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

Good morning, everyone. Thank you for standing by, and thank you for joining InflaRx's Conference Call to discuss the company's expected development plans for INF904, our orally available C5aR inhibitor with best-in-class potential. Presenting on today's call, we have Niels Riedemann, CEO and Founder; and Camilla Chong, Chief Medical Officer; with Renfeng Guo, CFO and Founder; and Thomas Taapken, CFO, available during the Q&A session. [Operator Instructions] Please note that today's call is being recorded. [Operator Instructions] I would now like to turn the call over to Dr. Niels Riedemann, CEO and Founder of InflaRx. Niels, please go ahead.

Yes. Thank you so much, Jan. We're really excited to have everyone on the call today to share with you our development plans and I will dive right back into our topic. But before I do that, I think next slides will be just a cautionary note on the forward-looking statements we're going to make today. So please take note of them. Next slide, please. So we are really about harnessing C5a and C5aR. That's part of the complement pathway for controlling inflammation in the I&I space. And we have, as highlighted, really uniquely targeting mechanisms and drug candidates. And these are validated mechanisms in the meantime, and they're a critical part of the inflammation cascade. We have a first-in-class highly potent anti-C5a monoclonal antibody known as Vilobelimab, plus a second-generation IFX-2 in the pipeline as a life cycle molecule. And we have a best-in-class potential of C5aR inhibitor INF904, and that inhibitor is exciting the team a lot because, first of all, we are trying to address certain invitations of the marketed comparator. And we are, at least from our Phase I data, clearly differentiated, especially on the plasma BK and inhibitory potential. But we also are excited because this is a pipeline-in-a-drug potential here in this candidate and that, that can address larger markets likely and also markets in the immuno-derm space, which we'll be talking today, but also outside. So we have set an initial focus here on immunodermatology and we believe that we can drive pipeline value in these markets. In immunoderm, we have a strong IP coverage and medical use coverage. And we have both Vilobelimab with a late-stage development Phase III ongoing in pyoderma gangrenosum and INF904 that will enter Phase II in 2 initial indications, that chronic spontaneous urticaria and hidradenitis suppurativa. I just want to make sure I do mention that we feel very lucky that we are supported by world-class scientists and researchers and clinicians, key opinion leaders in this space. We have a large upside potential in additional indications, and we are open and are exploring potential collaborations to unlock additional value here. We have a strong balance sheet that we just reported today, and that takes us at least into 2026 to advance our programs towards the next milestones. And our team has a proven track record in delivering clinical trials and also regulatory success with the emergency use authorization we received last year. Next slide, please. So why immunoderm? Well, first of all, there are several attractive multibillion dollar commercial opportunity markets to be explored. And then also, we have an identified crucial unmet medical needs that we believe INF904 may address strongly. There is a sound scientific rationale and also in the meantime, some clinical data on the role of C5a and C5aR and this new mechanism in this space. There are established end points that are established for approval. And there's no known safety concerns or potential -- and a broad potential therapeutic index for INF904. So this oral C5aR antagonist has a differentiated pathway that addresses a mechanism of action that is currently not addressed by any competitor in the immuno-derm space. And we are very excited about moving that in there. We have an established network of experts and also in-house trial expertise in this area, and we -- I mentioned already the strong IP coverage. Next slide, please. So this just depicts our initial focus here in immuno-derm, and we've been talking about these 2 indications, chronic spontaneous urticaria and hidradenitis suppurativa today, and there are others that we may explore in the future. Now we also list here a few selected indications in neurology and in the nephrology/hematology space. And that is to demonstrate that we've done quite a bit of work in many other disease indications. These are some where we are very excited about the opportunity, either from our research or also from initial clinical data for, for example, the competitor, [indiscernible], that had shown initial efficacy in some of the nephrology indications here listed, and of course, have got an approval in ANCA-associated vasculitis. Next slide, please. So this brings us to the pipeline here. It's basically showing our focus that I've just explained, so I don't want to reiterate that. I just want to make sure to flag the strong focus on immuno-derm and the potential outside. I do want to mention that Vilobelimab does have an emergency use authorization for certain critically-ill COVID-19 patients. And potentially go into broader ARDS and we will cover that at the end of the top briefly. Next slide. Okay. So let's talk about the strategic positioning, and let's talk about the target just for a minute before we dive into the indications. Next slide, please. So we are uniquely positioned here. We have 2 validated drug targets covered by 2 very exciting molecules. C5a, a ligand covered by Vilobelimab, and the receptor covered by INF904, our new small oral inhibitor. Now it's important to note that if you want to have control over this pathway, you need targeted inhibition. Why is that? Because upstream blockers like at the level of C5 or higher in the complement system, they lack the ability to block the cleavage that occurs through multiple enzymes. So in other words, while they're very sufficient in blocking the complement mediated cleavage, there's another mechanism that is not touched by them. So there's no evidence that these drugs can block C5a in humans in disease in a sufficient manner. So we need targeted drugs. We have 2. We're excited about them. Why? Because C5a is upstream of the cytokine network. It actually boosts a lot of known cytokines, some of them are listed here. It's a strong activator of neutrophils, macrophages and other immune cells. And what does that mean? It means that it attracts neutrophils, chemotaxis and it makes them generate oxidative radicals and granular enzymes. And then that is the tissue damaging effect we will see in many of the diseases. And there's an increasing knowledge around the role of C5a inducing NETosis. And I'm going to be speaking about that a bit later because NETosis is increasingly of interest in the immuno-derm space. Now there's over 6,000 publications in many, many different disease settings, and we are very excited, but we've chosen initial immuno-derm indications, and we will be showcasing them a bit today. Next slide. So I want to start with our running Phase III in ulcerative Pyoderma Gangrenosum with Vilobelimab, our first-in-class monoclonal antibody covering the ligand. Next slide. principally, just as a very brief recapitulation here, it's highly selective C5a blocker. It blocks it very effectively, up to 100% in human blood. It doesn't touch the MAC formation, so it leaves the defense mechanism that is known and important in the complement space intact. It's a fast binder. It's commercially available under the EUA that I mentioned. So it's uniquely positioned to be a fast and strong binder of the ligand. Next slide. So Pyoderma Gangrenosum is a terrible disease. There is no drug approved in the U.S. or in Europe. It's a neutrophilic skin disease that manifests with large, sometimes very large debilitating ulcers. Patients suffer from these ulcers dramatically as they are very painful. They can occur on all body parts, but typically start on the lower legs. And it's a rare disease. We're estimating about 50,000 patients in the U.S. and in Europe altogether. But there's a significant market potential because premium pricing is possible. We have orphan drug status in the U.S. and in Europe. And there's nothing else approved, and there's not even a consensus guideline yet in most countries how to even address this disease. So typically, these patients are treated with all sorts of anti-inflammatory attempts, sometimes even cocktails until either something works or they are referred to another physician. Next slide, please. So I just want to share with you some of the new research. So there's an increasing body of evidence why neutrophils and also NETosis, which I mentioned before, plays a role. And I want to draw your attention first to the picture on the lower right side. So this was C5a measurements here from a research group in wound fluids. And you see that the PG wound fluid showed a higher C5a load clearly. And also you see that these wounds were containing Elastase a marker for NETosis. And finally, these