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 we will 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, an 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 guest today, and again, we have a very special guest, Dr. Chris Sayed, from the University of North Carolina in Chapel Hill, 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 fearless leader, Professor Niels Riedemann, our CEO, who will be going into details on everything we wanna know about this new study. Myself, Jordan Zwick, Chief Strategy Officer, Dr. Korinna Pilz, our Chief Clinical Development Officer, and Professor Hoda Tawfik, our Lead Director for Dermatology. Welcome everyone, and I'm gonna 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're 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. InflaRx has developed a proprietary first-in-class technology targeting a very special part of the terminal complement space, the activation product C5a. We have various clinical trials running, which I will go through on the next slide in a second. Our proprietary technology is now accompanied by new technology, which we have very recently announced. Next slide, please. 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. 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. 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 two positive ANCA vasculitis studies. This is a rheumatological autoimmune disease, as you may know. We are planning to now orient 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, the 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, an oral small molecule C5a receptor inhibitor. We are very excited about this drug because it has best-in-class potential, which we have recently shown and announced. 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. It's really my privilege and honor to hand over to Christopher Sayed. Dr. Sayed is one of the leading experts in this field and has been really instrumental helping us in the development of a new primary endpoint. Chris, the floor is yours. I'm very thankful that we can hand over to you for this disease. Yeah. Thank you so much, and I'm very glad to be here. I could, you know, 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. Because it's something as we'll talk about that's often hidden by patients that has a lot of stigma attached to it's unfortunately something that I feel like I always have to start with the basics. I'll kind of try to give a disease overview and talk a little bit about potential for, you know, why C5a is a relevant target in the disease. You know, you know, as a disclosure, like, I've got partially selfish reasons for being here and why I've been, you know, involved and discussing things with InflaRx over time is because, you know, I see so many of these patients, you know, 40 or 50 a week. You know, on Tuesday, I saw, you know, at least 20 patients with HS. 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. InflaRx has been really passionate around HS and bringing a new therapy that can be helpful. For that reason, I'm glad to be here and to be able to discuss, you know, a great potential future treatment option. We can head to the next slide. You know, again, starting with the basics, you know, HS, this is, again, I wish an image that everybody, you know, 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, you know, painful nodules. You know, these tunnels that develop that drain pus in places like the armpits, under the breast, in the groin area and on the buttocks. Because it's, again, in areas that patients can cover and they tend to sort of keep covering and want to hide and not have to talk about with other people, it's something the general public has no idea about. I tell my patients all the time, you know, you've, you know, worked with people with HS, you went to school with people that had HS, and just like you didn't you know, nobody knew it about you, the, you know, the way you protected and kept it from everybody else, they were doing the same. There really are many, many patients out there that struggle with this disease. You know, it is something that is recurrent over the course of years. Much like people have rheumatoid arthritis or psoriasis, things that flare up over the course of, you know, 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. It is something that patients deal with for a very long time. It often comes up in adolescence, kind of very early in life, around the teen years or early twenties. It can come up at any time, though. You know, clinically, this is a good example here that we see in this photograph. There are two large abscesses here that you can see that would be exquisitely tender if you were to sort of push on these areas. Anytime the patient moves their arm, it's going to be very sensitive. You can also see there's, you know, areas where there's not necessarily a pus-filled space like an abscess, but smaller, you know, kind of individual nodules where there's just firmness and tenderness and some swelling. Then you see these areas that are draining a little bit of pus here, just right as the bandage is removed, and these other openings that you can't see active drainage at the moment. You know, with pushing in motion, you'd see pus kind of drain from those areas. Those are the openings to those tunnels that go under the surface of the skin that have such an impact and are very long-lasting. You know, down here, you know, there's I feel like these two data points at the bottom about, you know, almost pretty much 1% of the patient population or the U.S. population or European population likely having HS or symptoms that would match up with an HS diagnosis. Here it's saying greater than 200,000 cases. Really there's probably, you know, more than a couple 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. You know, there's, you know, different thoughts about why this disease develops. 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 sweat glands, but it's really more follicular inflammation. People often think they've just got a bad ingrown hair or bad shaving bumps from shaving in these areas. What likely starts this disease process off in early disease is that you see inflammation that starts right around a normal hair follicle that, you know, maybe you just see a small pustule develop or some very subtle kind of redness around follicles. You'll see this scattered within the sort of worst picture in patients with worse disease. 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. The hair shaft, whatever bit of bacteria happen to live in that follicle, the other bit of, sort of, you know, dead skin cell debris that builds up in the hair follicle normally over time, as the follicle ruptures and breaks open under the surface, all of that spills in, kind of underneath the skin. The body is so primed to inflammation, it 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. Because there is some disrupted, you know, regulation of the hair follicles or something with the wound healing that happens abnormally, sometimes these abscesses will rupture, and the skin can heal normally. Other times, it forms these chronic pockets where a pocket of, you know, sort of pus and inflammatory tissue, kind of like a, you know, chronic wound healing base gets entrapped under the surface of the skin and has multiple connections that chronically drain pus. Not every nodule becomes an abscess. Not every abscess becomes a draining tunnel. Whatever, you know, some percent of them do and become these chronic, long-lasting lesions that last for, you know, much more than just a few days. Next slide, please. As we think about how this disease progresses, this Hurley staging system is what's commonly described and used to classify patients. You know, John Hurley was a surgeon who wrote a random textbook chapter about HS, many years, like, decades ago. He thought of it like a surgeon. He thought, Hurley stage one disease, this is just bumps that come and go, abscesses and nodules only. There's no scarring or minimal scarring, and there's no tunnels present. I don't need to do surgery on this patient. Hurley stage two patients need a little bit of surgery because they've got some of this scarring developing, some of these kind of band or rope-like scars. They've got areas that drain pus from underneath those scars or where there were tunnels underneath these bands sometimes. Then a Hurley stage three patient has a lot of these tunnels and a lot of scarring, so they need a lot of surgery. 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. We don't expect to make a Hurley stage three patient go back completely to Hurley stage one 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. You know, current treatment of HS is, you know, complicated, and there's not a straightforward algorithm. This diagram here is from management guidelines created in 2019. As you can see here across these Hurley stages, there's not, you know, 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. You know, something about how the body reacts with normal bacteria in HS is different. It's like it senses normal bacteria as a threat. Reducing and changing bacteria can be helpful, which is why we use antibiotics as often as we do. They're not great long-term options. At the time of these 2019 guidelines, the only medication that had what's called, like, a Category A recommendation, meaning there were large-scale randomized controlled trials, was Humira, which we all know is approved now, and it can help a lot of patients. There is still this gaping hole of, you know, 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. About 25%, you know, in both of those studies, it was 26%-28% in those PIONEER studies also hit that same response because the disease naturally waxes and wanes some over time. That means that, you know, there's only about a 25% difference between placebo response rates with that medication. In real life, I think that plays out where about a quarter of patients, you know, 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, you know, it would be nice to have more tools to try to do better. About a quarter of patients kinda get no response from it, which is always very frustrating. 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. For some patients, the effect wanes over time, and we don't have any sort of secondary backup approved therapy at this point. 