely exciting is our data in Pyoderma gangrenosum, which Hoda is working also to figure out with the FDA, what a pivotal program would look like. So we are going to continue that focus. We also do have Phase III COVID data coming at the end of the first quarter that we have been guided to. That is certainly still going. Our oncology program is still ongoing as well. So that nothing is being affected by this program at this moment. So, thank you, Ed, for those questions. [Operator Instructions] Our next question comes from the written questions, and this is for Dr. Sayed. Of the 200,000 patients with HS, what proportion have disease that leads them to be willing to take a drug such as Humira?

That's a good question and not something that I think has been perfectly answered from a study standpoint of trying to assess. I think asking that specific question of, are you willing to take a biologic is your disease bad enough. And a lot of that has to do with -- I mean, there's also fear around medication as much different from a patient that you just, I think, were to take off the street as versus might you sat down and talk to risk benefit -- talk to risk benefits on. And again, I think it's much more than 200,000 patients. I think again in most population studies where if you look at -- and the way that people figure that out, HS is misdiagnosed all the time. So when doctors often look at, they call it an abscess or a Staph infection. So if you just look at medical coding, there are all these patients that get missed in the system. But if you start to do things like population-based health surveys and you ask things like, do you get boils and you're growing or like in places like the underarms growing, and does it happen -- does that happen more than a few times. A lot of people say, yes to those questions, which is -- highly suggests of Hidradenitis. And so in those studies as high as like 1% or 2% even in some groups -- or if you look at [indiscernible] look at patient's multiple abscesses over time and combine that with patients coded with HS, you got up to like that 0.7% to 1.2% range. So there are a lot more than 200,000 patients would be the first point I'd make. And the second one would be that, HS, like people have mild psoriasis. They can put on some ointment. They can clear up the few blacks they have around. Your mild psoriasis is often very, very manageable, not a huge burden in terms of quality of life. Whereas, if you talk about mild HS, like Hurley stage I HS, where people are getting 1 or 2 abscesses every month or 2, and abscesses have miserable experience. People get 1 abscesses in their life, they remember that week as being really hard, like they had something where they couldn't set a certain way or they were in very severe pain. And these patients constantly deal with it. So the patients who were sometimes sort of most frustrated are those were their normal 2 weeks every month and their in misery 2 weeks every month, they have this constant back and forth all the time. So many patients even with a mild disease, I think, will be willing to take a drug like this that meant disease stability. I think the patients have Hurley stage II and III disease, which makes up the large majority of who I see it, I think especially being at a referral center for it. Most of them come in, and they say, "Look, I'll let you amputate my arm, if you can get this under control, because it has that big of an effect on their quality of life." So, I think it is a very large proportion there is fear around like TNF inhibitors because of things like the lymphoma warning label that's on there that I think become exaggerated a lot of times in terms of the true risk that presents. Yes, patients dealing with this disease are often eager to do whatever it takes to get it under control. So I would say it's 75% or better. There are going to be always some patients who say, "No, I want to try to do something naturally or just too hesitant to start something like that, or I can't commit to it at this point. But I would say, it's the majority of patients who feel like, if I could tell them, look, this is going to work, the majority of the time for you and make your life better. They will make that sacrifice, if they can.

Great. Thank you, Dr. Sayed. The next question, I'm going to pitch to you, Niels, and I think it's important to go back and explain this is, when we look at the M HiSCR on SHINE, it didn't show a dose response. It just showed the high dose had a significant difference in efficacy versus placebo. The rest of the lower dose groups look-like more placebo. And maybe you could just go back and explain that phenomenon based on why given how the draining tunnels looked, think that may be helpful for you to reexplain that?