parameters correlated. So the higher the C5a, the higher the Elastase levels. that's not necessarily surprising knowing that there's a lot of research showing that C5a induces NETosis, and the same paper concluded that in the slide above that controlled neutrophils do not undergo significant NETosis. But if they are stimulated with C5a here in [ nanomole ] that are found in humans, you see that this is a staining marker here for extracellular staining and C5a by far, is the strongest inducer of this NETosis marker. One can even say they couldn't really find another one, maybe IL-8 after long-term stimulation, you see that on the right side, gave a bit of a signal. So that's -- there's an increasing body of evidence on that mechanism. Next slide, please. So we had a very interesting Phase II with a strong result on the benefit factor for the patients. So in our high dose group, we had 86% of the patients going into clinical remission. So these patients all ultimately closed their target also. And you see the overall results showed also in over 50%. That is across all 3 dose groups. And the remarkable other thing is that all of the patients that were evaluable, 17 altogether, had an improvement. Not everyone at clinical remission but over 50%, 1 additional patient had a response and then others -- 7 others stayed slight improvement. So we didn't have any safety signals of larger concern. We had 2 report the SAEs. You find them here below. One is a typical problem that these patients have, wound infections and the other 1 was a rash likely due to the drug as a hypersensitivity reaction. So we -- I mentioned the orphan drug status in the EU and U.S. and we also have fast track. We did discuss our Phase III trial with the FDA and that brings me to some of the results on the next slide, please. Why did we get so excited? Now when you see these patients, and when you work with these patients, you get excited when you can help them because they're really suffering a lot. And these are just 2 examples. The left side is 1 of my favorite examples because this is a patient that developed a PG ulcer under Adalimumab treatment under TNF-alpha inhibition. And that was the patient's medication for an underlying other disease, in this case, psoriasis. And this wound was difficult to treat. He was actually the fastest responder in the trial, and heal that also very rapidly. And on the right side, you see a patient that had multiple treatment attempts with a bad ulcer on the right lower leg above the ankle. And this patient was up-dosed from the medium dose to the high-dose group, which then ultimately closed the wound relatively rapidly when being up-dosed. And this is actually a remarkable result because these wounds above the ankle are very difficult to heal. Next slide, please. So this brings me to the running Phase III trial in PG. This trial is currently recruiting. This trial is a placebo-controlled trial with 2 arms, a simple, the 1 arm, Vilobelimab and the other one, placebo, both on a low dose of prednisone, which has tapered off during an 8-week process. And then the patients have reset dates, where we are checking for patient-level stopping criteria. And when a patient hits the stopping criteria, meaning the patient doesn't show wound improvement, then the patient is transitioned out of the trial and considered a nonresponder for the primary endpoint. This is the way we discussed the trial with the FDA. You see that we have an interim analysis after about 30 patients, 15 in each arm. And I want to just be talking about that just a second here because I think it's important to understand that this is an important interim for us. It is unblinded for the IDMC, but blinded for the team and for the trial. And it can lead to stopping of futility or to an adjustment of between a final total number of patients enrolled between 50 and 100. Now this is a meaningful size in PG arena. And obviously, to have a p-value positive readout with the patients in the range of 50 to 100 patients, you need to have substantial difference between placebo and your drug. And so for us, that interim analysis, if it doesn't stop for futility, is certainly a positive sign. And of course, if it were to adjust only to the minimal enrollment, this installs further confidence in us. However, it's important to note that we don't stop enrollment during this interim read. So at the stage, where we know if and how the trial adapts, we already may have reached the final enrollment, at least on the low end here. And so for us, this is an interesting read, and it's an important read and this will occur as we just today guided next year in 2025. Just to mention, the primary endpoint will be complete target of the closure, which we've seen with the drug in Phase II. Next slide, please. So this brings me to our exciting C5aR inhibitor or our oral drug INF904, and I'll be introducing the drug briefly before we go into the indications. Next slide. So the key features really. I'm not going to read all of this, but we are really excited because we were able to reach a very differentiated PK/PD profile, when compared to the reported data from avacopan. We had a 3-fold higher Cmax, 10-fold higher plasma exposure and which is probably most significantly increased blocking activity, which showed above 90% blocking activity for comparable doses starting at 30 mgs. And that was our goal. And this Phase I trial really reached all of our goals. We didn't have any safety signals of concern. We were able to show this over broad dose range. We also know that the drug has less inhibitory potential on the important liver and lung CYP3A4 and 5 when compared to the avacopan data. And we have a strong IP position. So we'll be taking this to immuno-derm because this is an oral drug, very differentiated mechanism of action, and we believe that this can really bring a lot of benefit to patients that have a high unmet need. Next slide. So this is important. I'm not going to go into the details of the experiment, but this is a head-to-head experiment preclinical in a live in vivo experiments in rodent [ C ] enhancers. And what that shows is on the left side that at the exact same formulation, at the exact same dose, in this model, in the hamster, we doubled the inhibitory effect with INF904 compared to avacopan. So this doubling of the effect was really very encouraging. And we've seen pretty much almost a doubling of the inhibitory potential in the Phase I already. So we expect that this will translate to a potential of higher efficacy in human disease as well. Okay. So again, I'm not going to go into the details, but I just want to flag 1 thing. You see the plasma concentration is quite different. And we believe that this is really an important differentiator that we reach very different plasma levels very rapidly with the drug. So we are just able to come into the range, where the drug can do the full trick, which may be a much more tricky task for our comparator. Next slide, and this gives you a visual. This is just the single dosing from our just reported Phase I study. And you can see in the red dotted line, there's a superimposed. So this is not a head-to-head study, but the data reported from avacopan are superimposed into this graph. And you see the comparable doses, the blue line of INF904 30 mg 1 shot. And you see that there's a very differentiated PK profile. You see that the time to max occurs, the peak occurs. Later there's a much broader area under the curve. And again, this confirms the 3-fold higher Cmax, but also the tenfold higher plasma exposure. And that was true for all comparable doses. And then you can see above the dose, we tested up to 240 milligrams without any safety signal. Next slide. And this is the side that we are most excited about is that shows, in this case, in a 14-day dosing multiple ascending dose with 3 different doses that we have a very tight control over the C5a-induced signaling. So when the drug is taken out of the blood, patients at trough, and we challenge that with new C5a, it blocks it over a very broad dose range up to 90% and higher. And that really is, for us, something that we wanted to see and really confirmed all the preclinical work. So next slide, please. So we will begin our Phase II development this year. Still we want to start with an initial Phase IIa demonstrating the pipeline and a drug potential really for this drug. This will be an exploratory study, but a PK/PD and safety basket study. That means a 4-week initial treatment in 2 immuno-derm indications, CSU and HS and we will also look into 3 different doses here to assess PK and safety. So the catalysts we want to start this trial end of year 2024, and we want to have data in 2025 that we can share while preparing for a meaningful substantial larger Phase IIb studies in this indication. And they're expected to begin also in 2025. Next slide, please. So with that, we're going down the road now to go into the initial indications chosen, and I'm very happy to hand this over here to our Chief Medical Officer, Camilla Chong, and Camilla, please help us and speak about Chronic Spontaneous Urticaria. Thank you.