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. You know, we use other things that are off-label, but that's always a fight, and it's a major struggle for these patients kinda waiting and hoping to be able to get other therapies. Next slide, please. To the next slide. Again, there are the three, you know, main lesions that we think about in HS, and I talked about this some earlier. You know, a nodule tends to be transient. It's there for a couple of weeks. It's tender, painful, and it can certainly be disruptive. You know, it's often on a bra line or along an underwear line or a bikini line where elastic bands rub. Something that's hard for patients not to think about and sort of plan their day around sometimes. Most of those lesions will improve over the course of a couple of weeks. An abscess is sort of, you know, an exaggeration of that. It's a nodule where pus starts to fill the space, and so you have a pus-filled, you know, sometimes it's the size of a grape and sometimes the size of a grapefruit. It can vary a lot. These are exquisitely tender, you know, very, very painful. Typically, they will drain over the course of a couple of weeks, or patients have to go get them drained by having a sort of a lancing or an incision and drainage procedure done to help relieve that pressure and pus, and they get some relief. These are worse, but they are at least typically transient and can resolve. Draining tunnels are what I kinda showed in some of those diagrams in the pictures of those openings that constantly drain pus. Those can be chronically inflamed and very tender. They'll drain pus every day enough so that patients have to constantly change bandages, sometimes once a day, sometimes many times a day. For a lot of patients, you know, they have a constant, you know, they have tons of bandaging material around all the time. They are spending, you know, 20 minutes, 40 minutes, one hour every day just on bandaging before they can leave their house. They constantly have a bag of, you know, bandaging material with them and a change of clothing because if something leaks around, they've got to change their clothing. These are a huge burden that patients, you know, like, you know, have to take time and effort and there's a lot of discomfort associated with these lesions. Because they can last for months or years, they're much more stubborn than the transient inflammatory nodules and abscesses we see. You know, I think you can have a sense that if you develop something like HS, you know, the impact on it would have on your life would be huge, right? It is, you know, clear from quality-of-life studies it has a bigger impact than things like atopic dermatitis and psoriasis. Not that those things can't be bad, you know, but it's, you know, nearly as common as those things and, you know, much worse on average. If we ask patients specifically, you know, what, you know, how do these different lesions affect you in different ways or what do you consider the impact of them? It's clear that, you know, it's not just the intuition of physicians or experts, but patients rate specific types of lesions as being worse. Inflammatory nodules, you know, clearly have an impact on this first column here. You know, this is, you know, quite a burden to deal with. You know, abscesses are worse probably because the pain is increased and because there's that worry about drainage spontaneously at any time. Then draining tunnels, because they are so chronic, you know, 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's, you know, where there's an easy light at the end of the tunnels for them. Non-draining tunnels, you know, eventually sometimes these areas do burn out or with treatment, they calm down, they stop draining, they become almost scar-like, and they can reactivate at some point. That is, you know, less of a burden, at least. You know, it can be a problem. The scar can be itchy or kind of sore, but it's not the same as an area that's draining. It's a major improvement when the disease transitions from, you know, lots of draining tunnels to non-draining tunnels and scar. Patients rate drainage as a hugely important, you know, aspect of impacting their life. As much, you know, pain is most often the number one, you know, problem that patients point out, but draining it is often rated number one also, or is close behind it because, again, that burden of constant bandaging, odor, having to deal with, you know, the chronic, you know, sort of upkeep, taking care of those areas. Next slide, please. Again, I, you know, how this impacts patients' quality of life, you know, again, it's not hard to imagine that if you have areas that are, you know, always painful, if it's on the buttocks, it's painful 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 under the armpits, it makes it very difficult to do certain types of work. You know, with it occurring early in life, it often affects patients' ability to attend school and affects their ability to sort of keep and maintain jobs or promote over time. In lots of studies that have evaluated these things, patients have more, they miss work more often, more school absenteeism, you know, less likely to be promoted, feel like they've lost jobs over time because of it. That becomes linked to things like lower socioeconomic status on average for these patients, to things like depression and anxiety and higher rates of suicide, which is, you know, tragic and unfortunate. If you look at certain things like, you know, number of children that patients with HS have on average compared to the general population, it's clearly fewer. Probably partly because of the socioeconomic impact, but partly because of difficulties with intimacy. You know, again, most people have no idea what this disease is. For a patient in their teens or twenties to explain to a potential romantic partner, "I get, you know, these boils that are in my groin area and all this scarring," you know, this is a very difficult conversation for a lot of people to have, and it takes a lot of trust. So there are major barriers that it creates for these patients over time. Next slide, please. What does treatment mean for these patients? You know, sometimes we can do very well with the treatments we have. 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, you know, much less drainage. You know, you can tell where this large abscess is kind of deflated. This patient is definitely in much less pain and much more functional. This is a patient who had two kids. She works a full-time job from home. She's in her twenties, like, you know, very active life, plenty to deal with already on top of all this. We can kind of take her from having, again, you know, there's less pain, less drainage, better quality of life. Here we're planning out surgery because some of these tunnels, you know, just haven't completely resolved, and there is still some drainage and discharge. It's still, you know, a fair bit to manage. Surgery is going to get her even better. She makes a big step forward with medication. Next line or next slide, please. Similar here, this is another patient who I would consider is having a good response to current therapies, right? At 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 that's there, a lot of inflammation, ulceration. 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 slight drainage. Again, he's able to sort of work more successfully, you know, sort of have much less impact on quality of life at this point. It is a huge, you know, benefit to these patients and what they can do with their life and how they interact with other people, their families, and their loved ones when we can get them improvement. Next slide, please. You know, again, we're going to switch gears a little bit here. I'm going to try to not make the science be kind of too complicated and not lose anybody here. You know, the general idea is that you know, C5a is a you know, something that we've known for a long time is important in inflammation. We often think about the complement pathway as important in bacterial responses to fight bacterial infections. It's been known for you know, nearly 50 years now that it is important for things like neutrophil activation, you know, bringing this you know, neutrophils or to these inflammatory cells to the site of things like infection or to other sites of inflammation, and creating a response to bacterial infections that results in things like the pus that we see around infectious processes. A lot of what's in pus are neutrophils. You can see here that, you know, when neutrophils are activated, they start to form all these little blebs to the outside as they're attacking, you know, foreign pathogens like bacteria. You can tell that in the presence of C5a, they go from being kind of calm here to sort of being really active, you know, with all of these blebs kind of here off to the side. Next slide, please. They are, you know, clearly very important in HS. You know, with all the pus that's present in HS, you know, it's no surprise that neutrophils have some active role in the disease. It's kind of hard to explain, I think, if you're not familiar, to looking at skin that are, you know, histopathologic images. Here you can see the border, you know, this kind of collection of cells that kind of looks like it's here in a stripe almost. That's the what borders. It looks like skin, but this is bordering one of these tunnels. This sort of white open space here is the middle of that tunnel. 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. It's very clear that neutrophils are attracted to these locations. They're important in creating the pus and a lot of the inflammation that we see. They're also important in things like, you know, breaking down tissue, that ultimately leads to things like scar formation as well, which is what we see later in disease. Next slide, please. C5a is important in regulating lots of inflammatory processes. You know, it's not purely just neutrophils. It has a lot to do with, you know, 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. Again, other things that are important in HS with like vasodilation and edema, that means the redness and swelling of the tissue around those areas. Also production of things like matrix metalloproteinases, these MMPs and fibrosis, which lead to the scarring process and contracture that we see in HS. It really is at the center of a lot of the processes that are important and a lot of the misery that HS causes for patients. Next slide, please. Again, it's hard to get into the weeds too much sometimes with some of the scientific background, but I'll tell you that when I was in medical school, the main thing I was taught about complement was that it was important for killing bacteria. Down here we see things like C5b through C9b, which are all important in sort of attaching to bacteria and, you know, basically killing them off directly. C5a never got much credit when I was in medical school. It was very clear at that time, and just something where there was, you know, all the links weren't quite put 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. C5a and C3a, other similar, you know, parts of the complement cascade work as those signal flares that say, "Hey, there's danger here. There is infection, and we need to bring in things to attack it." Again, that's how... That's, you know, the way that you know that initial bacterial response pathway recruits inflammation as part of that process. If you have an aberrant response where all of a sudden you're responding like there's bacteria around that are dangerous, even when there's not, like we see in HS. You start to mimic these pathways and to overexpress these pathways. When C5a is elevated, we get these exaggerated responses in an inappropriate time. Even though there's not infection around, we see what 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. You know, the sort of first proof of concept in HS, you know, really came with vilobelimab. It was, you know, described as IFX-1 at that time. In this early pilot study with just 12 patients, there was this clear signal towards improvement. Obviously, early studies that are open label and unblinded, it's very hard to read too much into them. 