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

Good afternoon, everyone. Thank you for standing by, and thank you for joining InflaRx R&D event focused on our orally available C5aR inhibitor, INF904. The structure of today's webcast is made up of a few main segments. First, we'll have Niels Riedemann, CEO and Founder of InflaRx provide an introduction to today's speakers and also a quick intro to INF904 and our strategy. Second, we'll have each of our 3 featured thought leaders present their viewpoints in their respective areas of expertise. This will be followed by our first question-and-answer section allowing our KOLs to address questions from the audience who may ask written or audio questions. And following our KOLs, we'll have Camilla Chong, our Chief Medical Officer, to discuss our near-term clinical development plans for INF904, and she will be followed by our CFO, Thomas Taapken, who will provide a commercial and financial perspective. And following that, we'll have our second question-and-answer session [indiscernible] really directed at the company at InflaRx, though we will provide for some spillover to KOL questions if there is enough time. We'll also have Renfeng Guo, InflaRx's CSO and Founder, available during Q&A, too. [Operator Instructions] Note that today's event is being recorded. So with that said, I would like to now turn the call over to Dr. Niels Riedemann. Niels, please go ahead.

Yes. Thank you so much, Jan. On behalf of the entire InflaRx team, welcome, everyone, to today's InflaRx R&D event. We are very happy to have you all on the call. I'll be making forward-looking statements today as a public company. Please take note of our important notices and disclaimers in the first 2 slides. And with that, please forward to the next slide. This is just the outline that was just explained on today's presentation. I'll be having the honors to start the whole thing. Next slide, please. And it's really our true honor and pleasure to have such esteemed experts and key opinion leaders in the field with us today. I'll be introducing all 3 of them today and then our team. So with that, we feel very lucky as a company to be supported by such strong scientific thought leaders. First and foremost, we have Prof. Dr. Jörg Köhl with us. Dr. Köhl is the Director and founding member of the Institute for Systemic Inflammation Research at the University of Lubeck. He's been many years Professor of Pediatrics at Cincinnati, Ohio. He's probably one of the most published authors in the world on the [indiscernible] receptor C5aR specifically and C5A and there couldn't be a better person talking about biology of C5a/C5aR inhibition. Professor Köhl has also been past President and very active in the complement space. And I think he's also scientifically chairing this year's Complement in Human Disease International Congress in Lubeck. Then, next, Professor Marcus Maurer. Professor Maurer is Managing Director, the Institute for Allergy Research at Charite University in Berlin. He spent many years also in research work. I believe in Harvard, the East Coast. Professor Maurer is particularly known for his research in the allergy and urticaria space. He's been instrumental in various drug developments. He is actively supporting our various companies and various approaches to foster the field innovation, and we feel very lucky also that we have such strong support for this particular disease interest. Last but not least, Professor Sayed. Dr. Sayed is Professor of Dermatology at UNC School of Medicine at Chapel Hill, North Carolina. He's the Active Secretary of the USHS Foundation and past Vice President. Dr. Sayed is instrumental in various drug development efforts in the field of hidradenitis suppurativa. He's been also participating in trials involving C5a and C5aR inhibitors, so ideally positioned to talk about the role of C5a and C5aR for this disease, and he's been working with our team for quite a while, and we feel very, very happy and lucky to be supported in this very exciting but also a very devastating disease. So our team, I have with me on the call, Dr. Camilla Chong, our Chief Medical Officer; my business partner, Co-Founder and CSO, Professor Renfeng Guo; our CFO, Dr. Thomas Taapken; and our VP, Investor Relations, Jan Medina, whom you've already had the pleasure of listening to. So with that, next slide, please. So very briefly, we, as a company, have a very recently focused and given the key focus of our development in the immunodermatology space. I do want to mention that our lead indication and our lead drug, vilobelimab is a monoclonal anti C5a antibody that is in Phase III development for pyoderma gangrenosum and other neutrophilic skin disease. This will not be today's key interest or topic. We may have a separate R&D event coming up that focuses on that particularly. But today's focus is really INF904, our new oral C5aR inhibitor, and we'll be talking about that and chronic spontaneous urticaria or CSU and hidradenitis suppurativa HS. But there are significant other opportunities. Some of them will be touched on today during the call for this drug as well. And last but not least, I do want to mention as it ties into the importance, the inflammatory importance of the C5a/C5aR pathway by the fact that our lead drug, Vilobelimab, known under the commercial name Gohibic has recently gotten an emergency U.S. authorization by the U.S. FDA for certain critically ill COVID-19 patients for a life-saving benefit. Now that should just be a testament to the importance of this pathway that we'll be discussing today. Next slide, please. So why immuno-dermatology, first of all, we believe there's a strong rationale of the C5a/C5aR involvement in various immunodermatological diseases. These are attractive potential multibillion-dollar commercial market opportunities. And this is a new mechanism of action, which is currently not addressed by any other drug development in that space. For CSU and HS, there are established endpoints, and there are still unmet needs and the potential to achieve clinical edge and prove to be a differentiated competitor and 904 is so far not burdened on the mechanism of action to have a known safety concern. So that's a great thing. We believe that the drug may have a broad potential therapeutic index based on our initial Phase I clinical data. And last but not least, we have a network of experts. Some of them will be speaking today that we feel privileged to be working with in this field. Next slide. So this would be my last slide here, and I just want to briefly reintroduce and speak about INF904, which is in the center of today's discussions. It's a highly selective C5aR1 inhibitor with best-in-class potential. Now why do we say best-in-class potential? Why do we believe that? Actually, this is based on 3 principal pillars. One, we do believe that we have a superior PK/PD profile as shown in the single ascending dose and multiple ascending dose clinical Phase I studies compared to the marketed comparator avacopan. We do have a favorable drug safety profile, and that is further supported by features of the drug, which include the fact that we have a significantly lower engagement with the liver detoxifying enzyme apparatus, CYP3A4 and 5. And so all this together gives us a reason to believe that this mechanism was best-in-class potential. I'm going to very briefly draw your attention to the right. We have a very differentiated PK profile. This is a single ascending dose depicting avacopan. This was not a head-to-head study. This is just a superimposed reported data from avacopan studies, and you see the blue line as it relates to the red dotted line. The blue line is the equivalent dose 30 mg one shot of INF904, you see that the Cmax is very different. You see that there's a tenfold increase area under the curve, different time to peak just a very different dynamic. And that just gives you a visual on how differentiated the PK setting is. Now that is important because we believe our data showcase that we reach therapeutic potential very early with our drug. And on the other hand, what's the meaning of that? Well, on the lower right side, you see that, at that dose, in multiple ascending dose, at levels that we find and measure in humans, here roughly 12 nanomolar added C5a that we have a pretty much complete silencing of the C5a receptor engagement here on neutrophils in the blood. So they don't get excited. The green line, dotted line is the control curve and all the other lines that you see close to being at 0 are the other lines that we tested here. So that gives us hope. And ultimately, I want to focus you on the key message here is that these properties should allow us for exploring a significantly more potent C5aR inhibition in patients, and this ultimately may lead to a higher clinical efficacy, and that's the core essence why we developed this drug. Now this could open significant additional market opportunities, and some of them we'll be discussing today. That brings me to our first expert that speaks about the C5a/C5aR biology. Next slide, please. So I would love to hand over here at this point in time now to Professor Jörg Köhl who will be speaking about our current understanding of the C5a and C5aR1 biology, and also how this ties into immuno-dermatology. Dr. Köhl, the floor is all yours.