Sure. Happy to do that. Maybe while I start, maybe we get asked that we jump to an appropriate slide back, which is go up a little bit. Look, a little bit higher, a little bit higher. Yes. Thank you. So I think the question was why don't we see those response on this slide at week 16. So we did anticipate the question, and that's why we put on the right side here, the key hints to why there's no dose response. So we had an earlier slide in the same slide at which we showed on numerous occasions before that only the high dose, only 1200 milligram was able to significantly reduce training tunnels. Now that makes a lot of sense when you look at the C5a data and the correlation now. And -- that means one of the 2 key requirements, the reduction of draining tunnels is only to be expected significantly reached by the high dose. So that's why with a dose that cannot move draining tunnels, which is largely true for the other doses, it is not to be expected that you have a huge difference in the modified HiSCR response. So this is why we are hinting to that already on this slide, and we made clear that significant reduction of draining tunnels is only there in the high dose, modified HiSCR, but demands 1 criteria and is a 50% reduction of draining tunnel count. So therefore, you can only see a real like significant response when you have a drug that moves to draining tunnels. I do believe that is particularly helpful question and also important for us, because we wanted to design an endpoint that really helps on is there for patients that have active draining tunnels. So you need a requirement that makes sure that you don't just get an overall lesion reduction, but you really help the draining tunnels. Now there was a discussion at some point where the reduction of 1 draining tunnel is important. And when you ask the patient -- I mean, Dr. Sayed, told that before, we asked that your patient, patient representative. Even I've been looking at this disease and trying to learn for quite some time now. I was done, how much, especially 1 draining tunnel can impact your life. I mean some of them can drain the massive amount of fluid. And that patient was also happened to be in a patient advocacy group really make that very, very clear what it even means if you just can lose that one draining tunnel. So long story short, that endpoint was designed to cater the mode of action, but to really then help the patients with draining tunnels. So I hope that it explains that very well, while we don't see a dose response, especially if you do not have a dose that moves draining tunnels underneath the high dose.

Great, Niels. And well, you're still so speaking, another question I think is important as people try to understand C5a, and the mechanism is, why we're not using C5a levels as a patient selection criteria? Maybe you can explain why we're not doing that?

Sure. So C5a levels, that's really something that we looked at for many years in different diseases. And while in some diseases, and I understand where the question comes from. In some diseases, for example, TNF alpha level is relatively indicative of a patient in need. That is not the case in the complement system. There's a big abundancy in how you produce how much you produce even interday differences in production. So you really look at this in a patient population that may be meaningful. But if you look at that on an individual patient, if you look at that during different times of the day, you would get different levels, first of all. Second, the pure fact that you're in the normal range of where healthy humans are, doesn't mean that you don't have ongoing complement activation. Generally speaking, even in the blood, if you do have a flare and you start new, you may have still a lot of receptors around on the neutrophils, which will absorb C5a. So you may have complement activation going on. You may not yet see it on the C5a level area. So you have to somewhat first fill the sink before you see it C5a. And the third thing is here, we're dealing with a skin disease, where we believe a large amount of C5a activation happens actually in that organ in the skin. And what you see in a plasma level, which is the only way we can assess C5a levels. There's no way we can assess that yet in the tissue. You always have to keep that in mind. So if we did a patient selection based on C5a levels, we believe we may lose a lot of patients that are still in need. So I do think the patient selection at this point in time should not necessarily driven by this specific marker, but rather by the pick of the expert on the clinic, like the clinical need that the patient kind of displays. And maybe also to a certain extent, whether the patient has an active disease, right? Because if you have HS, but you're well controlled, you have stars. And you're okay, that may not be a patient need for a biological therapy. But if you have constant waxing-weaning or active draining disease or painful disease then there's a lot more likely [indiscernible]. So I hope that explains it. It's really a complicated issue underneath the surface. And we are actually very surprised and very happy to see that tight control of C5a, however, seems to be indicative of a higher likelihood to respond.

That's great. Thank you, Niels. Great answer. We have another question for you, Dr. Sayed from one of our smart Wall Street friends here who is very thankful for the presentation. And he wants to know from you, if you can discuss ways in which the treatment of your patients with HS has changed in a post-COVID-19 world? And if you -- additionally, have you observed any differences in how patients access your care?