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. Fortunately, there's a lot more to the story which I'm not going to cover myself, but I'm always interested to hear it reviewed. Again, this was the first start towards really seeing C5a in action in HS. Next slide, please. 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, you know, out there. It is very common. You know, I am overwhelmed, you know, with the number of patients that I need to treat and under, you know, don't have the tools that I need to, I feel like, do it the best that I could as much as I try. You know, there is one treatment available. Again, that's been a huge paradigm shift in how we think about treating HS, but there are just, you know, too many gaps in what we have available right now. Clearly, you know, draining tunnels, which I mentioned, as having the highest impact on quality of life. How we measure HS right now with HiSCR, we're going to hear more about this. It really focuses mostly on abscesses and nodules and makes draining tunnels very secondary. 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. We need to really focus on, you know, tweaking them in some way to make draining sinuses more important and to really be able to reliably tell when there's improvement. C5a, again, you know, 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. 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 will be happy to answer questions as we get to that section. Yeah, 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. What we want to do now is zoom in a little bit on this potential new treatment for these patients, vilobelimab mode of action, and go a bit deeper on the role of C5a before we come to the data and the new endpoint. You know, the terminal complement pathway is known for a long time, especially there were drugs available or one drug specifically that targets C5. Now, C5a, however, is the key pro-inflammatory player that interacts with two receptors. The most well-known one is C5aR, and the other one that was later discovered and has some pro-inflammatory role is the C5L2. Now, the overall activation of these receptor leads into a strong pro-inflammatory response. There's 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. 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. For C5a specifically, the signaling results ultimately in HMGB1 induction, which has been indicated to play a real important role in the inflammatory disease and therefore also specifically in skin diseases. Overall speaking, C5a acts through two receptors, mostly through the 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, lectin, and alternative pathway, to activate the complement system, which ultimately leads into the generation of C5 convertases, 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 long known but really not paid attention to, that there are other mechanisms that can cleave off C5a, like the enzymatic cleavage sometimes referred to as an extrinsic pathway. That can be done through thrombin, trypsin, elastase, and other enzymes. They go to the so-called scissile bonds 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. 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. 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 C5, C5a, when it's cleaved off from C5, may undergo a certain three-dimensional change such that a new epitope or conformational epitope is formed. We discovered this epitope, and the fact that vilobelimab binds to this epitope led to two very important key features. First of all, it gives us full control over the signaling. We can really block signaling through C5a completely in human blood. Second, interesting part of that, epitope is when we bind 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. These are really unique features. Aside from the many, many known inflammatory actions that C5a causes, vilobelimab is truly able to inhibit them. Next slide, please. 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 a so-called neutrophilic skin disease. This HS, like pyoderma gangrenosum, is believed to be driven by neutrophils that are abundantly present around the lesions. You know, therefore, there is an implied role that they may have in this disease. C5a is really this chemoattractant. 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 uses NETosis, which has been implicated to be important also in skin disease. Next slide, please. When we talk about chemoattractant, that means there is this factor that attracts the neutrophils into the tissue, to the source or the site of inflammation. There's a great work from a Harvard research 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 mice. However, what that study really worked out perfectly nicely was the role of C5a on how it attracts neutrophils into the tissue. What you see here in green, these small green dots are labeled neutrophils that have left the gray blood vessels. It's a live image in a model of inflammation, of acute inflammation in the joint of these mice, rheumatoid arthritis model. 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. When you are disabling the interaction of C5a to C5aR, you see in the same model, literally no neutrophils sticking or transmigrating into the tissue. 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 wall, is solely induced by C5a. Without C5a receptor interaction, you do not get neutrophils into the tissue. C5a also induces LTB4 and CXCL1 and engages then the next steps, 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. Again, without C5a, C5aR interaction, you're not initiating the first step. Next slide, please. How does it all tie together into HS? 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. 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. This you see on the left side here, the first publication that we worked on with a 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 milligrams every week. You see that C5a levels during dosing on day 22 and day 50 were very well controlled with 800 mg of vilobelimab every week treatment. Now, on day 50, we stopped the treatment, and you see that C5a levels increased again. Next slide, please. Let's look into what we discovered and how we're moving forward. Next slide, please. Briefly, recall the SHINE study. This was a study where we treated and enrolled 179 patients and treated 177 of them in a six-arm trial design. Placebo group and five four dosing groups. A 5-arm trial design, for dosing groups with increasing doses up to the high dose of 1200 mg 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 five months, and we split them, so to speak, in two 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 mg every four weeks to see whether they keep their response. Now, those patients that did not achieve the HiSCR, the traditional HiSCR response, they were treated with what we call the medium dose, which was 800 mg every other week. 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. 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 switching to 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 briefly recap the HiSCR. The traditional score, HiSCR, means that you have to reduce the abscesses and nodules by 50%. 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 are two more requirements. You cannot have 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. When we took a closer look, and I'm just gonna give you two slides here at what happened otherwise. We saw that there was a somewhat dose trend, dose response trend when we just looked at the mean Abscess and Nodule (AN) count on the left side here. 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. 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 Abscess and Nodule (AN) count. Next slide, please. The logical thing was to look at that as combined total body inflammatory response, so to speak. Taking all inflammatory lesions, abscesses, 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. 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 day. You really need relatively high patient numbers to have a correlation. 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 worst skin pain on the numeric skin pain scale and also on the drainage impact. 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. You know, I would say in concept to what Dr. Sayed had described, what the patients themselves voiced about the impact, these data on a relatively small data set clearly indicated that the reduction of draining tunnels 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 slide that has not been previously published by us. This is the C5a concentrations in this trial from day 1, so pre-dose to week 16. You know, as you can see here, the white boxes are the placebo groups and, you know, then the colors up to dark blue is the high dose group for each time point. Just visually, it's very nice to see that at day 4, day... The first time post-dosing at week 2, we had a relatively tight control, maybe also because there was an introduction of three doses of 800 mg within the first eight days before we went to the every other week dosing. However, at week six and week 16, it became apparent that only in the high dose group, we had somewhat control over the C5a levels. While they were being still somewhat in the normal range, they were not as tightly controlled as before. Next slide, please. When we summarize our key learnings, we had to go through. We really had three main key learnings. 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. This was one important learning. The other one was the HiSCR has several shortcomings. There may be very high placebo rates. One of them is also supported by a recent trial readout with risankizumab, where there was also a relatively high placebo response rate with this score. We know IHS4 does not take into account reduction of draining tunnels. It's not part of how the score was constructed, but draining tunnels are really impacting quality of life. Last but not least, we found that the score, the traditional IHS4 is very much driven by the Abscess and Nodule (AN) count reduction requirement, and that may be because abscesses and nodules are the most frequent lesions, but also the ones that fluctuate a lot. 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 dose a bit higher. Next slide. This really led us to, you know, 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. The modified HiSCR considers reduction of all three 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. 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. 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. This is the modified HiSCR as it has been constructed by us, and I'm gonna walk you through this important slide. In the center of the slide, you see the three inflammatory lesions, nodules, abscesses, and draining tunnels. On the left side, you see the traditional HiSCR, and I'm not gonna repeat the three requirements. On the right side, you see the modified HiSCR. This score has two 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. 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. 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. At week 16, when applying this new score to the dataset of patients that had at least one draining tunnel at baseline, hence the slightly lower n size and numbers here, we saw that the placebo rate was well controlled with 26%, while the high-dose 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 statistically significant reduction in draining tunnels only achieved with a high-dose SCR. The modified HiSCR response demands at least 50% reduction of draining tunnel count to baseline to be a responder. 