Great pleasure to present Dr. Niels Riedemann, CEO, and John Medina, VP and Head of Investor Relations of InflaRx.
Thank you very much, and also thanks to the Jefferies team for inviting us. We are delighted to be here. Good morning, everyone. My name is Niels Riedemann, as introduced, and I'll be presenting our company, InflaRx, to you today. Before we do that, please take note of the forward-looking statement disclosures here. We're making on forward-looking statements since we're a publicly listed company. Thank you. This company is about the terminal complement pathway C5a/C5aR. In the broader INI space, we have a key interest in this, and we're uniquely targeting this complement pathway by two drugs. Our key focus now is on C5aR inhibitor INF-904, a new small molecule that addresses some limitations of a marketed comparator. We'll be looking into this quite in more detail today. This is exciting for us because this could be a pipeline in a drug.
Clearly, it has this potential to address large markets, particularly in the immunoderm space. We also have a first-in-class, highly potent anti-C5a monoclonal antibody that has already a certain commercial angle. We have a targeted development focus on immunodermatology, and here we're driving certain markets with INF-904 that we'll be speaking about today. Just on the upside potential, these are clearly large upside potentials outside the dermatology space as well in the broader INI space. Those we would probably address with the appropriate collaborations if we can get them in place. We have a strong balance sheet. We are funded into 2027 currently. We are funded to reach our next milestones, and we have a proven track record to get drugs over the finish line into the market.
We have a C5a/C5aR key interest, and I just want to very briefly introduce these two players, C5a obviously being the ligand, C5aR being the key receptor, sometimes also referred to as C5aR1. Why is this pathway interesting? Obviously, you may know that C5a is being released or cleaved off of C5 through certain mechanisms, but it's really a marker that is upstream of the cytokine cascade. It's sometimes referred to as anaphylaxis toxin because it can induce histamine release in different cells and even lead to anaphylactic shock. This is how it was discovered some 40 years ago. It also has boosting effects on various other cytokines. It's a strong activator of various immune cells, particularly neutrophils, causing NETosis and getting them into the site of inflammation. There's been substantial evidence of work of preclinical science on the role of C5aR in signaling pathways.
It's a very well-identified target. Just a few words about how C5a is released. There are very successful drugs in the complement pathways already, and sometimes there's a misperception that all complement C5a release comes from these pathways because as they form the so-called C5 convertases from these three different pathways, they can certainly cleave off C5a. There's also another pathway which is not really a pathway. It's just enzymatic activities of all sorts of enzymes or enzyme-like functions like thrombin from the coagulation pathway, trypsin, elastase. I will come back to that in a slide later, but this is an interesting endeavor that happens in disease, and this is completely not addressed by upstream complement blockers. I'm making this point here because I want to be very clear that it's not possible to control C5a or C5aR activation by upstream complement inhibitors tightly.
In various diseases we have looked at, it's not even lowering C5a at all if you're, for example, blocking per C5 with the known marketed inhibitors for C5. You need a targeted inhibition. We're focusing our work here clearly on the immunoderm space, and that's where we'll be focusing on today with INF-904, our small oral C5aR inhibitor, focusing on two larger indications: chronic spontaneous urticaria and hidradenitis suppurativa. We're running currently phase 2a studies in these two indications, and I'll get to that in just a minute. There are others in the immunoderm space that could be of interest. As I mentioned, there is potential outside of this space. We do also have a commercial angle with Gohibic vilobelimab, our C5a antibody that I mentioned before.
We have an emergency use authorization for certain critically ill COVID patients in the U.S., and we have it available for patients here. We recently got an approval in Europe, and we're exploring potential partnerships there for a co-distribution or collaboration in Europe on this. Why immunoderm? Clearly, these are very big markets, very attractive markets, many of them, several of them, a billion dollar plus markets. We have identified certain unmet medical needs that INF-904 could strongly address. There's a good rationale for this pathway. I'll get into that also from preclinical science. The pathways we're addressing, sorry, the indications we're addressing, they have established endpoints, so no need to rework that. INF-904 is an oral drug. There's no known safety concerns on the mechanism of blocking C5aR, which is certainly a potential big benefit for an oral drug with no known safety issues.
There is a C5aR antagonist that acts differently than anything else already used in the immunoderm space. You are providing a completely new mode of action. Last but not least, we have established a network of experts in the US and in Europe, particularly, and a strong IP coverage for this C5aR inhibition, not just for the molecule itself, where we have very newly issued patents in the U.S. and elsewhere, but also particularly in the immunoderm spaces we are working in. Just very briefly, I mentioned there is interest outside the immunoderm space. We are not going into this today, but particularly the peripheral neurological diseases or the chronic renal diseases, some allergic diseases could be of high interest for such future work and collaborations. Let's look at this new molecule, C5aR inhibitor, which we believe has best-in-class potential.