Yes, that's interesting. I mean certainly, it's had an impact in terms of -- especially in the beginning, clinics were mostly shut down except for very urgent issues, which come up more often in the HS. So I think I was probably even more active through those kind of very early days. And since done a lot of has to do with things like staffing issues and trying to sort of have enough bodies to support us in the clinic. So like many other practices, we do more virtual care, which can be done to some extent for HS, a lot of times you need the patient there to evaluate and feel and talk through things like whether procedures might be necessary. So it does certainly has an impact. And we also just can't see the same volume of patients or sorry, even still were a little bit less than we were in the beginning, kind of before the pandemic started. And so I mean that we've always had weeks I've got -- I'm constantly aware of like the 100 or a couple of hundred patients that are on the wait list with HS to get in right now. And I've got 2 other partners that see a lot of HS patients. So that is probably worse than some, just as our volume has decreased, we haven't been able to get to as many patients as we were before. But in terms of the drugs that we use, like there's -- I mean, around biologics, there's good data about TNF inhibitors and to some extent, some of the others that they don't have much effect in terms of worsening COVID outcome. So in the beginning, we were a little bit leery of that. We never stopped anybody these drugs, specifically because of the pandemic. And I still prescribe the same way I would have before, if I think a patient needs it, it is worth doing and the risk benefit kind of constellation is sort of the same. So in terms of prescribing happens, the treatments that I offer, that is relatively unchanged. It's more just again, things like volume and how our clinic and practice approaches patient care and the interface that we have to use.

That's great. Dr. Sayed and another really smart person from the investment community would love to know just your patient volume and maybe your patient volume with active draining disease, I think that would be interesting on whatever you want to share a month, week, whatever basis would be…

Sure. So yes, I split my time with some research and teaching 2. So I'm in clinic 5 half-days every week, previously before I had sort of geared up more with the research, it was 7 half-days every week. And then doing less of those other things. But on Monday, I probably saw between 10 and 15 patients with HS on Tuesday, I probably saw closer to 20. And for a lot of them, those were things like surgical visits in yesterday. I just had a half day in clinic and I saw probably 8 or so with HS. So in a given week, I'll see it probably around 35% or 40%. I think before I cut back clinics a little more, I was probably saying posed motor to 55 or 60 even most weeks. And if I look back over the course of like the last few years, like we have a registry where we recruit patients and in collect data and specimens for research and things. So we've got about a little over 1,100 patients in that over the course of about 3 years. That's even with the pandemic really slowing things down. So we have very high volume. And again, I've got 2 other partners now that sort of also run HS specialty-type clinics where they're not seeing quite as much as me, but they probably see at least a dozen every week, I would guess. And then -- so yes, that's my one. And then tertiary care center [indiscernible] I would say, 90% of my patients at least have early stage 2 or 3 disease and the majority of those have draining tunnels. Again, some of those patients are being treated and hopefully better controlled. So -- but especially the new patients that come in, it tends to -- which are 4, 5, 6 a week. -- the large majority of those have disease with draining tunnels.

That's great. Thank you, Dr. Sayed. That's great feedback for our audience. We're almost -- a little over time, but I think this has been an incredible discussion. So we're going to take one last question, and I think that this is -- have a lot of Niels start, but it would be great to get your feedback as well from you, Dr. Sayed as well as Hoda, and Korinna they'd like to share. We have seen an emergence lately of the IL-17 class with some other products that have been being studied in late-stage studies. And I think from a mechanism action perspective, vilobelimab definitely has an advantage on these training tunnels. But it'd be great to understand Niels from a scientific perspective, your view and Dr. Sayed your view on what you've seen in practice with IL-17s in relation to draining tunnels, Certainly, that would be helpful.