Okay. Thank you, Niels, thank you very much. I'm really delighted and it's my pleasure to give you my view on the role of C5a receptor in inflammatory skin disease and targeting this receptor in such diseases. Next slide, please. So let me get started with a brief intro into the complement system, one of the main functions of the system, and this is really to sense danger both exogenous danger and endogenous danger by multiple molecules such as MBL and C1q, which then start and activate the cascade, start proteolytic events that then activates C3 and drive the cleavage into different molecules shown on the right-hand side here. And these cleavage fragments they activate the complement receptors on a variety of different cells, but this does, it really transmits the signal from the fluid phase into a cellular response. And then the cascade moves on to cleave C5 into C5b, which nucleates the MAC and then C5 and C5a, which then interacts with 2 distinct receptors shown here on the right-hand side. This is C5a receptor one and C5a receptor 2. We have 2 ligands, the one is C5a and the other is C5a [indiscernible] which is converted from C5a by carboxypeptidase and [indiscernible]. And then activation of C5a receptor is either by G proteins or beta arrestins, whereas the second C5a receptor C502 or C5AR2 can only be activated by beta arrestin -- activates beta arrestin pathway. So what about the expression of these receptors on cells? Next, please. This is shown here. And the main expression pattern is on really myeloid cells. There is a strong expression in particular in eosinophils, basophils and neutrophils and a moderate one in dendritic cells and mast cells. And there's also a moderate expression on nonprofessional immune cells, for example, endothelial cells for epithelial cells or keratinocytes in the skin. Whereas when it comes to lympho itself, the expression is rather low. Next slide, please. To activate the C5a receptor, C5 needs to be cleaved into C5a. Where is that C5 coming from? So mainly, this is textbook knowledge from the liver. But I want to draw your attention here that also lungs, kidney, intestine and the skin are also strong producers of C5. So the complement that is coming from the liver is really important as a guardian of the [indiscernible] space. What it does is, it is recognizing and removing pathogens and [indiscernible] in the blood and the lymph. Next, However, when we look into tissues, the immune cell auto [indiscernible] complement is probably more important. It's probably shown here is the production of C5 and C3 in antigen-presenting cells and T cells. And that applies to most cells in the body that can produce almost all complement factors shown here is C5 and C3 that can be cleaved either by the C3 or C5 convertase or directly by proteases generating then the cleavage fragment that interact with the cognate receptor shown C3a receptor and a C5a receptor, and that promotes the local immune cell activation and also function. And last but not least, next. We have learned during the past few years that there's also an intracellular complement that is -- that complement within cells can be cleaved also directly by convertases or proteases such as [indiscernible] here on the left, and then there is induction of cleavage fragments that interact with receptors in cells, for example, on the lysosome or in mitochondria shown here for C5a receptor and this is important to control basic cell physiological processes of cells such as survival or differentiation. Next slide, please. So this shows you the multifunctional role of C5a in the distinct myeloid cells, and I want to draw your attention mainly here on the right-hand side, where I've shown you that C5a receptor is a strong activator of neutrophils in particular, driving gross release, which then induces the formation of so called neutrophil extracellular traps or NETs. And these are of major importance as critical drivers of inflammation in neutrophilic skin diseases that have already been mentioned by Niels before HS and [indiscernible] and I will come back to this later. Next slide, please. What I've shown you so far is that C5a receptor is activated by C5a as a single stand-alone receptor, but that's not the reality that we have to face in the tissues. There, it is heavily cross talking with other receptors, in particular, like [indiscernible] receptors, and this is of major importance in autoimmunity or with pattern recognition receptors, such as [indiscernible] receptors, and that is very important in infection. And most of the cross dock is really driving synergistic effects on inflammation. Next slide, I want to give you an example here in monocytes, where C5a receptor activation drives the production of IL-6 and that IL-6 then activates the IL-6 receptor, upregulating C5a receptor, and this amplifies the IL-6 production. Does it apply only to IL-6? No. Next, please. It also applies to other pro-inflammatory cytokines such as TNF alpha, or interferon gamma or arachidonic acid metabolites, such as PGE2 or [indiscernible] recognition molecules like LPS that all can upregulate C5a receptor massively. And this leads me -- next slide to another important function of C5a receptor, and this is the Regulation of the adaptive immune response exemplified here by the induction of the T17 development data from a study that we did a couple of years ago together with Shimon Sakaguchi's Group, where we have shown that C5a receptor on macrophages together [indiscernible] receptor activation drives IL-6 together with TGF-beta, induces the commitment of self-reactive T cells into TH-17. Also, production of GM-CSF attracts the neutrophils and the IL-17 is pretty important because it's well known and appreciated that TH-17 responses are frequently found in neutrophilic skin diseases, such as HS and PG. Next one, so it doesn't come as a surprise then, I think, to you, next and the next 4 or 5, that C5a receptor is really involved in a variety of different diseases shown here, like infectious diseases, cardiovascular, neoplastic, allergic, next, kidney, next, neurogenerative and autoimmune diseases. I want to focus and give you 2 short examples on allergic diseases and autoimmune diseases of the different roles of C5a receptor. Next, please. Before I do this, next, I want to remind you that the activation of C5 cannot only happen through C5 convertases through the different pathways as I've briefly mentioned. But next, also, through enzymatic cleavage at T-cell bonds, for example, by thrombin, trypsin or cell-derived elastase. Next. So when you target C5, that not necessarily prevents enzymatic C5a formation when you do this by antibodies, but only complement pathway-mediated cleavage. So this is not really suitable for tightly controlling the C5, C5a receptor interaction. This is the better way I consider is really targeting the C5a receptor 1 directly. Next. So this brings me to the example of allergic diseases. Next, where I want to show you different properties of C5a receptor as a disease driver in anaphylaxis. So what I've shown you here is a model that we have used where we immunized -- [indiscernible] IP, and then we came back by oral [indiscernible] which induces then gut permeability increase leading to diarrhea. And what you see here on the right-hand side is that after a couple of [indiscernible] you see that almost all mice, the wild-type mice developed diarrhea, whereas the C5a receptor mice arm is completely protected. Next slide. So mechanistically, what's going on. This slide summarizes the different mechanism of how C5a receptor really contributes to disease. So the first one, next, is that it really regulates the B-cell response, leading to the production of antigen-specific IgE. This IgE, the next cross links the Fc epsilon receptor. And what this does? It drives the upregulation of C5a receptor 1 mRNA and the receptors also, it induces C5 and C5a in those mast cells so that we have now 2 mechanism of activation of these mast cells to produce and release histamine. And finally, next, the sensitization of the vascular system towards histamine is also controlled and regulated by C5a receptor. Next, please. So these data are probably of major importance also for another disease where mast cells and basophils play a very important role such as chronic spontaneous urticaria, or CSU, and this will be addressed later by Professor Maurer. Next, please. Finally, I would like to give you an example where C5a receptor also has different roles and functions, important function in autoimmune disease. Next, in particular, neutrophilic skin diseases. So the first is hidradenitis suppurativa, where there is now evidence that there is strong and increased systemic C5a activation or C5 activation and C5a generation. There is also evidence for increased local C5a receptor expression and that there is a change in skin microboiota to [indiscernible] that express C5-cleaving enzymes. This will be later addressed by Professor Sayed. Next. I just want to share with you some thoughts about the hypothesis of bacterial-induced C5a receptor 1, TLR cross-dock that could drive the skin inflammation. And for this, I'll have to briefly turn to another disease, and this is gingivitis. There, it has been shown that the bacterium Porphyromonas in the oral cavity can cleave C5 into C5a and also activates TLR1 and 2. And this -- by this mechanism, the Porphyromonas subverts complement TLR-driven antimicrobial response. What this does is, it leads to a dysbiotic microbial community, which activates complement and [indiscernible] inflammatory cytokines such as IL-6 and 23, that derive TH17 expansion and neutrophil recruitment, and this feedforward loop really contributes to chronicity in this particular disease. Next. So what has it to do with HS? There are data out that show that microbiome studies where Porphyromonas has been identified in HS and is strongly associated with disease activity. Further, there is maladaptive TH17 immunity as a critical driver of HS. And finally, I've shown you data that C5a receptor controls TH17 development in experimental arthritis. It also applies, for example, to psoriasis. So it's tempting to speculate that the mechanism that have already been shown here for gingivitis may also apply here to HS in a similar way. Next, A second disease, as Niels already pointed out, which is not in the focus today, but I briefly want to mention it is pyoderma gangrenosum, where also high levels of local C5a have been shown in wound fluid, where C5a really drives strong NET formation and elastase production, which is critical for the disease and where also local C5a receptor expression has been demonstrated. Next. And finally, I want to share with you some data from pemphigoid disease, where I will show you that the lesion of the C5a receptor protects from the development of skin lesions in a preclinical model of BP. Next. So what is BP? This is a group of autoimmune skin blistering diseases where autoantibodies are formed against structural proteins at the dermal, epidomal junction located here between the epidermis and the dermis. And I want to focus today on a disease called Epidermolysis Bullosa Acquisita, in short EBA, where the autoantigen is type 7 collagen. So what has been already shown is local cells in the skin produce C5 and the auto antibodies activate complement to really generate C5a, which then attracts neutrophils, eosinophils and activate mast cell to produce [indiscernible] which is then a critical driver of the skin blistering. Next, please. So we have used a model here where we immunized mice with collagen Type 7 in [indiscernible] So this mice develop an auto-antibodies, which then bind to their target activate complement, and next, drive then -- the skin blisters. So this affects almost 10% of the body. And what you -- and I think, easily appreciate is that the C5a receptor-deficient mice almost completely protected from the development of the skin lesions. So what are the mechanisms? Next. So what we were able to show over time is that the massive neutrophil influx that you can see here in the wild-type mice is markedly reduced in the knockouts. Next. And that shows you -- that C5a receptor controls neutrophil migration into the skin. Next, in addition to this, what we found was that there is also a reduced switch from autoantibody IgMs to IgG in the knockout mice. Next. And that is really nicely in line with the critical role for C5a in the Germinal Center B cell formation that has been shown recently and points towards a more general role for C5a in auto antibody formation. And I think this also regulate auto antibody formation [indiscernible] where I've shown you, autoantibodies play an important role, and you will hear about this later. Next, and finally, I will draw your attention to this graph where it shows that the IgG autoantibody-driven ROS release from neutrophils is also controlled by the C5a receptor. So next, what I've shown you is that the C5a receptor drives the disease development in the experimental EBA at several levels. So first, hits the recruitment of neutrophils in the skin. Second, it's the early generation of the Type 7 collagen specific IgG autoantibodies. And third, it's the inflammatory potential of these collagen specific autoantibodies. Next. So with this, I would like to sum up. And come back to the initial question, why targeting C5a receptor in the immuno-dermatological space. First, next, there is now clear evidence for local C5a and C5a receptor expression in skin diseases. Next, C5a receptor activates and controls, key effector cells as I've shown you, neutrophils, eosinophils, basophils and mast cells, the B cell response and the TH17 development. Third, targeting C5a receptor in preclinical skin disease models, as I've shown you for BP, strongly reduces the disease development and last but not least, next, there is a clear tailor targeting effect plus blocking of C5a receptor leaves the upstream and the downstream complement as was intact. So with that, I would like to thank you for your attention, next, and I'm looking forward later to the answers -- to the questions that you may have. Thank you.

Great. Thank you, Dr. Köhl. Very, very informative. I know we could probably spend a lot more time on this today, but do appreciate you putting everything together in a very efficient way. Just a quick reminder for the audience that we will be holding the first Q&A session after each of our 3 thought leaders have presented. So with that, we will now start with Dr. Marcus Maurer to discuss his thoughts on 904 and CSU.