This is a slide that summarizes a lot of the work that we've done, including our phase I studies, and I want to walk you through this. How could that be differentiated from the marketed comparator? You may know that marketed comparator under the name avacopan. We identified a few areas where we could potentially differentiate the drug. First of all, we believe that you need to have a different PK and PD profile to be able to block that pathway in human disease. We have a threefold higher Cmax, a tenfold higher area under the curve at the comparable dosing levels. You see that on the right side here on the graph. These were not head-to-head experiments. This is just plotted.
These are the reported data from avacopan, plotted in red dots versus the blue solid line, which is the exact same dose, 30 mg, of our INF-904 drug. You can see the difference there already. Interestingly, we went up to 240 mg, and you can see that you get exposure levels that are very, very differentiated and that allow you to explore different, broader therapeutic index. That is very important for us because we've seen that this translates into a tight signal control of the receptor on immune cells. That is the graph in the lower right corner. You see that over a broad dose range where, on the x-axis, we add additional recombinant C5a to freshly drawn blood from patients who've been exposed to the drug for, in this case, two weeks, twice per day dosing with 30 mg.
Theoretically, if at this dose level, the neutrophils in this case, the immune cells in the blood are completely covered, you could not excite them with recombinant C5a. As you see, already low levels between 2 and 10 nanomolar on the lower x-axis will get the controlled cells very much excited, the green dotted line. The blood from the healthy human volunteers is really protected. Why is 10 nanomolar interesting? These are very high average levels. You find them maybe in hidradenitis suppurativa, we found 9 nanomolar. If you go above 12, and you can see here the red dots at 12, you have a complete tight control. This is among the highest levels reported, and we have this control over a broad dose range. This is very differentiated from avacopan.
They only reach about 50% blockade at around 10 nanomolar added, and that's exactly where we're getting at. We can probably increase efficacy. There are also a few other favorable things. We have a higher drug strength. We pack 30 mg already in one capsule. They have 10 mg per capsule, so we are able to dose higher without undue extra burden to the patients and having to take too many pills. We have a much weaker inhibition of the liver enzymatic apparatus CYP3A4/5, which is important to build down drugs and toxins, particularly also corticosteroids and others. There are potentially various levels of differentiation, but the biggest one clearly is the broader therapeutic index and the broader blocking activity. Does it make any difference? Here you see this in an animal experiment. I don't explain all the details of the experiment. It's highly reproducible.
What I want to show you here, we did a head-to-head avacopan with INF-904 at the exact same 10 mg and same formulation. In this experiment, we can double the efficacy at the exact same dose level. That means we can block the receptor quite a bit more tightly and reach really 100% inhibition of the signal. That is really why we believe it is important to have the right drug for certain indications to explore efficacy. This is just reiterating this in a bit more granularity here on the PK levels in the single ascending dose. You see on the right side the area under the curves and the reported ones for avacopan. Quite differentiated. This is a more detailed picture on the multiple ascending dose study that we did.
You can see that over a broad dose range from 30 mg QD over 30 mg BID up to 90 mg BID, we have an excellent control over the signal, always between, I'd say, 90% and 100% control, which is really what you want from a drug like this. Let's talk about the ongoing phase II studies here, phase II study in CSU and HS. Just to remember, CSU stands for chronic spontaneous urticaria and HS for hidradenitis suppurativa. In CSU, we're testing 45 patients in three different cohorts. We have three study arms, 15 patients per arm. One cohort gets 60 mg twice per day. One cohort gets a very high dose, 120 mg twice per day. Then we have the so-called refractory patients that don't benefit from treatment, from omalizumab treatment, the anti-IgE treatment, and those get the high dose as well.
On the HS side, we have also three arms, but this time three different doses, 60, 90, and 120 mg, all BID in 10 patients per arm. This is a short-term study, only four weeks, but we have, of course, the typical also primary endpoints included here, like the urticaria activity score 7. I'll be speaking about that a little bit more. We are looking into safety, we are looking into PK, we want to understand the right dosing in these patient populations, but of course, we are looking into whether there is good enough evidence that the drug has activity and can actually improve patients' medical condition. We are very excited about this running study because it has been quite a few years of pre-work, and I want to speak about that pre-work and the science behind this.