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. This was a great sign for us that this score really reflects what we designed it for, to be reflecting the importance of draining tunnel reduction for patients suffering from that. Next slide, please. How did that work in the long-term phase? When we treated the patients open label. Here you see at week 16, we grouped the patients according to the new score, the modified HiSCR. Every HiSCR-responder was in the 100% responder group, and the non-responders were 0 at week 16, of course. Keep in mind, these patients were dosed with a non-optimal dose. Most of the patients here that showed the modified HiSCR response were dosed down quite a bit. Most of the patients that showed no HiSCR response got a dose or a higher dose. What that showed is that long-term treatment really led to improvement in the modified HiSCR at 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. 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. 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. 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. The next thing we wanted to ask is, how does this new score correlate with some of the scores we had previously looked into and shown, or existing scores, and also to patient-reported outcome? I wanna walk you through this. Some of the scores we've recently been speaking about a lot was the IHS4 score. Clearly there was a correlation, I would say a good correlation, to the IHS4 score. Now keep in mind, the IHS4 score, you know, needs to go down in score, which shows improvement, so hence there's this negative correlation. When we made out of the IHS4 score a dichotomous requirement, like seeing how many patients achieved a 50% reduction of the IHS4 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. Improvement in skin pain, improvement in the life quality index. The lower the index, the better the patient. Also improvement in the draining, in the drainage. 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. 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. We looked at patients that showed C5a levels below 10 ng/mL with our validated ELISA. Even though these are low numbers, there seemed to be a clear signal towards a correlation between patients achieving this high tight control, low 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. 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? Not to our 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 ng/mL. We believe this reflects nicely the trend and the signal that C5a levels are important, and they correlate when they're tightly under control with this response in this new modified HiSCR. Next slide, please. I just want to recap. The modified HiSCR is a new primary endpoint for patients suffering from active draining disease. It does consider reduction of all three inflammatory lesions. It emphasizes the reduction of draining tunnels. 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 introduce 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 abscess 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 abscesses from baseline in an efficacy endpoint. I do want to share that we when we applying this extended modified HiSCR to the SHINE dataset, 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 a lot, but it is a requirement that we wanted to research in a 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. 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. 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 the 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. No, still in the same. Yes, exactly. Thank you. We look to the study population, the study population is the moderate-to-severe, early stage 2 to 3, HS patients with at least one active draining tunnel, which is estimated to be approximately 70%-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 USA, 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, multicenter pivotal study to determine the efficacy and safety of vilobelimab in patients with moderate to severe HS with at least one actively draining tunnel. After a screening period, the patient will be randomized in the blinded main period into two arms, placebo or vilobelimab, 1600 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 1600 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 four weeks observation till the end of study at end of week 54. Next slide, please. Here are the endpoints of the study. As you heard from Niels that the primary endpoint is the newly developed modified Hidradenitis Suppurativa Clinical Response (HiSCR). The response of this score is defined as the proportion of patients achieving both total body inflammatory lesion count Abscess and Nodule (AN) count reduction from baseline of 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 the long term. We have the extended modified HiSCR, the traditional HiSCR, and the IHS4, 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. The patient population of the study must have moderate to severe HS disease, early stage two to three, and Abscess and Nodule (AN) count at least three, as well as at least one draining tunnel at screening and at baseline. This disease should be diagnosed for at least one year and has to be stable for at least two months before screening. Patients must have an inadequate response to at least three months 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 tetracyclines within the four weeks prior to baseline is an exclusion criteria, as well as any systemic medical treatment for HS within the four weeks prior to baseline as well. Other therapies which interferes with the response measurement in the study or chronic systemic corticosteroid therapy within three weeks prior to baseline or deroofing surgery for HS within six weeks prior to baseline. Any history of certain preconditions related to other inflammatory diseases is also an exclusion criteria. Next slide. 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 three 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 digesting 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 immunodermatology. 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. You can ask a question in one of two ways. You can submit a question in writing to the Q&A button below the presentation window. I will then read the questions out loud. Or you can ask a question using the Raise Hand icon under the presentation window. So give everyone a few moments to get their questions in and raise their hand. Great. Our first question comes from Steve Seedhouse, Raymond James, who wants to ask a question. Yes. Hi, team. Are you able to hear me okay? Perfect. Great. Thanks. With respect to the C5a level data that you presented, this is on slide 45, so the less than 10 nanogram per ml. You know, 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 retained that level of C5a control at week 16. I'm curious, with the new dose now, 1600 milligrams, in the upcoming phase III study, what level of control, like, what proportion of patients with that, you know, level of C5a control have you modeled or do you predict you'll get relative to the 1200 mg? All right, Niels, why don't you answer that question for Steve? Yes. Happy to do so. Thanks, Steve, for this very important question. You know, you picked it out absolutely correctly at this level, at week 16, looking at patients with C5a levels below 10. This was only a smaller fraction of the patients. You know, this is a post-hoc dose effect, but keep in mind, we did a lot more modeling on physiological-based PK modeling, tissue penetration estimation, et cetera. Without being able to go into all these details, it was very surprising to us that the slightly higher dose, which is 1600, showed a very different coverage of the interaction with the receptor, especially in the skin. There was a surprising difference. Now, we are not necessarily saying it has to be under 10 because we grouped when we did this correlation analysis, patients below 10 and then 10 to 20 above, et cetera. We didn't go into that granularity. 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 mg every week. 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 it. 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. 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. We feel relatively confident that this dose is the ideal dose for us moving forward. Thanks for that, Niels. A question for either you or Hoda, just on the powering assumptions for the phase III study that the N of 143 per arm, given the new endpoint, what are you assuming for, you know, just placebo response and effect size, if you'd be willing to share. Yeah, Niels, why don't you take that and Hoda can jump in as well. I'm happy to start and then pass 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. You know that we had a 47.1% placebo response in the traditional HiSCR. In that same study, in all time points, we circled around 25 ± 5% or so. We do believe that at least in this SHINE study 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 four weeks. We show we've seen the exact same circling around the 25%, maybe up to 30%. We do also expect that when we drive this higher and have maybe certain other effects under control that we haven't spoken about today, but at another occasion, that we would not exceed that 25% a lot. This is kind of the range that I would like to give you. I pass on to Hoda. Again, we haven't disclosed it, but certainly, maybe Hoda you can remind again the primary endpoint and that we, you know, did a statistical. Yeah. Set up that for that endpoint. Yeah. Yeah. Actually we used the data of the SHINE study to give us the confidence about this new endpoint. 