Thanks, Niels. So next slide, please. I just wanted to start by saying that we are really thrilled to be able to first of all, collaborate with Professor Marcus Maurer, whom from Charité, Berlin. Who many of you who have worked in this space will know, is a world-leading expert in CSU. And it is really his conviction and persuasion that with the increasing scientific evidence that have been generated recently to suggest that C5aR signaling is involved in histamine release from both mast cells and basophils in CSU patients in an IgE independent manner. So this mechanism may play a role which is important for both described endotypes, which I will go into a little bit more later on so-called Type 1 and Type 2b. So there is also belief from his group and others that despite availability of current treatment options, such as antihistamines and anti-IgE therapy, there is -- and not an insubstantial number of percentage of patients of either, who have not responded to antihistamines or omalizumab therapy, who remain nonresponsive and is, therefore, symptomatic. We believe that, therefore, INF904 can be a convenient oral therapeutic option, particularly for those, who do not want a continuous subcut injection every month, and those who may not tolerate quadrupling therapies with antihistamines or IgE. We believe that the CSU market potential is estimated to exceed over $3 billion by 2032. Next, please. For some of you who are familiar with CSU, you will recognize that, as described in literature and by many experts that this is an immune-mediated chronic inflammatory skin disease, which have disregulated inflammatory processes involved, leaving patients very predisposed to symptoms, which are both debilitating and are chronic in nature, predominantly the development of itchy hives and wheals that do not go away for a period of over 6 weeks and some are often associated with angioedema. I think the important thing to highlight about this condition, as many of you will know, is that it has high physical and economic burden, not just for patients and families, but also for health care system. The estimated prevalence is -- has been described to be around 1% of the general population in most countries and that up to 20%, if not more, of this so-called population experience symptoms for more than 5 years. 20 to 40-year olds are particularly affected. Some have described 30 to 60-year-old and with women being impacted twice as often compared to men. Current treatments, as I've already mentioned, the only approved treatments are antihistamines and anti-IgE therapy. Next, please. So as described earlier, Professor Maurer and Group have done a lot of work, too, based on their observations of treatment in CSU patients, and they have described these 2 main endotypes for CSU. These are basically broken into Type 1, which is characterized by IgE autoantibodies directed to self-antigens, and therefore, the term Type 1 auto-allergens. But they also believe that there is a Type 2b autoimmunity of which this makes up something like 30% of the so-called CSU patients. And this is more IgE, IgG mediated antibody directed specifically to the anti-IgE or to the FC Epsilon receptor on both mast cells and basophils. So both these pathways is believed to involve C5a, and therefore, the C5a signaling is important in these 2 cascades as shown on the diagram on the left-hand side. Next slide, please. Now I know that this is a slightly busy slide. So if you'll indulge me to spend a little bit of time to walk you through it, starting from the left-hand side. So the left-hand side is basically an experiment in CSU patients where they measured C5a levels. And as you can see here, C5a levels are significantly increased compared to control group. So C5a levels are elevated we know in CSU patients. And then at the bottom on the left-hand side, what you would see is essentially staining of skin biopsy in CSU patients of C4D, suggesting that basically there is activation of the complement system. And then now, if you focus your attention to the middle graph, what's interesting here is that this was an experiment done over 20 years ago, where essentially, they've been able to show from healthy donors blood, C5a in itself can actually induce histamine release from basophils in a very nice dose-dependent manner. And then last, but not least, the last part of this graph shows that actually the C5a mediated histamine release is independent of the IgE pathway. This is an ex vivo human skin experiment, where they incubated it with a SYK inhibitor, which was a GSK compound that basically work predominantly via the IgE pathway, and they then added increasing levels of concentration of C5a. And as you can see, the C5a stimulation of histamine release is not affected at all via this IgE pathway with the SYK inhibitor, GSK2646264. Next slide, please So here, what I wanted to demonstrate to you is a piece of work done by a Japanese group recently published in 2022. And what they have tried to do is they took blood from CSU patients and measured the different levels of basophils after stimulating it with an anti-IgE stimulus. And on the left-hand side, what you can see is that basophils from these patients, with an anti-IgE stimulus and hence, they call it IgE stimulus positive patients with histamine release, they show a really good response. And I think interestingly, these basophils also showed histamine release in a dose-dependent manner in -- with C5a stimulation. If you then focus on the graph on the right-hand side, CSU patients, who do not respond to the anti-IgE stimulus continues to be responsive to C5a stimulation. Next, please. So what they proposed is that actually C5a-induced histamine release is important for both pathways, IgE dependent as well as IgE independent, whereby if you look at the IgE dependent pathway, C5a still plays a role in addition to the other pathway, where it is non-IgE-dependent. And I think in addition to that, what they have managed to also showed is that the C5a generation in CSU may be further amplified because of the activation of the coagulation pathways via tissue factor release. In addition, so this acts as almost like a continuous amplification loop, which further drives disease. Next slide, please. So in conclusion, I hope you would have seen that C5a signaling is involved in histamine release from both mast cells and basophils. And that certainly, this has been the conviction from Professor Maurer and group that the C5a mediated histamine release is suggested to play a really important role in both subtypes of CSU, even though it can be shown to be released independent of the IgE pathway. And we really believe that this C5a inhibition represents a novel mechanism to address an unmet need in CSU and that INF904 has the oral -- the potential to offer an oral drug, which is potent for the development in CSU. Thank you. I'm now going to hand back to Niels, who will take you through to our next indication.