Thanks, Jan. I'm very happy to be here. All eyes on urticaria now. You have heard a lot about the rationale and the role of what we're talking about today in urticaria. Urticaria is a mast cell-driven disease. Next slide, let me review some of the key features. And then come to the role of C5 and C5a receptor as a driver of the disease and as a target of treatment compared to other treatments that are currently under development. Next slide. So why do you have to know about chronic spontaneous urticaria. It's a really stupid disease to have. Devastating. This is because patients develop daily or almost daily these wheels that you see here. and patients get hundreds or thousands of wheels a day, and this is true in virtually all patients with chronic spontaneous urticaria, where there's no specific trigger. It just happens whenever and wherever these wheels decide to come. And then up to 2/3 of patients in addition to the wheels have angioedema, swollen lips, swollen hands, eyes which also drive quality of life impairment. Across the different skin and allergic diseases, this disease, chronic spontaneous urticaria, often always ranks the most -- the most disturbing diseases to have that comes with high morbidity and also mortality that are largely driven by suicide. So a lot of impact on all aspects of life, sleep, concentration, mental health. These people are really devastated. Give me one more minute, then we can go to the next. High epidemiology, but we're probably underestimating the prevalence. We have at least 1%, but the truth is probably more between 2% and 3%. It's a long-lasting disease, chronic spontaneous urticaria, and it's mostly females affected, 20 to 40-year olds most. Now, what do we have to offer to these patients? Not much. The guideline really only has 3 treatment options and only 2 of them are in label. Second generation, nonsedating anti-histamines as the first line treatment and they don't work in most patients, not even half of the patients get to the treatment goal, no more wheels, no more itch, no more angioedema with an antihistamine even at higher than standard dose. And then we have omalizumab which works in some patients, but by far, not all. Now let's look -- next slide, please, at complement C5. But we've got to start with a mast cell. This is a mast cell-driven disease and unlike allergies, mast cell here are driven by 2 distinct mechanisms. The first one called type 1 autoimmunity or auto allergy is similar to allergies. It rides on IgE that binds to the IgE receptor on skin mast cells. And when it encounters its antigen, then this causes degranulation. But here, the antigen is an autoantigen. So it's not stuff we breathe or each or put on our skin. It's endogenous, auto allergens that drive cross-linking of the IgU receptor. This is a bit more than half of patients with chronic spontaneous urticaria affected due to auto allergy. The more severe endotype is type 2b autoimmunity, where IgG antibodies in some patients, also IgM and others, bind 2 mast cell directly, and their targets are the high-affinity IgE receptor. You can see that on the bottom left of that mast cell there or the IgE bound to that receptor, and this leads to cross-linking of the receptor and activation of mast cells. Now a major pathway of mast cell activation in this context is the activation of the complement system with C5a resulting binding to the C5a receptor on the skin mast cells. And you heard from Jörg that mast cell express C5a receptor, actually the skin mast cells more so than other mast cells in the body, which may explain why chronic spontaneous urticaria is predominantly a skin disease rather than a disease that comes with systemic mast cell activation. And then there is a second pathway. And this has something to do with the coagulation system coming from tissue factor, which is activated in all patients with chronic spontaneous urticaria, where factors of the coagulation system, Factor IIa, Factor Xa, activate C5 to generate C5a that binds through the C5a receptor. So there's at least 2 major pathways by which C5a is generated and contributes to mast cell activation, which is of high relevance in chronic spontaneous urticaria. Next, let's look at some of the evidence that makes it so promising to target C5. How is C5a involved in the pathogenesis? How is C5a receptor involved? Well, what you can see here is work by [indiscernible] from our team here. She stained the skin of CSU patients for C5a receptor. And she stained healthy controls. And you can see a clear difference where the number of C5a receptor positive cells in the skin of CSU patients is up to tenfold higher than in healthy controls. And most of these cells are mast cells, the key drivers of wheel and angioedema formation. So mast cells in the skin of CSU patients are increased and show high expression of C5a receptor. Next slide, 3. Lines of evidence that point to the levels, the function of C5a in chronic spontaneous urticaria. I picked one slide here on the left as an example for several studies that have shown that C5a levels are up in patients with chronic spontaneous urticaria. That's on the left. When you look into the skin of CSU patients, you see that complement system is activated and possibly most importantly, C5a is a anaphylatoxin. It doesn't carry that name for nothing. It produces anaphylactic degranulation of mast cells, and it does that very potently. Jörg shared with you the insights we have on the role of C5a receptor in anaphylaxis. Now you can see here that there is a dose-dependent response of basophils and the same would be true for mast cells with C5a, which in low doses already causes high levels of muscle activation and subsequent histamine release. So it's there, it's up. It's in the skin where stuff happens in CSU and it is a very potent muscle activator. Let's look at how we can make use of that, next slide, to target this driver of degranulation of mast cells. What you can see here is 2 donors of basophils, which were activated with C5a and where this activation is stopped with INF904, the C5a receptor antagonist we're talking about. So, yes, it is possible to stop the activation of basophils, of mast cells via this receptor, bring it down to virtually 0, so that mast cells no longer degranulate, no longer release histamine. So that's cool, but there's more. Next. You can see that -- and this is a review of what Jörg already shared. Mast cells are among the cells that produce C5, and they also have a very potent portfolio of proteases that act on C5a to generate C5a receptor that then binds to the mast cells. So it's an autocrine mechanism and this mast cell activation by C5a results in further upregulation of this pathway. Basophils are also there. They get called by mast cells to the skin when they degranulate, and they contribute to the inflammation in chronic spontaneous urticaria. But the major target is C5a receptor on skin mast cells and C5a receptor as a potent granulator. But it is also in part, an activator of chemotaxis, proliferation. So you could argue that C5a receptor is probably, possibly one of the drivers of mast cell -- increased mast cell numbers that we see in chronic spontaneous urticaria. Okay. Let me conclude and bring this to clinical relevance. Next slide. We have treatments, but they don't work well. We talked about omalizumab. We have other treatments that are now close to finishing or have finished Phase III, dupilumab and remibrutinib. Both come with shortcomings, and I'm sure most of you are aware of the Phase III data with dupilumab in CSU. Remibrutinib has some safety baggage and can, for example, not be given during pregnancy. So it also is not a home run in chronic spontaneous urticaria. And Barzolvolimab is still in Phase II or Phase II completed, on its way to Phase III, with a number of side effects that weigh in. My main point here is, though, that we have very few drugs, high unmet needs, a lot of patients and a lot of patients who have given up on us as urticariologists who are untreated, undertreated, only 1 in 10 patients today gets a second line treatment, gets omalizumab and more treatments coming to the market, coming to patients will certainly increase the rate of patients receiving effective treatment. Next slide, please. The opportunities are right here. It's an oral drug, which is novel and cool. It works in the 2 recognized endotypes of chronic spontaneous urticaria in IgE-mediated and Type IIb autoimmune IgG-mediated pathways. And it will work, therefore, in anti-IgE, omalizumab naive and refractory patients. Patients with type 2b autoimmune since you do not respond to oma, and we can go into that. But C5a receptor blockage will help these patients. The onset can be expected to be fast and sustained action. We don't have a black box warning like for omalizumab and some of the other side effects that are seen, for example, with Barnzolvolimab are not expected here. Now my last slide, next, talks a little bit about the study plan where we have good data now from studies completed on what placebo does in chronic spontaneous urticaria on the left and what the different treatments have done. So on the very right then is our target. We need to hit -- change from baseline in urticaria activity score 7, that's the gold standard of measuring disease activity in CSU, of around 10. The more, the better, but I think it is fair to say that from looking at the change from baseline, we know whether or not we have a drug, we know that we will have a drug. Next slide. Thank you for your attention. Just a quick summary here. Again, C5a receptor is an important driver of histamine release and mast cell degradation by C5a receptor expressed on mast cells and basophils activated by C5a. It's independent of the IgE pathway and therefore, could complement the only other second-line treatment option we have today. It's a novel mechanism of action that will address a big unmet medical need in chronic spontaneous urticaria in all comers, but specifically and maybe most importantly, in those patients where we currently do not have treatment, the autoimmune chronic spontaneous urticaria patients. And that makes oral inhibitor of C5a receptor ideally positioned for the development in chronic spontaneous urticaria. That's my team.

Great. Thanks, Dr. Maurer. It's very good. Definitely a lot to go through. We've got one more section. We do have questions coming in already. So that's good, but we'll hold those until we finish with our next session. I think we've got Dr. Chris Sayed, who was able to make it in. And if we can get this video up and running, we should be good.

I hope I am up and running. Can you hear me?

Yes, you're good. Thank you.

All right. Perfect. I think hopefully, I'll pop in the window in just a second here. Here goes. All right. I believe I should be there now, but let's -- actually, it's saying the host stopped my video.

Dr. Sayed, you are good. You are live. We'll advance the slides for you, and see it -- we'll do that in your direction.