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. We got by this a confidence that even with the dose, the 1,200 mg, which would show a really good result compared to placebo within the data of the SHINE study. We are really very confident that even when we are going to 1,600 mg vilobelimab, that the significance would be even better. Yeah. Thank you. Maybe lastly, I just wanted to ask Dr. Sayed a couple questions. You noted some treatments that you used off-label. I'd be curious if you could expand just on what you typically use off-label after Humira. Then also, you know, when you think about vilobelimab and the new endpoint modified HiSCR, hypothetically, 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 in amongst other drugs that might have worked on the old HiSCR endpoint? Thank you. Sure. Yeah, all great questions. First I guess I'll tackle common off-label therapies. You know, yeah, adalimumab coming to market sort of really highlighted the TNFs. There was some old data on Remicade, you know, which is infliximab at lower doses at 5 mg/kg, kinda like we use for psoriasis. You know, that never works well enough for HS. You have to dose, you know, double that, you know, closer to Crohn's disease dosing. Usually, you know, double dose twice as often. Which goes to show, again, even if you think you're dosing aggressively to start with in a trial, the patients often need more. They're just so inflamed and so worried about this disease, they need more. If you do, you know, some very aggressive dosing with Remicade tends to be sort of next line after adalimumab fails. Then other TNF inhibitors like Simponi ARIA or just Simponi as a subcutaneous dose sometimes we'll also use. You know, those drugs are kind of hitting the end of their protective life, and so there's no way. Then there's already biosimilars for Remicade now, so there's no way those drugs are ever gonna 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. You know, I was using IL-23 agents like Skyrizi from AbbVie for a while, or guselkumab or just Tremfya from Janssen. But they both, you know, Janssen just published data on guselkumab. It was really just like you know, not helpful. That's not gonna be pursued. Like the risankizumab trials, those just kinda stopped early. IL-23s are looking like a dead-end. In practice, like I never felt like those were doing what I hoped they would. They weren't the step up, you know, that we saw in psoriasis when going from TNFs 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. Really you just kind of throw the kitchen sink at it sometimes, you know, JAK inhibitors, IL-1 antagonists. There is a long list of off-label biologics that we try to use and that are, you know, sometimes, you know, moderately effective. You know, but there is no, like, clear path. It's always, you know, a struggle to get drugs like that approved. And then, you know, we use things like antibiotics. There's like IV ertapenem, which we use as sort of a rescue therapy. But again, the algorithm from the management guidelines is all over the place 'cause the evidence is very limited still, and accessing a lot of those drugs is a big challenge. So hopefully that answers that one well, but I'm happy to clarify some things. I think the next question was, you know, if it meets criteria with this new modified HiSCR, how does that fit into the algorithm? Part of that's gonna depend on, you know, exactly how robust the responses are. If it's like, you know, we're not gonna have comparative data from, say, like, the PIONEER studies where we can do a direct comparison. If placebo response rates are gonna hang out at that 20%-25% mark, and we're gonna see treatment responses of 45%-50% like we saw in the PIONEER studies, I think people will read that in a very similar way. I don't think most people are gonna make too much differentiation where they say it's not the same measurement and they love HiSCR so much 'cause the HiSCR is not, you know. You know, it was a, it's a great first way that we measured disease. You know, it was a step forward because there weren't validated measures, but nobody is like, you know, in love with it and super strongly tied to it, I think, where they're gonna say, "I don't believe in 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 improved. So if it has a similar, you know, if it's similar, you know, kind of levels of improvement and differentiation from placebo, I think it will be, you know, very well accepted, you know, as something that is likely to help a lot of patients. You know, if it surpasses that, you know, it's gonna, you know, potentially be able to nudge in as a more commonly used first-line drug too. I don't fear. I think people are ready to see, you know, the HiSCR, you know, either be modified or other treatment measures be put into play 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. Hopefully that answers those two questions. I'm happy to expand a bit more to sort of if I've missed something there to go a little further. No, that was terrific. Thanks so much. Thanks for taking the questions. Thank you, Steve. Our next question on the line comes from Evan Seigerman at Guggenheim. 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? While Evan recovers, I'll ask him this question that he posted in the chat. One of his questions is. Oh, is that you, Evan? 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? Yeah, that's a great question. Like, the more I've sort of looked through this data and thought about that, had discussions with the FDA about the importance of an abscess versus a tunnel, you know, I don't think anybody knows the answer to that question. Like, I see plenty of abscesses that, you know, you drain it gets better, and it does all right. Nobody's done studies, I think, where they've tracked abscesses and seen how many turn into tunnels and how many don't. I think it's probably a minority, 'cause I see, you know, a lot of patients that, you know, that have especially smaller abscesses, that heal up fine, and tunnels, you know, certainly do not result. Patients can have even 50 abscesses over time and develop two tunnels, right? It's clearly a minority, although I think it varies patient to patient. Like, some patients, it feels like almost everything that pops up, you know, leads to scarring and tunnels. It's just how their disease, you know, kind of varies from others. I think there's a lot of variation amongst patients, but it's probably a relatively small minority of abscesses that actually become a tunnel over time. But it would be an interesting study to try to do where, yeah, we follow that over time, but that's more my curiosity than else. I think it's generally a minority, though. Abscesses can also form, you know, within chronic tunnels. What often happens is that there are these chronically draining tunnels that try to sort of scar over and seal at their drainage point. Because they can't drain anymore, an abscess builds up within them. A lot of abscesses are actually sort of a temporary flare or a temporary change in a chronically draining tunnel. Those are sometimes the worst because there's already this big pocket that's there for the pus to fill. Those abscesses can get really huge sometimes. You know, then that abscess calms down and, you know, it goes back to what the baseline was. That's great. No, no, thank you so much for that explanation. Hopefully it gets to Evan, and maybe Ho-Ping Tseng if he has follow-up. Another one of his questions, you know, for you, Niels and Hoda, is what has to be done in the eyes of the FDA for the modified HiSCR to be validated? Do you need to perform any additional analyses, or is this validation already built into your phase III program? Yeah, maybe I start, and Hoda, if you want to add- Yep. Please feel free at any time. Go ahead. You know, it's really difficult for us, and we should probably not try to speak for the FDA. I would say there is definitely general guidance, and we have discussed in principle how to fully validate. You know that the traditional HiSCR was also born out of, I wouldn't say a failure, but a not so easy readout of a phase II study back then from adalimumab. Similarly, this was born out of phase II study, the new HiSCR, new modified HiSCR. The traditional HiSCR was modified in phase III. That's the same thing we have to do. There are ways you are validating such a score. You know, there are guidelines as to how to do that. We have gotten also U.S. experts on how to do that, to incorporate that, and we have shared that with the FDA. 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. I don't know if you have much to add, please feel free to. 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 assessment, which will help us in the validation of our primary endpoint, as Niels said, as discussed with the experts, with U.S. experts and also discussed with the FDA. These are well-known tools, and we will get advantage of it. Great. Thank you, Hoda. Evan's last question. He's having some microphone issues, but I think his last question is, you know, how will the modified HiSCR be reflected in a label? Would this ultimately narrow your label in HS, specifically to moderate to severe active draining disease? 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 75% of the Hurley 2 and 3 HS patients in our data have active, you know, draining tunnels. But maybe Dr. Sayed can, you know, see what he sees in the physician community in terms of, you know, that proportion. Sure. You know, yeah, you know, Hurley Stage II disease is defined by at least a scar being present, and then typically there are tunnels that are present. You know, if I'm thinking about using a biologic drug or a patient who's going to potentially do home injections or infusions, you know, they're often going to have draining tunnels that are active more so than just old scars that are present. I don't think it's going to be a huge limitation. I think 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. You know, again, that 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, you know, they've got Hurley II disease that's very active in some way, like in reality, and I don't want to like, you know, I know there's regulation about stuff I can say, but, you know, 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, you know, argue it and appeal it. But if I know that it's likely to be helpful, you know, in my mind, I'm gonna, you know, sometimes be fighting for it in that way too. But I think, again, the majority of patients I already treat have draining tunnels. It is going to be, you know, a minimal limitation in my mind. That's great. Thank you, Dr. Sayed. Sure. We also have some more written questions. We have some more live questions, but I'm just going to answer I think the read out some written questions that I think are important here that have been asked by Joe Schwartz, or, you know, from Leerink. One of his questions he's asked, with the divergence between the phase II A and phase II B data, how are you thinking about trial sites in the phase III? What steps is InflaRx taking to ensure proper clinical trial conduct? What's the expected mix between ex-U.S. and U.S. sites? I think this is a good question for Hoda and Korinna Pilz, who was also on the line, if they want to answer those questions. Korinna, you would like to start and then I can continue? Not necessarily. Just go on. 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. We have a good relationship to a lot of sites in the U.S. and also in Europe. As I said, we will have about 60 sites enrolled in the first study. How we will put weighting in one or the other region. I would like to wait with this information till we start the study, and then I can give this information later. Generally, we would like to have information from the two areas, U.S. and from the other side of the Atlantic. Maybe if I may, I will also add to it what I think Joe may also reflect a little bit to the question how do we control proper trial conduct? I may be able to say a few words and, you know, please feel free to add. You know, the SHINE study really taught us a lot. Of course, you need to make sure that you don't have side effects, so you don't want to have one side enrolling one-third of the patients. This is something we are definitely installing. There's also other things you can install in the way you stratify. 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, you know, if you think about with the emphasis on draining tunnels, you also want to know is this balanced in the groups. 