Yes. Thank you so much, Camilla. Really appreciate it. I'm excited now to speak a bit about hidradenitis suppurativa. Next slide, please. So this is another indication that we want to show the potential of the drug and show that the drug is active initially. So when you look at this disease, it's probably well known to some of the people here on the call. There's still new mechanisms are needed, and that's what we hear from KOLs, and we are very, very attached to that scene generally speaking. So especially moderate-to-severe patients, who have active draining disease. They're oftentimes left with non-ideal or nonworking options, even though recent progress has certainly produced drugs that are approved, like the anti-TNF-alpha class, or like [indiscernible] actually and some anti-IL17 agents at least 1 approved the other 1 on the path and the third 1 coming. So -- but these patients that respond to these drugs, they're known that this -- for them, it's known that a significant number will have the efficacy or the effect weaning over time. And so there is a high unmet need for additional mechanisms. And again, there may be also a need that is not ideally addressed by these drugs. So we know that HS patients have a preference for oral medications or injections that has been suggested in research. And we have an oral C5aR inhibitor with a mechanism that really is addressing something, and I come back to the word NETosis here, but also just the effect on neutrophils, again, HS is a neutrophilic dermatosis that is not necessarily addressed by any of the other drugs. And there's clinical evidence I'll be speaking about here in a second about the pathway that this pathway, when addressed, can reduce lesion counts in HS. And this drug has a favorable PK/PD profile with a broad dose range for systemic exposure. Well, that's set aside, the HS market has been described to be a very attractive commercial market. There are estimates that this market has a multibillion peak potential for drugs by 2032, and that is an exciting side note, of course. Next slide, please. So I'm not going to be speaking too much about HS as I believe it's been much discussed by also recent research. And I just want to mention that this -- for the patient effect that this is really a truly living nightmare, especially those that are progressed in the disease to moderate, severe stage and those that have active draining tunnels. Because they can -- a single tunnel and if you go on the Internet and research that there are -- I think there's even a video that shows that a tunnel produces up to 1 liter of pus. Just 1 single tunnel because the tunnel is the outside that you see, but underneath the tunnel is a deep seeded lesion. And these lesions are in the skin. They're hurtful. That the pus is really carrying a huge social burden and you have to imagine that this disease occurs under the armpits and oftentimes in the groin area. So it really has a social life destroying character. Okay. So next slide, please. Maybe the last thing I wanted to add is that, this is clearly a market with a lot of patients affected. There are varying reports about how large it is, but it's clearly more than 200,000 patients even in the moderate-to-severe stage in the U.S. So on this slide, I want to just basically convey 1 message. I don't want to walk you through the whole slide, but there's recent progress on the understanding of the pathogenesis of the disease. And this just shows that research, which is -- which is not coming out of our group, but out of people we know, suggest a central role for C5a and C5aR in the pathogenesis, in the mechanism that is set into place, when these follicles rupture and when, in the initiation phase, an immune reaction to this rupture, to this follicular rupture, this is the current hypothesis is set in motion. And so it's really recognized in the field that this is a central role. Next slide, please. So we produced data a while ago that these patients have elevated C5a levels. This is with a validated [ Eliza ]. And this is not surprising and actually in the Phase III study that we -- sorry, in the Phase IIb study that we ran, we showed quite substantial C5a levels in these patients. Now we also have shown some interesting data that HS patient plasma strongly provokes neutrophil activation. So when you take plasma from HS patients, and you subject fresh neutrophils from fresh donors to that plasma, they get activated immediately. And both drugs, Vilobelimab and also new data with INF904 with our oral C5aR inhibitor have shown that they can pretty much completely abrogate that activation. So meaning that, obviously, it is C5a in that plasma from HS patients that excites fresh neutrophils and stimulate them strong. Next slide, please. So is the receptor present, a recent study have shown that beautifully for all 3 stages of the disease. So you always have the common tissue haematoxylin, eosin staining in red above. And you see that the lesions are marked. And then below there is a staining for C5aR and neutrophils, but it's also found in other cells like histiocytes and giant cells. And you see that C5aR staining is found strongly around these lesions, particularly in the middle -- in the stage -- early Stage 2 also around when patients develop draining tunnels. They tend to rupture and they tend to create that large intradermal lesion. You see that when that happens, there's a lot of C5aR around and then also on the right-hand side in the most progressed [indiscernible]. So C5aR is present, not surprising because neutrophils are present certainly in all 3 disease stages. And something that I won't show you with a slide, but we will go into more detail and another day is that NETosis occurs quite substantially in these patients, and that's also new research, again, C5a being 1 of the key inducers of NETosis in neutrophils. Next slide, please. So there's clinical evidence I mentioned, and I just want to go into that very briefly. So with Vilobelimab, we did a Phase IIb study, and that clearly created on the high-dose level evidence that C5a inhibition can reduce the inflammatory lesions and all of them. There was a particularly noteworthy effect on the draining tunnels that we spoke about. And this was actually the higher -- the tighter the C5a levels were controlled, the higher the draining tunnel reduction was. And