Perfect. Excellent. So yes, thanks so much for having me. I'm Chris Sayed. I see a lot of patients with hidradenitis suppurativa like 40 or 50 every week and can never keep up with the demand. So it is something that is near and dear to me and I'm desperate to help my patients more because they suffer so terribly. And I'm really excited to get to come and talk about C5a for HS. And this -- I always look back, I was part of the studies for a Phase II study for Vilobelimab. And I look back at is -- just this huge missed opportunity. Like makes my experience in those trials with many of the patients were very, very positive. And even now, I have patients that come back and ask me about this drug. And I think reasons we'll talk about with the Vilobelimab study, I think the effectiveness of it was kind [indiscernible] low based on looking at primary endpoint, things like placebo response, we'll talk about more later, but I look back at, is this something that I should have in my hands by now, right? It's something that I wish I had to offer to patients already, even sort of based on the data that was there before, my experience with it. And so the only silver lining I see is that I get to come back and talk about now perhaps a drug that will do even better with 904 and it really -- I want to make that case that again, there was something to this drug. As much as that primary endpoint wasn't met, and I think -- that's the main headline that people often talked about. I think there's a lot more to it than just that. And that's what I want to really drive home with this. Next slide, please. So I think most of this audience is probably familiar with HS. If you're here attending this call, we all can do a very quick overview, it is a miserable disease. Unlike most other things on the skin like eczema and psoriasis, which we can put some minor drug and 6 weeks later, they'd be totally clear and look great again. This is a disease that is disfiguring, at least scarring behind. Even if you calm the inflammation down, there's a lot of damage that's been done. So it is hugely important that we treat this disease better and more aggressively and have better drugs to sort of save all that damage that has caused in the long run for patients. And despite the fact that it's actually a very common disease, like probably 1 in every 100 to 200 people, because it is so hidden and there's somewhat stigma, patients just don't talk about it very much. It's got very little sort of public footprint where people kind of didn't know what HS is. But I tell everybody all the time, you have met somebody with HS, you just don't know what it is. It is something that is hidden and out of sight, that people are hesitant to talk about because it's a lot to try to explain. And as many -- I see a lot of HS patients. I do feel like we have better tools than we used to when it comes to taking care of HS patients, but I still -- every day see patients where I've been on 3, 4, 5, 7, 8 therapies, many of them off-label at this point, combining biologics together, just struggling to make a difference for the patients the way that I want to. And it is -- every case is a bit of a tragedy. And when you struggle with those people you are seeing for years and you don't have them or you want them, it just really drives home the need for better options, things that will kind of lead to deeper responses, avoid the issues with side effects. So there is a huge role here. Even though we've got one or 2 things on the market, maybe a few more things coming over the next few years, there is still this massive gap in terms of what I can offer patients, but I think I'll be able to offer them for the next several years. Next slide, please. Next slide. So I want to talk a little bit about an overview of HS and its pathophysiology relevant to C5. I think C5 mechanisms [indiscernible] covered very well previously. I'm just going to hit the high notes of why I think it's very relevant in HS because it really didn't make much sense to me. Why C5a would be important in HS when I first heard about Vilobelimab several years ago. To me, Vilobelimab -- or sorry, to me complement was in medical school at least taught to mostly just have to do with the MAC complex. This idea that bacteria was around, it would activate it. Once you got down to C5b, you could get this MAC complex that would kill bacteria and C5a just kind of disappear off to the ether. But this whole left side of this chart here, really was not on my radar at all. And it makes sense that C5a is not just going to disappear, right? Like you body waste nothing. And so I think of C5a is like the signal play, right? If complements activated, the body is going to go fight bacteria. It's got to alert the rest of the immune system, hey, something is going on here, and it's time to draw on that innate immune response and attack, right? So this is how the rest of the immune system gets revved up in response to bacteria being present. And so blocking that signal flare, keeping that immune system for being overactive, is key in HS. And I can tell you that like the most effective medication that I can possibly use for an HS patients still is a very strong IV antibiotic like IV [indiscernible], like 95% of the time, these patients look fantastic when they're on it, but you take it away and things go back to the way they were. And that's because there is something about this immune response related to just resident bacteria probably things like Porphyrimonas like we mentioned earlier, that when those are present, the body overreacts for these patients for some reason. And if you cut out that trigger for a while, things come back down. But that normal triggers is going to come right back in again. So this to me is the one therapy that bridges that link so far between -- like this idea that bacteria play a role that linked to the overactive immune response and trying to break it. So it really fits exceptionally well. And as mentioned before, like Vilobelimab does that well with anti-C5 antibodies, probably the C5a receptors may be a better strategy and is based on pharmacokinetics knowing how it's suppressed INF904 is hopefully going to be even better at that. I think it's like the one silver lining is that Vilobelimab not coming around, but maybe there's going to be more focus on an even better drug. So hopefully, that being delayed a few years means it really pays off in the long run. Next slide, please. And this was covered very well before also with the role of C5 and C5a receptor in HS. If you look here on the top left, this is an area where there's a tunnel here, not sure if the audience can see my mouse or not, but there's this tunnel [indiscernible] that kind of overweight structure. And all around that, there is this area where there's a big pocket of pus that basically a large abscess around that tunnel. And we know that the C5a receptor is highly expressed all those inflammatory cells, really drives neutrophils and other inflammatory [indiscernible] to the area [indiscernible] where the neutrophils are activated. They extrude content. We know that there's like auto antibodies that maybe helped maintain those nets once they've developed. We know that, again, antagonizing complementing that C5a pathway probably blocks this neutrophilic influx and the maintenance of those nets over time. Next slide, please. All right. So let's look more closely at Vilobelimab and a little bit of avacopan too. Because when we have some lessons we can learn from those prior studies, and I want to drive home again why I think such a missed opportunity. Next slide, please. So this is the initial pilot study, open label, with just 12 patients. When you see pilot study looks this good in a small population, you always have to make sure you verify it later on. But 83% response rate over the course of about 6 months, was really, really promising. Like nothing kind of has reported a high score response rate that high as time has passed. But again, the C5 -- the Phase IIb data is -- Phase IIa data is going to be more important. So next slide, please. And again, there's good photographs from the study, which is one nice thing. And I can tell you that HS is highly variable. We're going to talk about placebo response rates where things can just improve by chance over a short period of time. But these are the kind of patients that you're less likely to see that happening, right? This first patient on the top has a very wide area with all these scars and tunnels that are kind of trapped underneath these cars. And to see it shift much within 21 days like this is an area that has probably been chronically inflamed and looked relatively stable like this for months now. So over 3 weeks to see all that redness kind of fade away and to see the beginning of things moving in the right direction that quickly. It feels like something has shifted for a patient like this. I can say the same for the bottom patient, like that area that's kind of here with -- that has multiple drainage points at kind of 2 at the top and 1 at the bottom to see it kind of the edema go down, that redness go away. There is something that there's a clear sort of tamping down of that inflammation in that lesion. And something, maybe by chance, but there is something to it. I think most of the time with a patient like this. Next slide, please. And they look over a longer period of time. This is like a classic [ hide the ] [indiscernible] on the far left side. You see these very large [indiscernible] ridges, this deep purple color where it's highly inflamed, -- these little sort of nubs of red tissue that are at the openings of those tunnels that are draining all the time. And to watch that over the course of months to basically just being like probably an asymptomatic sort of bridge. It just looks like a bit of a raised scar. That is a huge shift for this patient, right? This does not -- and that's actually at the top of [indiscernible] earlier. But that's a huge shift, right? A patient who like sitting down would have been miserably painful probably is going to sit very comfortably at this point. And then the same for the scrotum like every step for a patient like this where their scrotum is swollen and red and inflamed to be able to go to the point that, that skin looks pretty normal like that. That is a stark shift, that's not chance alone. And this is what I saw in the trial for some of my patients who even now a couple of years later, like remember back to it, still ask me like, is that drug going to come along? Is there any progress on it? And I've been down beat until now, knowing that something else is coming. Next slide, please. So it made sense seeing these early results to look at a larger study and to sort of try to look at dose responses. And all of these treatment arms had lower dosing than what was done in that exploratory study, the exploratory study was 800 every week. The highest dose in this study was 1,200 milligrams every 2 weeks. So not quite the same as what was dosed there, but the idea was to try to spread it out as soon as possible. I'll point out to you, this is a very small placebo group, right, 36 patients and the idea was to kind of match it with the other populations in terms of numbers, but this was a lesson learned here that we'll talk about where if you have a placebo group of 36 patients, 5 patients by chance, one way or the other is a 15% difference. And so it kind of really sets up a lot of risk in the study. We'll kind of show -- what kind of happened with that in a moment. Next slide, please. And so here, we have that -- the primary endpoint response and this is kind of what makes the headline afterwards, whether or not something hits its primary endpoint. So if you ignore this bar over here on the left, -- if all I showed you was that there was between a 40% and 50% response rate across these dosing arms, and there was no placebo there, you use something like a historical placebo, you would feel like this was a very positive outcome. And I'll kind of show you these numbers compared to other drugs that are on the market now. But having a 47% placebo response, that tells you there is a problem with how we're measuring placebo responses or some other factors that affects that placebo group. It's relatively standard to see placebo responses of about 28% or 29%. That's around the median. We thought of things like guselkumab and risankizumab being -- 47% is like top 5 percentile, maybe the top 2 percentile when it comes to placebo response rates across study. So it is -- it feels like an unfair comparison in many ways and just again, a factor of probably very bad luck, where again a few patients moving one way or the other -- you would have said this was a positive primary outcome for the study just based on like 5 patients, right, which is unfortunate that the headline gets skewed by such a small group. Next slide, please. And again, to put into context, if we look at that Vilobelimab that 1,200 milligrams every 2 weeks, which was kind of in the middle of those responses. And you see how that stacks up against other things. So you've had [indiscernible], for instance, here, it's placebo response rate was 23%. So even though its primary outcome measure was only 38% for the treatment group, it went on to Phase III studies based on that, based on there being a delta present. But again, they had a larger study, but the larger placebo group, and they used historical placebo control as opposed to having to develop a very placebo group. And 45% is very much in line with things like bimekizumab, secukinumab, a little bit higher than what we've seen in PIONEER 1, one of the biggest [indiscernible] studies. So again, just looking at this by itself, you have said great outcome. But again, a 47% placebo response really hurts in a situation like this. Next slide, please. And over time, again, like to see patients continue to move the right way on average, so to see that about 40% of people who didn't respond by week 16 were actually responding over those next 3 to 6 months. That's, again, a better indication that those patients are stabilizing, healing as more time occurs. And I definitely had patients like this that went from -- I had one patient that went from 60 lesions down to like 32 lesions. So a huge shift but not quite considered a responder. I think over the next month or 2, they were even better because they had more time to heal. And you see the inverse here also where you see that most patients who will respond to begin with maintain that response over time despite the fact that the dose was decreased. So there was this kind of lingering effect and sort of consistent healing even with under-dose drug for this. And in the end, about 55% of patients responding at 9 months, which it can tell you that over a long period of time, a large proportion of these patients did see improvement despite the fact that the dose was probably lower than it should have been. Next slide, please. And again, more time often tells the story better. So it's 16 weeks. This is our placebo responses on the left here, the numbers that are the decreased percentage in AN counts, draining fistula, draining tunnel count and these other measures that take into account the fistulas that are present or tunnels that are present which are probably the most recalcitrant lesion and based on the studies asking patient opinion, the most impactful lesion on patients. So it's really where it's important to capture and it's not captured well by a HiSCR response. But you see that over time as patients were all on drug over longer period of time where more healing could happen, very clear and relatively dramatic reductions in AN counts, draining tunnel counts and scores like IHS-4, they're well validated at this point. So clear signal here towards a continued improvement as more time passed. Next slide, please. And again, looking more carefully at this data, HiSCR has its pitfalls, and that could be like its own hour long discussion. There are some things that are good about it. But what it misses are things like draining tunnels. So if you add that to the AN count, which is what you typically -- which is what is usually counted for a HiSCR response, you see that there is a clear dose-dependent response that tends to happen across these groups, right? So very modest at the lowest dose range and the highest over here at the highest dose range. Same for IHS-4 score, you get another validated disease measure, that you see that there is a dose-dependent effect. And so despite the fact that even that highest dose is probably not dosed as well as it could have been, you see this clear trend towards even suboptimal doses leading to improved responses over time. Next slide, please. And draining tunnels, in particular, again, that's the most impactful lesion that patient can have and the one that is often most recalcitrant to treatment because it's the sort of most chronic, long-lasting lesion, this very clear dose response. It's very dramatic in that high [indiscernible] age group. That's where you have chronic draining tunnels in [ mitosis ] and tunnel and that chronic inflammation that's present. And to have 41% of patients in that highest dose range who do not have a draining tunnel after 16 weeks. I mean that is -- it's hidden in that initial data that you see with looking at HiSCR, that is dramatic for patients, right? To go from a patient wearing a bandage every day, just to capture drainage happening, so they don't stain their clothing all the time to have no bandages at all anywhere is a huge shift. Any company these days that we talk about sort of put sort of certain data first, we talk about draining tunnels and their sort of DT100 count. That's going to be talking about more and more. It's already being talked about and they would all sort of sing this out loud, if they could. Next slide, please. And there's avacopan, which, again, I think first seeing the avacopan data, like when they announced it and they announced a positive result because they looked at only the Hurley Stage III group here, and they saw a difference here with the higher dose only. And they were probably also underdosed. Even with that 30 milligram BID dose, and it took time to even reach steady-state drug concentrates. It's almost like 12 or 13 weeks beyond when they were measuring their primary outcome. But despite that, they saw some positive responses that felt a little bit cherrypicked to me. But I think where it kind of tells the story the best is if you actually look at there are things like AN count reduction and IHS-4 over time. And seeing this bit of a dose response start to develop and even with the suboptimally dose drug, makes me think that there is definitely something to this one, too. I don't know that you have to I think dose much higher to really get to where you need to with this one. But as a proof of concept, it just tells you that yes, there is something happening in these patients. It's slower than it probably could be. But I think with more time and more aggressive dosing would have done even better. Next slide, please. And so next slide again, please. So just to kind of summarize that [indiscernible]. The main thing I want to drive home is that despite headlines that not look as good as they could have when this drug was when from the SHINE study in the beginning, I still think there is a ton of positivity to it. And having experienced firsthand, watching patients improve over time on the drug and sort of the history of looking back at this point. I mean, it's not perfect for every patient that was in those trials, many were probably underdosed. But clearly, it was doing something. And again, it felt like a huge missed opportunity. Just it is -- not at the over time, but like did that drug failed and what it felt like the wrong reasons, right, so a very high placebo response that took the wind out of its sails too early. And so I'm excited to see it coming back around again. We know that probably Vilo and avacopan were underdosed. I think that is something that INF904 could fix because its PK and PD profile looks much better here initially. And for an early dose finding study will hopefully kind of tell us what we really need to achieve, the correct profiles for that drug. So that's maybe the one big silver lining is Vilo would have been good. I think this has the potential to be really, really great. So I really look forward to seeing what it does. Next slide, please. Okay. Hopefully, I'm not going over too much of my time. I get excited talking about HS. So I'm happy to talk more, if more questions come up.