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, ultimately, next to these very important control mechanisms which really relate to having similar groups 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. We, you know, we believe that looking back at our data with that endpoint, we have the most important way to control placebo response. I think together with the mechanism installed that I kind of hinted to, that should give us a really good handle. It's not an easy disease. There's fluctuation. The recent golimumab data show that people struggle with a traditional score. Dr. Sayed also really, like, you know, alluded to that there is certainly the need for more control. With our post hoc analysis, we believe we will get that. Now, we don't know if that's the case looking forward, but the data we have show that. 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. From the operational point of view, a strong CRO and a strong team in-house. That's great. Thanks, Hoda Tawfik. More questions coming from Joe in terms of the trial itself, and I think this is an interesting one, you know, how many patients are projected to have active draining tunnels? Can they resolve spontaneously, or do all patients have active tunnels? I think this is more of a specific question. Then kind of digging into that, you know, little bit clear is how are these tunnels going to be characterized by investigators? What is the evidence that supports that a patient actually has one? Are these patients that have active draining tunnels always considered early stage three, or as clinicians, do they have a different rubric to apply and evaluate response? Niels, maybe I don't know if you want to take the first crack at this. Yeah, I can give it a first stab. I'm sure Dr. Sayed is probably the most appropriate person to answer that, to certain aspects of that. I do think that you know early 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, I think Chris, you already mentioned that a lot of the early stage two patients have active draining tunnels. So I would not kind of narrow this to two or three. 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 differ if you go to different regions in the world. 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. The last part of that question was also do they 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 gray zone. Like with all these lesions, there's always an inter-rater and intra-rater variability. I don't think that anything can take that away. The way that a draining tunnel was diagnosed in our trial before is really there has to be a physical examination and also applying gentle pressure and palpation on the area around the draining tunnel to see whether that provokes the discharge of liquid pus. If it is completely dry, it's certainly not a draining tunnel. 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 that then in four weeks or two weeks down the line may no longer be diagnosed a draining tunnel. 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 will have a draining tunnel at one point without interfering with the drug and that no longer being a draining tunnel next time. I don't think it's a large amount of patients, at least not in our data. I pass 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. Sure. Yeah, you know, evaluating HS from a clinical standpoint, whether it's Abscess and Nodule (AN) counts or being able to say with complete certainty that something is, you know, there's a time with a drain versus no drain. There is a gray area there. It's imperfect, but usually, again, like, if there is drainage and it's been occurring through the day, you know, when the patient takes their bandage off, you're gonna see some drainage that's kind of collected around whatever drainage point there is. You know, this tends to be kind of a constant process. On the bandage you're gonna see that there's no yellow discharge that's been there because it's been draining through the day, or, you know, when they lift their arm, you're gonna see again where some pus is kind of, you know, sitting on the skin, irritating it near those openings. It's usually relatively straightforward. You know, as the disease improves or as it waxes and wanes and calms, there may be less drainage, where again it takes some gentle palpation to have a small amount of pus come to the surface. You know, generally patients, you know, we're talking to the patients and, you know, asking them too, you know, "Are you seeing drainage from anywhere?" You know, it's something where it's, you know, there's some back and forth that goes into it too, of trying to, you know, ask them if they're noticing it or not either through the course of a day. You can generally, you know, assess, you know, 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 know, you asked a lot about, like, natural history, like can a tunnel that's draining spontaneously go to non-draining over time? Yeah, there are times where the disease can wax and wane and, you know, somebody can have, you know, four or five draining tunnels at one point and the next time three by chance because one is calmer or I mentioned how they can try to sort of seal over and form an abscess over time. If it does that, it's not actively draining, it's non-draining, there's an abscess there instead. There is this, you know, possibility of some waxing and waning, but the chance of somebody who's got, you know, 10 draining tunnels going down to five draining tunnels spontaneously, that is pretty unusual to see that big of a shift over time. You know, whereas individual tunnels can vary some, you know, over that period of time. It'd be more unusual to see, you know, globally a patient improve to that level. I tell patients all the time, you know, if there are draining tunnels or even kind of non-draining tunnels that are active from time to time, you know, for me, I can't predict if it's gonna be active for, you know, six months or six years or 16 years, you know, with this, the back and forth all the time. That's where we start thinking about, you know, surgery over time for a lot of these patients too, because it's just impossible to predict. There are certainly patients who, if they've got, you know, some tunnels in their twenties 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, you know, there is just too much uncertainty, and it's a lot of suffering to have to wait that long. So yeah, whereas there is again, some variability over time, you know, to see a major global shift in them over the course of 16 weeks is atypical. Which is why I think you see the modified HiSCR perform better from a placebo response standpoint, that is you're not gonna see that happen quite as often, especially in patients with more draining tunnels, to get that big of a shift over time. Thank you, Dr. Sayed. Another question coming from Joe Schwartz is, you know, based on the regulatory pathway and wanted to understand, you know, what the agency is looking for at approval, if they have provided any other guidance for what a successful trial would look like. Secondarily, while we're answering this as well, is trying to understand how long full enrollment would take. Maybe Niels, you can, you know, begin and pass it to Hoda with additional commentary. Sure. Happy to do so. First of all, thanks, Joe, for these great questions. You know, 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. I cannot really comment to you know how the FDA sees every detail. Usually, you get relatively general guidance. That's my I would say. Well, that's my experience. It's difficult to make, like, a broader disclosure here, what the FDA would concretely look for 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 approved, and then we've seen vice versa. I think that's very difficult, so I hope you understand that it's really difficult for me to comment. 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. It took us a lot of energy and conviction that we are on the right path to make our arguments, and I do believe they've been heard, which is, you know, reflected. Whether that leads to approval, I have to be really cautious in that. I do believe one thing pretty strongly, that we've listened to experts like Dr. Sayed and others, that if you have response and so show a substantial reduction of these lesions, and that's why I put the slide in. It's always derived from the three same lesions. From all of our, you know, post-hoc correlation work, achieving that score is more difficult than the traditional HiSCR and is more meaningful, likely, looking forward. The post-hoc data show that. Looking forward, I have to be 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. I pass on to Hoda for the second part of the question. Enrollment. The enrollment, could you please repeat the second part, the enrollment forecast? Yeah, Joe and some others have also asked some more questions in terms of enrollment timelines. When would we expect Okay. When is the enrollment to be reached? Okay. 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 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. We have our plans. I would say realistic plans and promising plans and projections when we can finalize the enrollment in the study. Thank you, Hoda. I will concur. You know, once we have an idea on- Exactly. On more concrete timelines, we certainly would educate the public on where that may land once we've started enrollment and see how that's progressing. Correct. Correct. Thank you, Hoda. Thank you, Joe. Hopefully, we answered all your questions. If you have any additional ones, feel free to email me. Our next questions come from Anupam Rama, our analyst from J.P. Morgan, 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 CR in parentheses, relative to placebo? What is the minimal delta that would get you excited that you may see in our pivotal study? You know, yeah, you know, purely looking at change in Abscess and Nodule (AN) count is gonna be, you know, that'll be a secondary endpoint potentially. I don't know, you know. I'll be interested to see, like, some groups have started reporting things like a HiSCR 75, so looking at a 75% versus a 50% reduction. I mean, hitting a HiSCR of 50 right now is still, you know, kind of the gold standard as far as, like, a disease reduction, which is important. It tells you that you're shutting down, you know, certain aspects of the disease. You're hopefully preventing progression, meaning there's not as many new lesions coming up anymore. 