the key learnings from our like substantial work in the field was really that we -- that Vilobelimab was needed to adequately control C5aR signaling only when it's given in a higher dose. So in other words, you need a very high dose, the dose we've chosen is probably what's according to our PK/PD and top PK modeling, not enough to adequately cover the signal. So that's the key learning. But the other learning is it is an interesting path that it's promising for the future to decrease these lesion counts. On the oral C5aR inhibitor side on avacopan, there's also been studies done, and I want to share with you that at a standard dose, which is the approved dose in another disease indication at ANCA vasculitis, which is 30 mgs twice per day. There was a p-value positive efficacy signal when they looked at the subgroup of severe HS patients, early Stage 3 on high score with a clear separation from placebo group emerging late only mostly on -- at week 12. Now I do you want to mention that the study was also negative on the overall study population when it comes to HiSCR. There was also a very high placebo response in the early Stage 2 patients, which probably just able to see an effect. But the interesting part is really that in the Stage 3 patients, these groups and the lesion count separated really at week 12. And so when we looked into the -- switching to ANCA vasculitis, which is the area where avacopan is approved, the filing data showed that the drug has a very strong accumulation pattern, 4x, and it takes approximately 3 months until it reaches the plateau like an -- of the accumulation phase. So that fit quite well with this observation. I'm going to show you a picture in just a second. So how we interpret that is that 30 mgs twice per day dosing regimen of that drug because of its PK features, was probably not adequate, not high enough to show an efficacy earlier and the separation early. And of course, we conclude from that, that is a problem that could be handled with the right PK and the right drug. Next slide, please. So these are the data from the Chemocentryx reports back then from the AURORA study. And again, I mentioned that the overall trial results were not p-value positive, but the early Stage 3 patients showed the separation. You see the gray curves are placebo, the orange curves where avacopan at the dose that I explained, and you see the AN count on the left side, you see the nodule count in the middle and you see the draining tunnel count. And you see that really the separation starts only to be like strongly visible at week 12. So somewhere between the last visit at week 8 and -- the second last visit at week 8 and week 12 there, there was a separation occurring, and you see the high HiSCR treating [indiscernible] here on the right side. Now again, I explained already that from another disease from the ANCA disease, we learned about the late accumulation. And again, our conclusion is that this may not be the right dosing and the right PK profile, but there is efficacy. Next slide. And this is the -- that we graphically work this up. This is the publicly filed NDA filing for the ANCA-associated vasculitis, PK accumulation, again, it's a different disease, but it's interesting because it shows this roughly fourfold accumulation. And you see the steep curve has kind of started flattening out around week 12. In fact, it was week 13 where the steady state was reached and the plasma exposure is given here on the right side. So next slide, I'll come to a conclusion here. And the conclusion is, overall speaking, with the available evidence and knowledge is that there's a strong scientific rationale for the role of C5aR in HS. Now both C5a and C5aR are signaling or blockade of that signaling has resulted in signals of efficacy in HS patients. We believe that a tight control over the signaling of C5aR signal is required to achieve an optimal efficacy. So we all know dosing is important in HS, which is basically true for all drugs tested, if you consider that some of the approved drugs were only showing efficacy when their approved dose from other indications was doubled. Take, for example, Humira. So that brings us to our conclusion that INF904 is ideally positioned as an oral C5aR inhibitor with optimized PK/PD profile to address an existing high unmet medical need in these patients, and we are really excited to move this drug. So at the end of our presentation, I want to speak about Gohibic briefly. Now this is for the Vilobelimab, where we got the emergency use authorization. And I want to first mention that our team feels privileged, honored and is very excited about the fact that we were able to get an emergency use authorization. This was the only emergency use authorization granted in 2023. It's the only 1 for a small biotech company. And it's also the only 1 with a first-in-class mechanism that addresses an unmet need in the immunomodulatory space. So we're excited. We are definitely committed to continue making the drug available to patients at need. We have recently press released our commitment program that helps addressing some of the issues that the acute [ chaos ] that hospital health care system has. And we're in active discussions, and we get a lot of good feedback about this commitment program. And so next slide, please. So this just summarizes the Gohibic emergency use authorization, and our commitment to keep the drug available for patients. And also, we did talk about the fact that we may get a full BLA with 1 additional study in the ARDS trial. Now we are very frugal with our spend in this area because we had never anticipated and cannot anticipate how this market may look like, which comes along with the situation switching from a pandemic into maybe an endemic state. So we're very frugal, and we also mentioned that we would only look into such development, if we get public funding or the help or other non-dilutive funding in the company. So with that statement, I want to close out our today's presentation and open for Q&A. Again, I want to summarize the excitement of the entire team to focus now on immuno-derm with our upfront running Phase III program, but also with the new additions with our oral INF904. So with that, I hand back to you, Jan. And yes, thank you for your attention, and we are -- the team is happy to answer any questions you might have.