Great. Thanks, Dr. Sayed. Okay. So we are going to have our first Q&A session. We've got quite a few things rolling in here, so we'll get through them over the next 15 minutes or so. [Operator Instructions]

So we do have a few. I'll go ahead as we're waiting for some potential questions from the audience directly. First one, Dr. Maurer, relating to [indiscernible] the auto immune CSU and the non-auto immune, if you suggest targeting one just the autoimmune disease patients with 904 or both?

Yes. Look, so given that there are multiple pathways of complement activation, it's certainly an all-comer treatment potentially. But zooming in on autoimmune CSU, the endotype with the highest unmet need but also a very strong complement activator, this is a patient population where you would expect exceptionally good responses. Now on the other hand, going back as long as there is complement activation, as long as there is 5a, mast cells will get activated in the end, it doesn't really matter whether it's through the coagulation system, or which is valid for all or in addition, by the auto antibodies that target mast cells. It's an all-comer treatment that will especially help the Xolair refractory autoimmune CSU patients because they are underserved with the treatments that we have today.

Let me just a bit of a follow-up to that. So in Slide 46, you showed some UAS7 responses with previous mechanisms and one area showing that minus 9 treatment effect, right, was some kind of threshold. So I'm wondering as you look at that slide, considered 904, if you think that's an appropriate way to look at what you would want to see or expect to see from Phase IIa study or if it's not quite apples to apples with that?

No, I think we can compare these treatments. Once we have the data, we could compare to other treatments that target activating receptors. What we're doing here is we're using the gold standard, UAS7 -- UAS7 to measured treatment responses. And we know the minimal clinical important difference. We also know what to expect from placebo in that population. So we know that when we hit [ 10% or 9% ], possibly more that this is a meaningful outcome. The interesting question will be, do we see the same level of response across the different patient population as characterized by type one autoimmune, auto allergic versus [ type 2b ].

Great. So let me -- I'll come back to you, Dr. Maurer. Let me go to more kind of broader mechanism with Dr. Köhl. In terms of if you believe that the upstream blocker treatment like, let's say, [ etilitimab ] or C3 or Factor D inhibition cannot do the same kind of efficacy for blocking C5a, C5aR as compared to 904.

Yes. So the issue is that targeting the upstream pathways really takes out many of the effects that I have mentioned, for example, like dealing with infection [ optimizing ]. And this is something you do not necessarily have to consider when you're targeting the C5a receptor. So the general view is that the more specific you can be in targeting the pathway, the better you're off. Because it's difficult to foresee what adverse effect you can drive when you are hitting the entire pathway. And there are some examples. For example, in [ AMD ], where C3 has been targeted. And then there were some events that you didn't foresee, there are infectious events there as inflammation going on. So whenever you have evidence that -- for example, the C5, C5a receptor pathway or other downstream cleavage fragments are really important then the more specific targeting is the better way of doing. And then leaving the rest of the cascade intact so that complement can fulfill its tasks. And that is -- yes, that is desirable.

Great. So we have a couple of live questions. I'll go to those real quick. The first one is from Yatin Suneja at Guggenheim. [Operator Instructions]

Jan, can you hear me?

Yes.

Perfect. So I have a -- hold on. I have a couple of questions. And question is for both Dr. Sayed and Dr. Maurer. Could you -- so both HS and urticaria are very distinct diseases. Could you talk about this mechanism as it relates to its onset of action, how do you view the onset of action with this mechanism? And the reason I'm asking this is because the company at this point is limited in terms of its ability to dose patients. I think this is most likely going to be a signal-seeking 28-day study. And some of these indications have higher placebo rate. So do you think that 28 days is enough for them to show the signal. Is the onset fast enough to capture that within that 28-day time frame? And then one specific question for Dr. Maurer. Do you think CSU is the right indication? Why not explore something [indiscernible] where you do have a lower placebo rate?

Be happy to go first. Chris can add to that. Take the last question first. So [indiscernible] is also a target disease where we have a high unmet need and a strong rationale. We do not have that strong autoimmune component, although it does exist. It's a strong autoallergic component. And together with the C5 produced by mast cells and then cleave by [ trip ] days also from mast cells, this disease also offers a strong rationale. So I do hope that the company will also explore this approach in chronic inducible urticaria. Onset of action should be very fast. So C5a is a very fast-acting activator of mast cells when you block it. Mast cells should stop getting activated by this mechanism and this should translate into clinical benefit within a couple of days. It is very different from a mechanism where you need to downregulate receptors or where you need to kill mast cells to see a response or where you work upstream on autoantibody production that will then affect mast cell activation. So I do think the 28 days will give us the answer. Is it super important to have that fast onset? Well, maybe not so much. No, this is a disease that in most of these patients has been going on for a long time. As long as we know that this will help a couple of days or even weeks don't make much of a difference. But it is nice, of course, for people with very high disease activity to experience benefit fast. And I do think that we will see it.