50% is good. You know, obviously, I love better. You know, seeing a 75% reduction is a big leap forward for most patients, especially if that's an average 'cause that means some patients are at the 50% mark and some are at the 90% and 95% mark. You know, if I could, you know, if it was like psoriasis where I expect 90% and 100% improvement scores to be reported, that's the dream, right? But I think right now 50% is where people feel, like, happy from a comparative standpoint. You know, that if we can hit that mark, you know, in a significant number of patients, you know, that's a clear win compared to what I have to use right now. If we had, you know, 75% that is like, you know, at the same rate that other drugs at the 50% mark, that is clearly a big leap forward. I mean, I think, you know, at least having what we have now, you know, and having a backup option of some kind would be very, very helpful. You know, something that surpasses that, you know, it would be even more valuable. Great. Thank you, Dr. Sayed. Anupam has one more question. You know, how do you think about the positioning of our study versus other studies that may be focusing on just early stage three patients and how you view that kind of trial design versus how we're focusing on the early stage two and three with patients that have active draining tunnels. How do you view that in terms of clinically? I mean, I don't know of many studies that are only looking at early stage 3. You know, most of them, like the most common criteria is early stage 2 or 3 disease with some minimal number of Abscess and Nodule (AN) count, like three or five, depending on like, you know, the PIONEER studies had a minimal of three. Some use a minimal of five for an Abscess and Nodule (AN) count for inclusion criteria. There aren't many that are looking at only early stage 3. In my mind, like, I need to prevent patients from getting to early stage 3. I'd much rather have a drug that is applicable to both early stage 2 and 3 patients. You know, a perfect world, even early stage 1 patients, if we could show some way that we're blocking progression. Yeah, early stage, you know, you know, I don't wanna have to just play catch up when a patient's already early stage three. I want something to use earlier. You know, much more important tool to have, and will apply to many more patients if we can show that in early stage two, we're helping people too. Great. I think another one of his questions, Dr. Sayed, was in terms of the route of administration. You know, vilobelimab is an IV and, you know, there are other products like in the market that are either subcutaneous injection or I think some of the other, you know, JAKs or orals and as well as, you know, there's a C5aR inhibitor in development for HS that is oral. So how do you feel about the route of administration in terms of this patient population and their ability to, you know, easily receive infusions of this nature? I mean, for some patients, it's a challenge, you know, having the time and transportation to go somewhere frequently to receive a drug, but there are many patients who prefer that. You know, a lot of patients are needle-phobic, and the idea of injecting something at home is terrifying, but they don't mind somebody starting an IV for them. Some patients, you know, have a lot more nausea. They're kind of leery of oral drugs. The idea of something where, you know, they can go get it, they don't have to worry about remembering to take it. They schedule their appointment, they show up, and they get it done. Some patients actually prefer that, believe it or not, which for me, I feel like it'd be hard for me to do that on a regular basis. For patients who have, you know, flexible scheduling, it is often, you know, very appealing. Yeah, right now, like, you know, again, I use a lot of infliximab, a fair bit of Simponi ARIA. Those things require infusions that are often much longer. I mean, those infusions can take, you know, 2.5-3 hours sometimes for Remicade. Patients with HS, like, they are willing to do it if they know it's gonna help, and they are scared to stop it if they, you know, once it starts to work. That with a disease this bad, you know, patients are willing to do it. One barrier is gonna be, you know, making sure more and more providers get comfortable with it. You know, they're. Like we use infusion. Like I use infusion centers across the state and have a you know a good network that I know how to use. You know, some providers you know don't do that as often as prescribing sub-Q drugs. There will be you know some. But more coming back to it, I think, especially around HS, knowing that Remicade ends up being sort of a second line therapy for a lot of patients. And with you know a lot of other IV drugs kind of coming in too for things like lupus, there are you know more and more you know routes for patients to be able to get infusion medications. It you know there will be some challenges there, but again, I have had at least a few hundred patients on Remicade over the last few years. As much as it's a barrier for some, it's you know not gonna keep people from wanting this drug that 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 raised his hand. 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. Yeah, we can hear you. Okay, good. Yeah. With regard to the safety with the 1600 mg every two weeks, I would like to refer also to our PG data that we recently published, where we administered an even higher dose of 2400 mg every two weeks. In none of these studies where we used 800 mg every week, 1600 or 2400 mg every two weeks in PG as highest dose, we saw a safety profile or safety findings that were new to us, compared to the lower doses. Expectations on the 1600 mg dose is that it will be most likely good, show a good safety profile, and we will see what we have seen before. We will never know, but 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. You know, 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. You know, our view, two studies are needed for approval in this indication. We have not disclosed how much those will cost and, you know, we wouldn't quite yet. You know, I think in terms of, you know, other programs, you know, 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. We are gonna continue that focus. We also do have phase III COVID data coming at the end of the first quarter that we have been guided, so that is certainly still going. Our oncology program is still ongoing as well. That nothing is being affected by this program at this moment. Thank you, Ed, for those questions. If you have any additional questions, I know you had your hand up, you know, feel free to raise your hand again or ping me. 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. You know, I think, you know, asking that specific question of, you know, are you willing to take a biologic? Is your disease bad enough? It's a lot of that has to do with, I mean, there's also fear around medication. It's much different for a patient who you just, I think, were to take off the street and ask versus somebody you sat down and talked their risk benefits on. You know, and again, I think it's much more than 200,000 patients. You know, I think, you know, again, most population studies where if you look at. The way that people figure that out, you know, HS is misdiagnosed all the time, so when doctors often look at it, 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 ask, you know, population-based health surveys and you ask things like, "Do you get boils in your groin or, like, in places like the underarms and groin, and does it happen, and how often, you know, does that happen, you know, more than a few times?" A lot of people say yes to those questions, which is highly suggestive of hidradenitis. In those studies, it's as high as like, you know, 1% or 2% even in some groups. If you look at algorithms that look at patients with multiple abscesses over time and combine that with patients coded with HS, you get up to, like, you know, that 0.7%-1.2% range. There are a lot more than 200,000 patients, would be the first point I make. The second one would be that, you know, HS, you know, like, people have mild psoriasis, they can put on some ointment, they can clear up the few plaques they have around. You know, mild psoriasis is often very, very manageable, not a huge burden in terms of quality of life. Whereas, you know, if you talk about mild HS, like early stage one HS, where people are getting, you know, one or two abscesses every month or two, you know, and an abscess is a miserable experience. If people get one abscess, you know, in their life, they remember that week as being really hard. Like, they had something where they couldn't sit a certain way or they were in, like, very severe pain. And these patients constantly deal with it, you know. The patients who are sometimes sort of most frustrated are those where, you know, they're normal two weeks of every month and they're in misery two weeks of every month, and they have this constant back and forth all the time. Many patients, even with mild disease, I think will be willing to take a drug like this if it meant disease stability. I think the patients who have early stage two and three disease, which makes up the large majority of who I see, I think especially being at a referral center for it, you know, 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. You know, 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, you know, become exaggerated a lot of times in terms of the true risk that it presents. Yeah, patients dealing with this disease are often, you know, eager to do whatever it takes to get it under control. I would say it's, you know, 75% or better. There are gonna be always some patients who say, "No, I want to try to do something naturally," or, "I just, I'm too hesitant to start something like that," or, "I can't commit to it at this point." I would say it's the majority of patients who feel like, you know, if I could tell them, "Look, this is gonna work, you know, 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. You know, the next question, I'm gonna pitch to you, Niels, and I think it's important to go back and explain this is, you know, when we looked at the R on SHINE, it didn't show a dose response. It just showed the high dose had a significant difference in HiSCR versus placebo. The rest of the lower dose groups looked like more placebo. Maybe you could just go back and explain that phenomenon based on why, you know, given how the draining tunnels looked. I think that may be helpful for you to re-explain that. Sure. Happy to do that. Maybe while I start, we could ask that we jump to the appropriate slide back, which is this. Yeah. Go up a little bit. Nope. A little bit higher. A little bit higher. Yep. Thank you. I think the question was why don't we see a dose response on this slide, so at week 16. 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. We had an earlier slide in the same slide deck, which we showed on numerous occasions before, that only the high dose, only 1,200 milligrams was able to significantly reduce draining tunnels. Now, that makes a lot of sense when you look at the C5a data and the correlation now. That means one of the two key requirements, the reduction of draining tunnels, is only to be expected significantly reached by the high dose. That's why, you know, 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. This is why we were 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 one criterion is 50% reduction of draining tunnel count. Therefore, you can only see a real, like, significant response when you have a drug that moves the draining tunnels. I do believe that is particularly helpful question and also important for us because, you know, we wanted to design an endpoint that really helps and is there for patients that have active draining tunnels. 