Thanks, Niels. So audiences concludes the formal presentation. So we'll open the call to questions now. And there are 2 ways you can do so. First, you can submit a question in writing via the Q&A button below the presentation window. I'll then read that question aloud during the Q&A session. Or you can ask a question live by raising your hand icon under the presentation window and then we'll announce the call for each person at that point. So we do have a question from Steve Seedhouse.

Can you hear me, okay, Jan?

Yes. Okay.

Great. Thanks so much for hosting this call and for the overview and all of the detail on contacts. A couple of questions here. Just starting with HS maybe. Obviously, interesting opportunity you have experienced here at to maybe offer an orthogonal mechanism to IL-17 or TNFs and also the oral presentation is a differentiator. But widening the lend also just seems like an opportunity to establish really in patients the PK/PD advantages of INF904, if that translates from what you've seen so far versus avacopan or IFX-1, of course? So just curious in that regard, will you be sort of closely analyzing PK/PD data in these patients? Will you be able to compare to maybe some of the avacopan data that's publicly available, you shared some ANCA vasculitis or your own IFX-1 data and really determine if you're getting a better coverage of C5aR inhibition essentially in patients in this Phase IIa?

Yes. Thank you, Steve. I'm happy to take that question, if I may. So first of all, it's a great question. Thanks for asking that. And the answer is yes. We will closely monitor PK. This is a PK-focused study. And on the PD angle, we're looking, of course, at various efficacy signals. Now you may see that it's a 4-week initial exposure. And we, of course, have done a lot of work into thinking what can we show at 4 weeks. And we're quite convinced that with the high doses that we can administer our drug INF904, and we will -- and being a small molecule and anticipated high tissue penetration levels that we can see a differentiation or that we can see also the efficacy signals at week 4. Now there are comparatives. We have the week 4 data with our slightly under-dosed Vilobelimab trial. We have the week 4 data, at least in the early-stage [ we ] reported by avacopan, and we have a lot of in-house data. So I think the goal is really to say on the PD level. That may translate into, I would say, a signal that when you compare it especially to known placebo responses at week 4 that will at least give us a good confidence that we're seeing efficacy of the drug here. So we've done a lot of -- and we will go into this into more detail. The press release today has also announced that we are planning an R&D Day in due course. So 1 of our goals for the R&D Day is to have some of the experts we're working with speaking about what we're doing and about what they get -- what excites them, but also a bit more into exactly such details that you just mentioned about the trial. Now what is difficult to do is the PD as we've done it in the Phase I where you have the flow cytometry data on the neutrophil ex-vivo excitation, which requires really a very full on-site training of a team that on-site does the measurement with a fresh drawn blood. So that can be done in trained Phase I units, but you have to almost train the entire team. And we're looking into whether we can get some of the data may be at a few sites, but that is something we cannot fully promise at this point in time. That would be, of course, nice because you can directly compare that to the Phase I data then.

And just -- I mean, you guys have more experience than maybe anyone with regulators discussing HS and the endpoints in the evolving landscape. I guess where are we at today from your perspective with draining tunnels and end points and how to develop something to the finish line in HS?

Yes, great question. So first of all, I want to make sure that it's clear that we're not like basing the entire development on draining tunnels or in whether or not we can maybe develop better tools to show something. We believe that we -- that this drug can also be successful on this HiSCR. It's an oral drug. There's an improved end point, which is the HiSCR. The orals have in the past, shown consistently lower placebo response rates when you compare that to IV infusions, for example. And that has to do with placebo responses. But that set aside, we know that there is a very special additional mechanism of action, as you pointed out, on the most severe lesions. And of course, that can be worked out nicely, either on secondary end points. Yes, we've come back then very close. I think we have with the minimum ambiguity had, had an agreement on a running into a Phase III trial with a new end point. We are consulted by former office directors of the FDA. On that end, there's certainly something we can work out. But I do want to flag that we're not like basically basing our whole development on whether or not we can come to terms for exciting research, we think that we can win the game and win the market approval also on the HiSCR.

And then just to wrap the parallel track here in CSU is interesting. So 2-part question on that. First, I mean, do you view this as really just the sort of lowest hanging fruit, proof-of-concept for mass cell biology in general that would open up myriad development opportunities across the spectrum of mast cell biology, or is there something specific about CSU that drew your attention? And then also, do you think -- you mentioned the 2 endotypes and the contribution of C5aR to both. Is that something that you think you can parse out the relative activity in this Phase IIa? Or would that be too challenging to do?

Yes, I'm happy to pass this over to Camilla and maybe I'll chime in with an additional thought, but Camilla, please.