Yes. And I can answer about HS. I think the main point of a forward study in HS is more going to be to make sure that before going to a bigger study, I think the dose is right. And then that pathway is suppressed the right way. And for avacopan for instance, study states weren't reached so much later. I think the data Niels showed earlier is very convincing that you suppress that pathway very effectively, very complete, and you reach steady state very quickly. So I think making sure that proof of concept stands for not as healthy control for HS patients, where notoriously, you have to dose those patients more higher than expected than you might see based off pharmacokinetic you see in a healthy control patient, whether they're metabolizing drug faster or just the inflammatory burden means they need to have higher doses to reach similar levels. I think it's going to be -- I think that's the most important data to get out of that initial study, making sure you suppress it effectively and pick the right dose going into the longer-term study. When it comes to disease improvement, that -- you can see the beginnings of that within 4 weeks for some patients. I think there will be some trends that could potentially emerge. But the different -- something like chronic spontaneous urticaria, a wheel comes and goes within a day. And so if you shut that pathway down effectively, then within days or weeks or a week or 2 weeks maybe like you should see the skin respond to that in my mind. Where with HS, like there are chronic wounds that have been there for weeks, months, years and just because you shut the inflammation down, it doesn't mean there's not a time period during which healing occurs. So you see the beginnings of [ erythema ] going down, you might see abscesses and nodules begin to reduce. Maybe a tendency for draining tunnels to be draining less or for some of them to resolve. But if you look at disease response curves across any study, even drugs we consider very fast-acting, you need until week 12 to 16 to see things really kind of hit around where they're going to settle out. And you often see continued improvement because the longer you suppress it the more healing there is. So again, the 4 weeks in my mind is a is a way to make sure that the dosing is right to try to sort of help foolproof in some ways that next -- sort of the next larger or longer-term studies, and may be enough to see a trend towards improvement. But it's going to be hard to interpret -- to fully interpret efficacy, I think out of a study that short.

Maybe if I can add to that, CSU is very different. No, there are no structural changes in the skin. You're either lesional or non-lesional or post-lesional as soon as you take away the activator, mast cells will stop degranulating and you'll see no more wheels. So that's why I think we'll see the effect much faster.

So we have a couple more questions I want to address, have those 2 guys for the next 10 minutes. Steve and Sam, I know you have a few questions, so I'll run through both of you. So Steve, we'll tee you up first, Steve at Raymond James.

It's a little bit of a science question just on the PK of the drug and the exposure. So just bear with me. And Dr. Sayed, you alluded to, obviously, in HS. There's a history trailing drugs here of sort of needing to go to higher doses in this inflammatory [indiscernible] affecting maybe the exposure on the metabolism of the drug. So I'm just curious, as you think about both of these diseases and now in this case, using a small molecule, so there would be different considerations versus maybe some of these antibodies that have been tested historically. How do you think maybe that's going to change in terms of just the PK in the skin. And then what I want to get at specifically is this particular small molecule, I think when you target C5a receptor, there's a sort of a lipophilicity aspect of the drug that's now necessary to get at the target. And so specifically, the features of this drug may be unique for a small molecule, just more lipophilic than other small molecules. Is there any way to sort of triangulate this and model for exposure in the skin, given all these maybe unknowns, or is this just a situation where you think you empirically run the Phase IIa, see what the 4-week data show and go from there? Just any overall thoughts or any data that you'd seen with drug exposure in the skin, I'd just love to hear your thinking around everything.

Yes. I mean, it's really an important question of where it penetrates. Small molecules in general, because of smaller size, they're going to maybe have more ability to get to places like around where the cutaneous tunnels are and into like sort of smaller area like sort of more end organ like in the skin areas that are highly inflamed and -- but I totally agree with you that like that pharmacokinetics dynamics may be different in a patient who's got a highly inflamed skin, where delivery of the drug might be better than healthy skin because there's high blood flow in areas like that. [ Lipogenicity ], I don't -- how lipophilic it is, I'm not like -- I'm not aware of that off the top of my head to where I could sort of say how much it's going to accumulate in adipose tissue and is it going to take longer for it to sort of reach steady states for that reason? That's something somebody else may be will answer better for you. But in reality, like with any drug, like there's a lot of theoretical stuff that can happen with it. In the end, it's seeing what happens in the actual trial, how it performs is the most important thing. I think the data that is there shows that like at the doses that will be used in this HS study, I think it goes -- the lowest dose that's going to be used in that Phase I study is going to be probably adequate or should be adequate to sort of suppress that receptor pretty well. I think they are very right to go to those higher doses and really sort of push it some, not to the point that it's unsafely high. But to the point that they're going above what they think they need to. So I think they're aiming high as they should, and it'd be very surprising if they don't suppress things pretty well. I mean there's a systemic inflammatory response happening in that disease. So suppressing that systemic inflammatory burden is going to be important beyond even just the skin. And if that means a little bit of delay of the effect on the skin, that will be okay. I think over 12 to 16 weeks even out, but somebody else may be able to describe or sort of know about how lipophilic it is and how that might affect skin distribution in particular.

Yes. Maybe the only thing to add from a urticaria point of view, this is a disease driven by extravasation. So you're going to enrich skin that is affected for anything that comes from the blood to the tissue, and that may then increase drug levels, especially at the sites where you need them. Blood vessels open up. I mean, you have edema, right? You have edema that's a wheel when it's superficial and [indiscernible] when and that is all that fluid that comes from the blood vessels, including the drugs that circulate to the sites of inflammation.

Great. Thank you. And then we'll have one last question here for this part of the Q&A. It will be Sam Slutsky at LifeSci Capital. Sam?

I guess for Dr. Maurer, so there's obviously a few mechanisms approved and in development for CSU, these include by IgE and anti-Fc epsilon, you got the broad mast cell mechanisms like [ KIT ] and potentially [indiscernible], you got X2 and now C5aR all in development. I guess given that mechanisms of anti-IgE X2 and C5aR don't necessarily overlap with each other, how do you make sense of where each could work versus others since they're independent mechanisms?

Yes. Thanks, Sam. Good question. Look, I think we need to really distinguish between drugs that act on activating mechanism that would be omalizumab, for example, or an anti-X2 or an anti-C5a receptor. The mast cell depleting and mast cell silencing treatments are quite different because they're downstream of the activators and the activating mechanism. But when you look at different activating mechanisms, we would be naive to think that certain mast cell activating pathway are entirely and only relevant in distinct subpopulations. Now mast cells are known to have these many receptors and to respond to different ligands acting on different activating receptors in concert. So it will be a mix of certain activating mechanisms across patients. And I think the benefit that we have here with C5a is that it works where others do not work. No, omalizumab does not work on this autoimmune IgG autoantibody-driven mast cell activation. And you bring up X2, and that's great, very interesting receptor, but we don't know what blocking X2 mast-related [indiscernible] receptor X2 does in chronic spontaneous urticaria yet. It may be a primary, it may be a co-activator. So it's certainly good to go for major activating pathways and to figure out how blocking these pathways -- this pathway will help patients across all patient populations and what patient populations have a more pronounced response than others.

Got it. And if I can just ask -- fit in one more. Just for the InflaRx team. Maybe I missed this, but will you be measuring C5a levels as a potential biomarker for future development? In CSU as well as, I guess, HS? And then is it expected to have a clear correlation between baseline levels and response?

So Sam, we'll address that during the InflaRx section of the Q&A. And actually, Camilla is going to be starting in just a moment on her section.

Maybe I can add to the point with the C5a receptor and the exclusive impact on directly working on the C5a receptor pathway only. I mean as I have shown you, and this is, of course, a preclinical model, but there are now several data out in different models showing that the C5a receptor seems to act on the [ germinal ] center reaction and also has an impact on the -- not only the IgG response and the induction of auto antibodies of the IgG subtype, but also IgE. And when you then target, in particular, 2b patients where you have the auto antibody response, there is good reason to believe that C5a receptor may also have an impact on those other antibodies that are formed, and that should also be taken into consideration.

It's a good point, Jörg, and that may actually then result in disease modification and possibly cure. So that's cool.

Great. Okay. So I think at this time, we will bring in Camilla for the discussion, her discussion on the clinical development plans and then Thomas, our CFO after that. We'll take just a moment here to get her live.