Sure. Happy to start. So I do think it's fair to say that IL-17 has been indicated to play a role in HS. I think that's really fair to say. There is clear research around it. So IL-17 certainly works at least to my knowledge, a bit more on the T-cell side of inflammation. And so the mode of action is very different from C5a inhibition because, as I said one of our most important targets, aside many others, and interestingly, we do have -- there is data that shows that C5a feeds into IL-17 signaling as well. So C5a is kind of in a core center. It's not cytokine like the interleukins, it's a complement activator. And it feeds into many cytokine networks. So there is some interlink also TNF alpha, by the way. However, the strength of our technology is probably really more on the neutrophil controlling side, which is very different from IL-17. Now I'm not in a position to comment on whether there is a strong effect or any effect on draining tunnels, which can be to other mechanisms, maybe, and that's certainly where Dr. Sayed can add a lot more color than I can, okay, I could ever do. But the differences when it comes to the profound knowledge on both IL-17, but more so even on C5a are clear. So I would say rather than just looking at the different mode of action, I would add like 2 points that I think are very important. One, is, to me, one of the most important points, and that's an open question, whether as a point, whether there's a long-term effect of your treatment, right? And either they're earning, and I'm hoping that we can do the site as well to that long-term treatment that you have something where the patient knows it's working is making a very, very big difference. So if you had a drug that really long-term supported a level of control or even of improvement over time, that would be probably game-changing for some patients. So that -- with that mechanism, we are feeding to. We have a lot of indication that there's a long-term benefit for at least a large amount of patients when we looked at our open-label long-term treatment. So that's something we're hoping to investigate as well and hoping to see in the Phase III that could be a differentiator. Second differentiator is the mode of action. And with that, we have chosen a different patient population because of the mode of action. So I see them both as valid targets and probably complementary, but a pause here.

Thanks, Neils. Dr. Sayed, any comments?

Yes. I mean I can't make the plan enough that like we have such -- so our options are so limited right now that like I need like 2, 3, 4, 5 more things than I have right now. And I think IL-17s like are going to be -- are promising. Like there's no doubt about that. Like I thought theoretically IL-23 should have been great, they bombed at this point. So they're kind of off the playing field. In the 17s, I think are still very much in it. And I think for some patients will be a very good fit, but there are going to be a lot of patients, because I'm using some IL-17s in practice now who don't respond to TNFs, and don't respond to IL-17s. And we've got to have another mode of action. And then from a safety standpoint, again, there's going to be intolerance among certain class like IL-17s for patients who have Crohn's, which there is a big overlap between Crohn's and Hidradenitis. I can't use IL-17 antagonist in those patients, because it makes Crohn's worse. So there is a -- even a '17, like we assume that secukinumab, bimekizumab, which has a Phase III program going. Both of those hit the market. I'm still going to have huge gaps in what I need. And I'm going to need to offer patients multiple options to think through because one of those is going to feel like a better fit the other based on just individual patients discussions with patients or how they work. And a lot of that is going to be stuff that. I also think I'm going to feel out as I have better access to these drugs for the general population, getting a deal for who tolerates which drug better, looking at longer-term control and how that kind of pans out for patients whether those patients with a lot of draining tunnels are the ones who really need a C5a antagonist versus an IL-17 inhibitor. But we have this deep bench of treatments, I've got like a dozen great psoriasis treatments. And I end up needing to pull from a lot of those over time. And right now I have no simple backup plan or no simple second line or alternative first line, so it's a better fit for HS. So at this point in time, the IL-17s, I think are likely to have patients where they're successful. I think regardless of that, there's going to be a big role for a C5a inhibitor.

Thank you, Dr. Sayed. This is fantastic feedback you shared with us. And I just want to thank everyone for joining. This finally brings us to the end of our event. Our panelists here were fantastic. Dr. Sayed, we really appreciate your time in doing this with us, and we can really feel your passion for the HS community and that's why we feel very compelled to do everything we can to potentially bring this drug to market. I want to thank everyone for their interest today in InflaRx, Vilobelimab and HS. Today's slide deck and recording will be available on our website, like I said before, under the Investors section, Events and Presentations section, very shortly. If you have any additional questions, feel free to reach out to me, and we'll do our best to get back to you as soon as possible. Thank you, everyone. And have a beautiful day.