Yes. I'd be happy to perhaps answer the last part of your question. So we believe that in our Phase IIa study that we're looking at that we should be able to address both endotypes, right? And we're not just restricting it to the very refractory type of CSU patients. So there is no reason why it should not work in either endotype, firstly. And I think CSU is 1 of those conditions, where you can show relatively quick clinical effect within 2 weeks, if not up to 4 weeks. Now obviously, that's different from showing maintenance. But I think this could be a very quick indication for us to be able to really dwell in to -- to really be able to explore the biology of this drug. And the endpoints are fairly straightforward. They're fairly well accepted by regulators. So we feel that this would be a relatively -- not easy, but it would be a less complicated 1 to be able to do plus the fact that it's not a rare indication. So we will get the patients that we would need to be able to study this in a relatively efficient manner?

Yes. Maybe -- and just to add to that, Camilla, I think we are very close here with the team of Dr. Maurer at Charité in Berlin. They've worked out the concept. They initially suggested to us that we should do this development some while ago with VILO. And when they heard we have the oral, we came back into really strong discussions. So yes, the idea would be, and there is a strong support. So they are willing to support us also by recruiting patients and by recruiting both subtypes, as Camilla just said. Now you asked for the more broad general like mast cell biology, I would say, at this point in time, we are focusing on this attractive market and we know, and that was part of the central discussions with Maurer team is we know that there's like really a decent number of patients that are underserved even with the treatments. And 1 of the thoughts is they may be underserved because that second angle, which is independent of IgE is not addressed. And that's exactly -- if that's true, we may address a very broad patient population. We may address all of the population, and that's something we need to work on. So that's too early to make that statement. But we are excited about this indication and all the work that the Maurer group and others have done so far. Whether we take it to a more broader mast cell, I think we would definitely not make these conclusions before we don't have the data to speak about it.

Great. So we have a few here from -- that have been submitted in writing. So I'll go to the first by Joe Schwartz at Leerink Partners. So the first part is asking us about the goals of the Phase IIa study in terms of what kind of early efficacy end points will be including? How informative we think the endpoints will be at 4 weeks, and anything we'll be looking for as we consider a go/no-go in either of the indications?

Yes, I'm happy to tackle that. So that's very straightforward. On the efficacy side, this is exploratory, but Camilla already mentioned, in CSU, there is the 7-day score established that is the primary endpoint in trials and very broadly used and accepted and that gives you a very good look and should give you a read whether the patients respond to the drug in 4 weeks or not. So that is something you can definitely scout at 4 weeks, and that endpoint is clear. So the [indiscernible] 7 is something that is broadly used. Then in the hidradenitis suppurativa population, we will look at reductions of all 3 lesions and compare that to the 4-week reductions either reported from other drugs or seen with our own drug to scout. And we just shown you some of the data that were public from the avacopan trial. And we've shown you that there's a very late onset of efficacy. For example, if you know that the draining tunnels did not even move before week 12. And we will definitely see and compare that and hope that we see already these signals moving at week 4 quite a bit. And of course, we will -- with these 3 lesion counts established, we can then, of course, derive all the typical endpoints that you look at, obviously, with a lower number and the PK focused study, things like HiSCR are not extremely informative. For us, the key is at that stage of the development to show you how much the 3 lesions moved at week 4. I hope that helps for -- and again, we will probably provide them more color in our R&D event following...

Great. And we have a follow-up there in terms of the preclinical tox work. Can you remind us where we are in the progress. And if this will be a gating factor for the Phase II? Or will the timing line up where you can start -- go seamlessly into the Phase IIb next year?

Yes. Maybe I can take that. So yes, for tox, we already start with the chronic tox, as we mentioned earlier that we have plan to do 6 months rats and the 9-month monkey those already start early this month. So yes, we are planning simply with all the clinical development, including Phase IIa, Phase IIb data expected for 6 months rat will be end of this year and early next year for 9 months monkey. So to answer your question, we are [ plan this ] together with all the -- our clinical development.

And so we have a couple of questions from Evan today, with Guggenheim. Again on the preclinical. What kind of preclinical work have we been done with 904 and CSU? Can 904 decrease the number of mast cells. And given its unique MLA, how are you thinking about positioning in CSU?

Yes. Maybe for the second one, we don't know, if 904 going to decrease the number of mast cells, in theory we'd issued it. And there's no reason to believe that -- to believe the mast cells based on model actions. For the first one, in the literature, there's a ton of study that's already been worked out for the role of C5aR in CSU with the CSU patient samples especially with the [ serum ] of plasma samples with blockade or C5aR and with antibody or peptide, as you can all show like pretty good blockage to the [indiscernible] we needs for either master cell or from basophils. So we are currently working with a pretty well-known laboratory for CSU [indiscernible] to workout on more details with an [ IL-4 ]. So yes, I think the second question, Niels and Camilla already addressed the [indiscernible] we're not thinking that it's going to be just to treat a few days, but -- basically, we are able to -- should be able to treat both type of CSU.

Got it. And then a follow-up. What would you expect the C5aR coverage required for clinical benefited CSU and HS would they be different in 1 risk of the other and in the other indications?

Yes. For CSU and HS, they both are skin disease and we generally believe that you do need a higher dose because you need a good coverage on the skin for the drug. So yes, so maybe -- but I don't -- there's no reason to believe that there's going to be a different dose to disease at this point, but we have to remain to see the data because in our [indiscernible], we do plan to have pretty broad dose coverage, [indiscernible] and to able to work out a dose. Regarding to the other disease, I think it's too early to say for that. So that -- it's the area for [ uncover ] probably you don't need a lot of coverage because of the focus on the [indiscernible]. And that's a pretty general answer for this one.

Great. And then we've had a couple of questions regarding the partnering strategy that we mentioned. So I'm wondering if you can provide us some high-level thinking of strategy on how we would approach or could approach partnering?

Tom, do you want to take that?