Yes. Thank you. Right. Next slide, please. I'm very excited to be able to share with you our clinical development strategy. You have heard that we are clearly going to study in patients with CSU and HS. And really, we want to do this in an open-label basket study approach. And the reason for that is to really to determine, first and foremost, the right dosing regimen that we would be taking forward in a placebo-controlled, a larger placebo-controlled Phase II clinical program. And I think we want to do this in a careful manner and really choosing the right doses with safety and PK. But obviously, within our study, we will be doing some efficacy measurements. In addition to that, we have had this basket study approached agreed with the FDA for a single IND submission. So I think speed is of the essence to some extent to try and get quality data so that we are better informed for our Phase II clinical program with a first patient in schedule for the end of this year, quarter 4 this year and some preliminary results expected for summer 2025. I think that's the advantage of being able to do an open-label study so that we can get data and be able to assess that as quickly as possible whilst planning -- whilst we have started planning for a larger Phase IIb study. Next, please. So this is what the basket study looks like. It's very straightforward. You've heard that it's 4 weeks. The primary and secondary endpoints are essentially the same for both CSU and HS study population. But I do want to point out the differences in the 2 different study population and the differences in terms of our exploratory clinical endpoints, including PROs, which are more specific to each of these disease populations. So on the left-hand side, you will see that our CSU study, we'll be recruiting 15 patients per arm using 3 different -- 2 different doses, 30 milligrams BID and 90 milligrams BID. And this will be for all comers because as you've heard from Dr. Maurer that we believe the INF904 should work in those who are either IgE-naive patients or potentially those who are IgE-refractory patients. And in particular, to respond to this idea that we may play a stronger role in these type IIb patients, i.e., the anti-IgE nonresponders. We will study, in particular, a separate arm using 90 milligrams BID specifically to enrich this population. And because this patient population will be a little bit more difficult to recruit, we don't necessarily want this to slow down the study, so we are doing the CSU study for all comers. And I will go on to describe the HS study in a little while. So next slide, please. So here, you will see in more detail how we are planning to randomize these patients. We have 3 arms, as I mentioned earlier, First, arm 1, we will randomize them to the lower dose, 30 milligrams BID and then the highest dose. And in addition to that, we would also enrich the CSU study with this group of so-called Type IIb autoimmune patient population. Our exploratory endpoints are fairly standard. It would include the urticaria activity score 7, which is a component of high severity score 7 as well as the itch severity score 7. We will also be capturing the angioedema activity score because there's no reason why it shouldn't work on that. In addition to that, we will have other PRO such as urticaria control test as well as the chronic urticaria quality of life questionnaire. In addition to those, we will be measuring biomarkers, and these are just some examples, as well as where we can to capture and to be able to measure tryptase, IgE, IgG and anti-TPO levels and C5a. The primary endpoints are safety as this is a primarily safety study as well as a PK study. So various PK parameters will be captured, which will go to further answer the question around PK exposure specifically for CSU patients. Next slide, please. So these are the main inclusion criteria. They are fairly standard across some of the other competition. And we're looking at moderate to severe patient populations with a confirmed CSU diagnosis for a minimum of 6 months. They have to have presence of itch and hives for more than 6 consecutive weeks prior to screening, and they will be allowed to use antihistamines during -- according to the local treatment guidelines. And as per physicians guidance, the UAS7 score should be more than or equal to 16 and the UCT score will be less than 12 during the 7 days prior to randomization. In terms of the third arm, I've already mentioned that we will be recruiting those who are nonresponders to anti-IgE therapy as defined by previous treatment with at least 300 milligrams of anti-IgE therapy for the previous 4 months, and who have had an inadequate response as confirmed by the investigators. Next slide, please. So this is a study designed for HS. It consists of 3 arms, but they're slightly different because we have introduced a medium dose arm here. So we have the 30 milligrams BID, a 60 milligrams BID and 90 milligrams BID with 10 patients per arm. Our exploratory endpoints will include all the ones that you can see there, such as total lapses counts, inflammatory nodules, draining tunnels, the separate counts for each of these lesions. And of course, with being able to capture all these end points, we can do various HS lesions-related scores such as HiSCR 50, 75, IHS-4 and so on. We will also be capturing clinicians' global impression of change as well as PROs, which are relevant for these patients, such as the patient -- the global impression of change in general quality of life related to HS, skin pain and DLQI. The primary and secondary endpoints will be similar to that of CSU, which is primarily to capture important safety and PK data. Next slide, please. These are the inclusion criteria for our HS population. They are moderate to severe HS patients, early stage II or III with abscess and nodule count of 5 or more. And these inflammatory lesions should affect at least 2 distinct anatomical regions with a confirmed diagnosis of HS at least 6 months prior to baseline visit. And they must have had inadequate response previously to 3 months of oral antibiotics for treatment of HS, or have demonstrated intolerance. Patients are allowed a certain number of antibiotics, mainly doxycycline, tetracycline and painkiller, tramadol is allowed for the duration of the study. So hopefully, that's given you a snapshot view of our clinical strategy for both CSU and HS. Thank you. Now I'm going to hand over to Thomas, who will go through the commercial aspect of our market potential.

Yes. Thank you very much, Camilla. I hope you can hear me. And in light of the advanced time, we are a little bit ahead of our schedule. I would try to be as quick as possible. But I would like to share a few ideas on where you see the [indiscernible] and for going forward. Next slide, please. So as Neil has alluded at the beginning of today's presentation, we have the company decided to focus our development activities in the field of immunodermatology for several reasons. From a commercial perspective, we find the immunodermatology field interesting since we are seeing a robust and are expecting a further robust growth in the market. And this is driven really by the advent of better diagnostic opportunities and treatment methods, especially new therapeutic options being developed in the field that are actually significantly growing the market. In addition, this growth is also attracting an increasing number of pharmaceutical companies to the field, which we see as a positive and encouraging sign. And in order to be able to capture a significant slice of this commercial opportunity across the different immunodermatology diseases, we have to develop 904 with an appropriate profile to properly address the disease, the medical needs and the competition in the respective markets of the different diseases. So if we succeed, we see several multibillion-dollar opportunities for INF904 [ venture ], and we're very excited about that. Next slide, please. So what does it mean to have a differentiated and attractive profile for 904. I think we have heard most of the elements already earlier in the presentation. So to sum it up, first of all, the ease of administration and patient acceptance of an oral therapy, we see this as a very big advantage, especially if we can dose once daily or twice daily manner. The safety aspect is very important in these diseases since we would like to position INF904 as a very strong alternative to other drug classes in this area. We believe that this is going to provide us with the possibility to capture a significant portion if we can do that. And of course, it will be important to address the areas within the individual diseases of high unmet medical need. We heard about this quite extensively. So I don't want to read it and repeat it, but there are in CSU and HS very particular elements of the disease that are not addressed properly with current treatments today. And therefore, a differentiated mode of action in our view is seen as something very desirable and positive for C5aR inhibition. Next slide, please. So if we look at CSU, we see that the market is currently growing at a rate of about 10% a year and is expected to do that at that rate to grow and exceed $3 billion market size by 2035. This is a conservative estimate based on market research. We see that if we profile and position INF904 appropriately taking into effect -- into consideration the elements I just mentioned, especially the strong efficacy in the disease, especially in treating of omalizumab refractory patients with maintaining the clean safety profile and the convenient oral dosing, we think that we could easily capture a market size -- a market potential of over USD 1 billion at maturity. So next slide, please. These numbers are all derived from proprietary market research that we have conducted, interviewing physicians in the field. So it's not out of thin air, but really the result of a -- or exercise that we have done. And here in HS, we see that the market opportunity is actually even bigger since the market is growing at about 15% per year and expected to exceed $6 billion by 2035. And that's mainly driven really by the different treatments that are being developed in parallel right now. So we feel that, again, here, for HS, it means that we have to show differentiated activity, especially on draining disease, but also on durability as response. As Dr. Sayed mentioned today, these are important elements. And again, if we maintain the safety profile of the drug, we are quite certain that the potential that we could capture could exceed $1.5 billion at maturity. So next slide, please. Of course, we have heard in the beginning that inhibition of C5aR or the pathway inhibition [ C5a and ] C5aR actually leads to opportunities in a significant number of autoimmune and inflammatory diseases. So we have, of course, with immunodermatology pick one area where we feel our strengths lie, our experience resides, but we see a lot of opportunities in a variety of different indication fields that could significantly grow this market opportunity of 904 altogether. This also opens up the possibility for partnering since we believe that we will, as a small company, not be able to address all these areas of disease ourselves. Next slide, please. So for next steps, what we see here is that we have, first of all, sufficient resources to run the Phase IIa study that we have discussed today. We will hopefully have results from this HS and CSU basket open-label study available in 2025 to help indicate where to develop further and how to develop further. So we're very excited about that. And with that, I would like to close. And we think that we are on a good path to execute our strategy to become a strong player in the immunodermatology field with a high level of recognition and visibility over the next years. So with that, I would like to hand back to Niels. Thanks.

Right. Thank you so much. I'm really just going to sum this up, and not too much to add. But first of all, I want to thank everyone. So far, it's been really great discussions. Next slide, please. So I think we have something in our hands with INF904 that has best-in-class potential shown already in the Phase I data compared to the marketed comparator. And we think it can become a pipeline in a drug, not just in the immuno space, but also in the broader I&I space. Next, please. Well, I really believe this is here really based on cutting-edge signs, not just inside the company, but really also in the field. And what we've heard today speaks testimony to that. And particularly the roles in CSU and HS, we find very compelling. Next slide. So with that, it's really just -- my last pleasure here, but also my wish to really thank on behalf of the entire InflaRx team, our 3 experts here on the call, Professor Jörg Köhl, Professor Marcus Maurer, Professor Sayed. It's been really great for us, great experience to work through this and get your perspectives. And I hope that the audience enjoyed it just as much. So with that big thanks, and I'm happy to turn it back to Jan to open for a general Q&A view.

Great. Thanks, Neils. So yes, we're going to have a second question-and-answer session period now. That's really more directed at the company. There's quite a few on the clinical Phase IIa protocols, but also if we have time, we have for some spillover to the KOLs. [Operator Instructions] We have quite a few questions already submitted via writing. You can try that, and hopefully, we can get to you. But we're going to be wrapping up here in about 10 to 15 minutes or so. So we'll hopefully address just what we can, and we're also available for follow-up questions in the coming days and weeks as well. So while we're waiting for the live Q&A to build, I'll go over some of the previous written questions. The first is from Joe Schwartz, Leerink Partners, about CSU and then how we see what hurdles we may have or the data we want to see? So specifically on new UAS7 as an endpoint, which is relatively standard in CSU, how we think about potential go/no-go, on what we see their placebo-adjusted data? And how important is the speed of onset in that data, whether we'd like to see something at day 1, day 7 or how we're looking at that?