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 whether reduction of one draining tunnel is important. You know, when you ask that to a patient, I mean, Dr. Sayed told us that before, but we asked that to a patient representative. Even I've been looking at this disease and trying to learn here for quite some time now. I was stunned how much, especially one draining tunnel can impact your life. I mean, some of them can drain a massive amount of fluid. That patient who was also happened to be in a patient advocacy group really made that very, very clear what it even means if you just can lose that one draining tunnel. Long story short, that endpoint was designed to cater the mode of action, but to really then help the patients with draining tunnels. I hope that explains that very well, why we don't see a dose response, especially if you do not have a dose that moves draining tunnels underneath the high dose. Great. Thank you, Niels. While you're still speaking, another question I think is important as people try to understand C5a and the mechanism is, you know, why we're not using C5a levels as a patient selection criteria. Maybe you can explain why we're not doing that. Sure. C5a levels, that's really something that we looked at for many years in different diseases. While, you know, 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 abundance in how you produce, how much you produce, even inter-day differences in production. You really look at this in a patient population that may be meaningful. 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 that 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. 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. 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. If we did patient selection based on C5a levels, we believe we may lose a lot of patients that are still in need. I do think the patient selection at this point in time should not necessarily be driven by this specific marker, but rather by the pick of the expert in the clinic, like, the clinical need that the patient, you know, 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 scars, and you're okay, you know, that may not be a patient in need for a biological therapy. But if you have constant waxing, waning or active draining disease or painful disease, then there's a lot more likelihood for need. I hope that explains it. It's really a complicated issue underneath the surface. 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's very thankful for the presentation. 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. If you know, additionally, have you observed any differences in how patients access your care? Yeah, that's interesting. I mean, you know, certainly it's had an impact in terms of, you know, especially in the beginning, you know, clinics were, you know, mostly shut down except for very urgent issues, which come up more often in HS. I think I was probably even more active through those kind of very early days. You know, since then, a lot of it has to do with things like staffing issues, and trying to sort of have enough bodies to support us in the clinic. You know, like many other practices, we do more virtual care, which, you know, can be done to some extent for HS. A lot of times you need the patient there to evaluate and, you know, feel and talk through things like, you know, whether procedures might be necessary. It certainly has an impact. We also just can't see the same volume of patients or so we're even still a little bit less than we were in the beginning or, like, kind of before the pandemic started. You know, I mean, we've always had waits like you know. I've got you know I'm constantly aware of like the 100 or couple hundred patients that are on the wait list with HS to get in right now. I've got you know two other partners that see a lot of HS patients. That is probably worse in some, just as our volume has decreased, we haven't been able to get to as many patients as we were before. 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, you know, COVID outcomes. In the beginning, we were a little bit leery of that, but we never stopped anybody's drugs specifically 'cause of the pandemic. I still prescribe, you know, the same way I would have before. If I think a patient needs it is worth doing and the risk benefit, you know, kind of calculation is sort of the same. In terms of prescribing habits, the treatments that I offer, that is relatively unchanged. It's more just, again, things like volume and how our clinic and practice, you know, approaches patient care, and the interface that we have to use. That's great, Dr. Sayed. Another, you know, really smart person from the investment community would love to know, you know, just your patient volume and maybe, you know, your patient volume with active draining disease. I think that would be interesting on a whatever you wanna share, month, week, whatever, basis would be up to you. Sure. Yeah. I split my time with, like, some research and teaching too. I'm in clinic, you know, five half days of every week. You know, previously, before I had sort of geared up more with the research, it was seven half days every week, and then doing, you know, less of those other things. You know, on Monday, I probably saw, you know, between 10 and 15 patients with HS. On Tuesday, I probably saw closer to 20, and for a lot of them, those were, you know, things like surgical visits. Yesterday, I just had a half day in clinic, and I saw probably eight o r so with HS. In a given week, I'll see, you know, probably around, you know, 35 or 40. I think before I cut back clinics a little more, I was probably seeing, you know, closer to 55 or 60 even most weeks. You know, as I look back over the course of, like, the last few years, like, we have a registry where we recruit patients in and collect data and specimens for research and things. We've got about, like, a little over 1,100 patients in that over the course of about three years. That's even with the pandemic really slowing things down. We have very high volume. Again, I've got, you know, two 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 12 every week, I would guess. Yeah, that's my volume. Again, I'm in a tertiary care center. I've got an HS referral practice. 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. You know, but especially the new patients that come in, you know, it tends to, which are four, five, six a week, you know, the large majority of those have you know, disease with draining tunnels. That's great. Yeah. Thank you, Dr. Sayed. That's great feedback, yeah, you know, for our audience. You know, we're almost done. We're a little over time, but I think this has been an incredible discussion. We're gonna take one last question, and I think that this is, you know, we'll have Niels start, but, you know, it would be great to get your feedback as well, from you, Dr. Sayed, as well as Hoda and Corinna, if they'd like to share. You know, we have seen an emergence lately of the IL-17 class with, some other products that have, been being studied in late-stage studies. I think from a mechanism of action perspective, you know, vilobelimab definitely has, you know, an advantage on these draining tunnels. It'd be great to understand, Niels, from a scientific perspective, your view and, Dr. Sayed, if you have a 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. 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. You know, 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 data that shows that C5a feeds into IL-17 signaling as well. C5a is kind of in the core center. It's not a cytokine like the interleukins. It's a complement activator, and it feeds into many cytokine networks. There is some interlink. Also to 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 through other mechanisms maybe. That's certainly where Dr. Sayed can add a lot more color than I could ever do. The differences when it comes to the profound knowledge on both IL-17 but more so even on C5a are clear. I would say rather than just looking at the different mode of action, I would add, like, two points that I think are very important. One you know is to me one of the most important points, and that's an open question more than it is a point: whether there's a long-term effect of your treatment, right? I learned and I'm hoping that we can hear Dr. Sayed 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. 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. With that mechanism we are seeing, too, 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. That's something we're hoping to investigate as well and hoping to see in phase III. That could be a differentiator. Second differentiator is the mode of action, and with that, we have chosen the different patient population because of the mode of action. I see them both as valid targets and probably complementary. I pause here. Thanks, Niels. Dr. Sayed, any comments? Yes. I mean, you know, I can't make the point enough that, like, you know, we have such, you know, so, you know, our options are so limited right now that, like, I need, like, two, three, four, five, you know, more things than I have right now. I think IL-17s, like, you know, are promising. Like, there's no doubt about that. Like, I thought theoretically, IL-23 should have been great. They, you know, bombed at this point, so they're kind of off the playing field. You know, the 17s I think are still very much in it, and I think for some patients, you know, will be a very good fit. There are gonna be a lot of patients in it 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 gotta have another mode of action. From a safety standpoint, again, there's gonna be intolerance, you know, amongst certain classes 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 antagonists in those patients because it makes Crohn's worse. There is gonna be even an IL-17, like, we assume that, you know, secukinumab, you know, bimekizumab, which has a phase III program going now, even if both of those hit the market, I am still gonna have huge gaps in what I need. I'm gonna need to offer patients, you know, multiple options to think through because one of those is gonna feel like a better fit than the other, you know, based on just individual patients, discussions with patients or how they work. A lot of that's gonna be stuff that I also think I'm gonna feel out as I have better access to these drugs for the general population. You know, getting a feel for who tolerates which drug better, you know, looking at the longer-term control and how that kind of pans out for patients over, yeah, whether, you know, those patients with, you know, a lot of draining tunnels are the ones who really need a, you know, C5a antagonist versus, you know, an IL-17 inhibitor. You know, we have this deep bench of treatments. You know, I've got, like, a dozen great psoriasis treatments, and I end up needing to pull from a lot of those over time. Right now I have, you know, no simple backup plan or no simple second line or alternative to first line, so it's a better fit for HS. You know, at this point in time, you know, the IL-17s, I think are likely to have, you know, patients where they're successful. I think regardless of that, there's gonna be a big role for a C5a inhibitor. Thank you, Dr. Sayed. This is fantastic feedback you shared with us, and I just wanna thank everyone for joining. This finally brings us to the end of our event. Our panelists here were fantastic. Dr. Sayed, 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, you know, do everything we can to potentially bring this drug to market. I wanna thank everyone for their interest today in IFX, vilobelimab, and HS. Today's slide deck and recording will be available on our website, like I said before, under the Investor section, Events and Presentation 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.