Yes, happy to do that. Well, I mean, obviously, our focus in immuno-dermatology will lead us to put our efforts in this area, but we see the broader potential, both of INF904 and Vilobelimab in other indications. So we have initiated discussions with a variety of pharmaceutical companies that might have an interest in also helping us develop it in other indications. It's at this point, maybe too early to really say what it would look like and how these relationships could ultimately shape up being. But I think that to exploit the full potential of both drugs, it would be very advantageous to have somebody who would have an interest to focus on some of the areas that for resource reasons we have to leave on the side for the time being.

Yes. So it's really like our wish to find path ways to faster unlock more value for the drug, right? We -- as Tom just said, we are really convinced that there's a broad applicability to this pathway. So our idea is like what can we do to speed up and unlock as much value as possible.

Great. So we've kind of covered this already, but I'll just bring it up as it was put in through the written dashboard. Again, from Joe at Leerink Partners, saying the prior oral C5aR inhibitor, show better efficacy in HS patients who were more severe or early Stage 3, will you be targeting any particular kinds of HS patients in the studies? And can you give us your thoughts on how trial endpoints and studies may have evolved since your initial BLO studies? And what learnings can you apply to the development of 904 with that? So I covered a fair bit of that, maybe just kind of covering again.

Yes, I think it's I think from the general understanding of the disease, we all have learned that there are 3 lesions, and they need to be reduced if patients want to just like experience an improvement. We know that the most difficult to treat are the draining tunnels. They are not captured by the currently used score, the HiSCR. This score is established. It's been used now many times. It's been used in Phase III studies. People have used the old HiSCR 50. Now there's even high school, HiSCR 75 being explored, but we've also learned that HiSCR is not used by physicians. I don't know any physician that would say I'm assessing my patients with a HiSCR. It's a score that's only applied in clinical studies, and we've also learned that oftentimes when you think about the IL-17 studies in Phase III, they came in a bit underwhelming. So the score may not necessarily reflect a good path to differentiate from existing mechanisms, right? I think IL-17s are thought to be probably better drugs than anti-TNF in this disease, but yet on the HiSCR, this could not be shown. So in other words, the field has the understanding about the limitations have involved, but it's been used. And so it's the path to win the game. But I think as far as we know from our discussion, there's still a pretty high unmet need in patients with active draining tunnels. There's a belief that draining disease is still not adequately addressed, even though there is a signal in IL-17 inhibitors that may not be strong enough to cover a lot of the patients. And so there are areas of unmet needs that relate to active training disease, which is 1 area that we're definitely interested in looking in whether we can bring more benefit to these patients. But at the same time, as I've shown you with [indiscernible], there's no reason to believe why the drug shouldn't work in the overall patient population. Second thing is also on maybe the -- if you asked for the other endpoints. I think the established endpoint is the HiSCR. I mentioned that already. And then there's the lesions itself and then there's lesion-derived scores that don't vary as much. Most of them emphasize the draining tunnels as the most severe. So I would say there's another need I want to flag, which is I mentioned in the talk that a lot of the patients on these active drugs that are approved may have an efficacy loss over time where the efficacy wanes. And I think 1 need is also to demonstrate at least in the Phase III study that can certainly not be demonstrated early that a long-term exposure leads to a significant improvement, long-term improvement in more patients. That is a big need. So if the average patient doesn't think that, over the 50% my efficacy wanes in the next 6 or 9 months, but I have a good chance. If I'm a responder to stay a responder, that would be a big win. So I would say we understand the need that has evolved. There is need for new mechanisms, especially sustained improvement and our work on the active training disease. It's too early for us to tell you exactly which 1 we will focus finally. But I would say, generally speaking, it is our belief that the drug works in all disease stages and that's our starting point. Okay.

Great. And so we have 1 more before we wrap up. It's again a written question asking us in terms of efficacy and safety, how does 904 compared to avacopan? And are there any significant advantages or improvements for 904 as a better choice for patients and for treating physicians? So I think I just need to summarize that we've discussed on that.

Yes, I want to handle this very briefly and Renfeng, please chime in if I forget anything. So I will start with the safety first. We -- the 1 thing that is known about avacopan I think in all standards, it's been a very, very safe drug. I don't -- that there was 1 liver tox in the ANCA approval that was heavily discussed, and that may have to do with the drug being like many oral chemical inhibitors, a CYP3A4 liver enzyme blocker, meaning it can lead to plasma accumulation of other drugs like corticosteroids or other drugs. And that can lead to other drugs getting higher and causing liver tox. Now we have in preclinical trials that have shown that we have an over 30-fold less inhibitory potential to CYP3A4. So we have really very low minimal engagement with CYP3A4, which is, of course, comforting as we move forward. But again, flagging that, generally speaking, avacopan was a relatively safe drug as far as we know from the filings. So I hope that covers the safety question. Now the other question is the efficacy question. Yes, we actually do believe that we can show a different efficacy, and that is based on the fact that I showed you how long the drug takes, avacopan takes to accumulate and what they are finally reaching, which was a bit over around 3,300 the area under the curve. And we can reach that with a higher dose on the first day of exposure and on the equivalent dose certainly within the first 14 days. So we have a very different bandwidth of reaching such an exposure level that they have at their maximum accumulation, and we can exceed this by multiples. At least that's what our Phase I data indicates. Now of course, we have to still prove that, that translates into a better efficacy in humans, and there may be diseases where you can show that well and diseases where you cannot show it so well. We believe HS is a disease where you may be able to show that, especially with a more early onset and a more sustained reduction of these lesions. I hope that covers that.

Great. So we are finished with the Q&A session. For anyone in the audience, if we didn't get your question or didn't address it suitably. Please feel free to reach out to [email protected], and we can address it at that point. So right now, I'll turn the call back over to Niels for closing remarks. Niels?

Yes, I'll make it short. Thanks so much for joining. We are very excited to have you and to share more with you to come in an R&D Day that we're planning, and happy to take calls and happy to take a question through the IR route as usual in due course. So thank you, everyone. Have a great day. Bye.