Yes, sure. Maybe I'll try and take that one first. I think some of it has been addressed by Dr. Maurer already. So I think speed of onset would be great because obviously, we believe the INF904 should work rather quickly. But I think as Dr. Maurer has pointed out, these patients have lived with it for years. Now obviously, we would like to be able to show a fast onset of action. We like to be able to see that at the minimum, within 7 days, if not before. So these patients will have their UAS7 and the components of it measured on a weekly basis. So we will have that data. I think in terms of the clinical meaningfulness of UAS7 in this particular 4-week open-label study, I think Dr. Maurer has already alluded to the fact you can look at some historical placebo rates and you can compare it. And so we will be looking to do the same. I think we would also be looking at not just those components because obviously, we have a third arm, which are composed of the autoimmune type, the type 2B who are more difficult to treat and of which we believe that we may have an effect. So we would like -- and the UAS7 for those -- for that group may not be the same as that for the general population. So we will have to consider that very carefully. So in other words, we have some idea what we will be looking for, and we just need to be careful that we don't have a generalized UAS7 across all patient populations, but we'll take those into consideration and to also see whether there are some differentiations, such as AAS 7, which we will be looking at very carefully, too.

Great. So this is a related question for Dr. Maurer. We've had a few questions about IgE dependent, independent. But a corollary to that is a question is combo use -- potential combo use or thinking of potential combo use of Xolair and 904, whether that would be additive, synergistic, maybe a bit of a requirement for good efficacy. So Dr. Maurer, we're able to get you back on the line. If you could address that, that would be great.

Yes, sure. I don't think we need to combine, but there's certainly no problem if we had to. These different drugs target different pathways of mast cell activation. We know that mass activate -- mass cells are a key driver. When you take all of the mast cell activation out, you cannot have the signs and symptoms of chronic spontaneous urticaria. So I think the question that this study will answer is how broad across the patient population is the response? What is the responder rate? And are there differences in the effect size based on the underlying activating mechanism that drives mast cell degranulation? Again, I don't think we need to combine. I think that this is a major -- the major pathway of mast cell activation in the autoantibody driven endotype. But whenever there is C5a in the skin, mast cells must degranulate. They can't -- not degranulate. Now this is a very, very potent mechanism that will get them let up. And I do think that the evidence shows that there is activation of complement in the skin that we have C5a levels that spill over into the blood. So I think this is a very promising outcome of treatment.

We have a follow-up question from Sam at LifeSci Capital, and this is related to -- is again directed at [indiscernible] in HS. Since the main impact of C5aR inhibitor -- inhibition may be on draining tunnels, is there a certain enrollment criteria to better control the placebo rates, while allowing for treatment to show a more pronounced impact on the high score? So a bit of a design enrollment question on that and is related to 904.

I'm happy to give it a first shot. It's a very good question. If you don't mind, Camilla, I'm jumping in as I've been too involved in HS, in order to say something. So first of all, really good question. I mean that when it comes to the primary end point to high score, there is measures we all have understood by now that may help to keep the placebo response down. One is try to avoid an IV drug because you have a lot of touch points to frequent IV infusions that may have the ability to drive the placebo rates up. So we don't have that. Orals have been historically lower in the response rates, not in the 40s, at least. So it's a matter of also trying to avoid the patients with very low baseline AN counts. To give you an example, you have a patient with 1 abscess and 3 nodules. So the baseline count is 3 plus 1, that's 4. So just a change in 2 nodules could make that patient a responder, which may happen every other week, depending on how this patient fluctuates. So you want to avoid that. So most modern studies enroll patients of 5 or higher, which is what you see. So there's a few measures. And of course, you control like the placebo group sizes, right? You want to go to a meaningful study, which is one of the reasons why we want to make sure we take the right doses forward into that. So I think all these measures are understood, and that's how you can master the placebo response rate to a certain extent. You have variability, in that you can only counteract by group size. That's understood. But there are some measures. Now do we believe this is only active in draining tunnels? No. I honestly don't believe that biologically. This makes little sense, and we have shown quite good AN count reductions with our drug as well. We haven't gone into all that review today, but we did share that previously. So we do have AN count reduction, which looks like a dose response as well. So we do not believe that the drug is only active. So summing the whole thing up, we may have that great situation where we are active on draining tunnels. We may be able to explore higher dosing levels and have been explored so far to suppress this pathway. And we believe we work on AN count that we'll be able to handle the high score. So long answer, but I hope it ties it together.

Great. So we have a question also from Ed Tenthoff from Piper. He's asking, based on Dr. Sayed's comments, at what dose levels do we need to be reached with 904 to show activity in HS?

Yes. I mean that's the question that I think this next phase study is going to answer. I think it's -- based on healthy controls, it looks like even that lowest dose should suppress that pathway pretty well. But again, it's different when you have a patient with an active inflammatory disease state. So I think going to 60 or 90, like getting a sense of what it takes to suppress it in affected patients as opposed to healthy control, that's only a question I think this next study can answer. It'd be shocking looking at the healthy data levels or the healthy patient data that the highest dose range in that study would not effectively suppress it. But again, shocking things happen to be unlikely though. And as a comment on that last question, like Neil and I have talked about this in the past, like whether abscess and nodules might be affected by the drug or not? Or is it just draining tunnels? I really don't think it should be limited to draining tunnels. I mean there's a lot of crossover between the inflammation that's in those tunnels and it's in the newer abscess and nodules. I mean you put patients on things like antibiotics, which, again, I think, have some similar ways that they help for patients like this, like the abscess and nodules get better too, right? So it should be across the board improvement, whether -- again, I think there were some cohorts to the SHINE study that made it hard to pick those things apart, but I have a reason to believe that you'd see a global improvement. And my skin in the game is that like, I want to see -- I want to be able to treat all the patients whether or not they have a draining tunnel. So I'd love to see a study that does all of those things. But I think based on some of the data that comes back, maybe there'd be some sense of that and who should really need to target treatment audience.

And if I may add one aspect to -- thanks so much, Chris. I want to add one aspect here that I think it's important for exposure levels. The reported filing data of the avacopan filing for a different disease, ANCA vasculitis showed accumulation with steady state reached over 13 weeks. So that's like 3 months or so. And interestingly enough in the reported data from the [indiscernible] subgroup, where they showed some more granularity, they showed the separation of counts really occurring mostly maybe after the drug accumulated, but mostly between weeks 8 and 12. So really only at the last time point where they measure. And that, to us, is a certain hint that you need to reach a certain exposure level before you start seeing really more efficacy. Now our Phase I data to tie that in have shown that we can reach these exposure levels very rapidly within a week or 2 at the equivalent dose, but even on day 1 with a higher dose. So our goal is to say, let's aim at that kind of target dose and then explore efficacy from their upwards, right? So -- and ideally, we reach that immediately within a few days, a couple of weeks or even on day 1, depending on the dose. So we are quite confident that with that, there is a good rationale why higher dosing should also relate to higher separation and more effect on these lesions.

Great. So I think we have time for a couple more questions here. We're going a little bit longer. So I appreciate everyone staying with us. So the first question, Camilla, I think when -- in terms of the biomarker measurements, we did measure -- we did say we'd be measuring C5a levels. Is that correct? We do have the...

Jan, maybe I can take that. Before I take that, I think I'll probably just shed some light for the question about tissue penetration. I think that's already been addressed by presenters. But I think I just from the clinical perspective, I want to stress that I have before, just like avacopan is a highly lipophilic compound. So you already just have a compound that gets into skin really well. So we already actually proved that in the preclinical tissue distribution study. So this actually get into skin really well. So just -- that's the one that I hope to address Steve's question and concerns. The second one for the sample -- yes, for the measurement of C5a. Currently, C5A measurement is not defined in the protocol. The reason for that is because we have block C5aR and not block C5a in this case. So C5aR predominantly does not necessarily reflect the disease or the efficacy of this drug or the potency. So that's why we did not include that in the protocol. However, we do have several time points that we'll collect samples as exploratory. So we will potentially measure C5a or maybe some other potential markers [indiscernible] over the drug activity.

Great. Thanks, Renfeng. Last question here for you, Thomas, related to 904, obviously, and how you're thinking about potential partnering opportunities and that general framework?

Yes. So we are seeing an increasing level of interest from pharmaceutical companies, as I said, both in the immunodermatology space and more specifically, looking at novel approaches in this field. So we are actually having a lot of early conversations with companies showcasing what the drug can do in the different areas. And obviously, we are very much committed now to moving this forward in immunodermatology. But we feel that there might be opportunities beyond this indication where partnering could make sense in order to accelerate the overall development of this drug towards the variety of markets it can address. So I would not promise anything at this stage, and it doesn't make sense. But I think it's certainly an area that is catching more and more interest in the pharmaceutical world, which we find very encouraging, I have to say.

Great. Okay. So we're done with that, Niels. I did not get any final comments. Otherwise, I can close out the event.

No real final comments other than thanking everyone, has been really an exciting endeavor, tying also the basic science, translational science into it and hearing experts about the needs for their patients. So I think fascinating experience for our entire team. So again, on behalf of the team, big thanks to everyone involved, especially to our 3 experts. That's all guys. And thanks for joining to everyone on the call.

Thanks for having us.

A replay will be available. So appreciate everyone.

Thank you. Bye.

Bye, bye.