Chronic spontaneous urticaria is really a pretty widespread disease that affects a lot of patients, typically younger patients, like in the age of, let's say, 30 to 50, but with a broad spread, a bit more women than men. It is an autoimmune or immune-mediated condition that is not fully understood, but it is particularly manifesting with these hives that can form and are extraordinarily itchy and really disturb patients' lives quite a bit, up to patients not being able to participate in work, getting depressed. There's a lot of downstream impact of this disease, which is sometimes overlooked as, "Oh, you just have some hives and they itch." It can be devastating. Sometimes patients develop this Quincke edema that can be life-threatening that is also known in anaphylactic reactions of different types.
Twenty percent of this population experiences symptoms for more than five years, so that's a quite nasty thing. The current treatment options, there are various ones. You start with usually antihistamines, but many patients do not respond when they develop the chronic spontaneous urticaria, and those then go typically on the anti-IgE treatment known as omalizumab. Despite these upfront treatments, there's a significant number of patients that are underserved, do not have good disease control despite this therapy. There are multiple other drugs under development because of the size of the market. How is C5aR involved in all this? Why would that make sense? I mentioned already that it's known to induce histamine release in different cell types. Obviously, histamine is the key factor that induces the hives. Let's look into this a little bit.
There is clear scientific evidence that suggests that the C5a receptor is involved in this release in mast cells and basophils in CSU patients in an IgE-independent manner. There seems to be a direct degranulation, a direct histamine release when the C5aR receptor is activated by its ligand. This mechanism could play a role in both, in the two subtypes, in the overall patients, the type one, and also the sometimes referred to as autoantibody or autoimmune type of type 2B patients. I mentioned that, and I want to reiterate, 30%-60% of these patients are underserved right now. They do have symptoms or severe symptoms despite other treatments. If this comes to play, this could be a very convenient oral therapeutic option, hopefully safe, but at least there is no known safety issue on the pathway, and that is exciting us a lot.
The market potential is large, could exceed $1 billion per year despite the current competition. This is external research we conducted. There are two subtypes, type one I mentioned, type 2B. The one is really the one that responds to the anti-IgE treatment, the omalizumab, because it is usually characterized by presence of IgE antibodies that react with self-antigens, and they cause the cross-linking and the histamine release. The type 2B is really recognized by not being able to be addressed by omalizumab because it is not the IgE-mediated path. It is really more IgG-mediated. That could be a big plus because there is a clear need, medical need in this next subtype. There is also quite a bit of evidence that there is coagulation involved in this, interestingly, and C5a is cleaved off in coagulation pathways from C5.
That has been something that we've been discussing with our former KOL, Dr. Maurer, who brought this idea to develop the drug in this indication to us. As you may probably know, unfortunately, he deceased tragically by an accident, but I think he drove this field in many different ways to success for different drugs, and we certainly want to recognize his input in this. On the next slide, you see a bit closer the role of C5aR on mast cells. As you can see, these cells start expressing the receptor in the middle, and they also release tryptase. As you may know, that's a marker for mast cell activity. Tryptase can directly cleave C5a off of C5. This is already textbook knowledge, if you will, despite the fact that nobody has ever tried to block the complement pathway in this disease.
That's why we're quite excited. As I mentioned, the coagulation is going on. There are different ways you can generate C5a through thrombin from coagulation pathways and also directly through tryptase. If that's true, there could be a loop mechanism by which the body starts making more and more C5a, and as long as you express the receptor, you have histamine release. What is known in human disease? On this slide, you see on the upper left corner that CSU patients do have elevated C5a levels. That's already established. On the lower left, you see that complement activation is the sustaining for C5a is ongoing in skin disease of affected areas of these patients. In the middle, you see quite dose-dependent histamine release, quite high-risk histamine release in basophils from these patients, from donors in this case, sorry.
On the right side, you see an interesting experiment that histamine release you can induce. This is a skin ex vivo model. You can induce this even though you put a blocker to the IgE cross-linking pathway. This just establishes that histamine release from C5a is independent of this IgE pathway. The next slide is a bit more in detail. This is basic science in an IgE model. I will not go into too many details. I just want to mention three interesting things, and this is work by Jörg Köhler and his group and others that is fascinating on an IgE-mediated model and preclinical science. They found three potential ways how C5a, C5aR are involved in this IgE-mediated disease model. One is by the plasma cells producing IgEs impacted by the C5aR, so you could have a long-term effect on that.
The second one is by the mechanisms we've been describing that these cells start expressing the C5a receptor and they directly degranulate. They also have an impact on FC epsilon receptor. That is where the cross-link of these two pathways could come together. Three, interestingly, histamine was not alone enough to cause this water efflux, so the diarrhea in this model. You needed C5a for that. If that is applicable to CSU, you do not get hives without C5a. If you block that pathway, you should have an effect. That is very interesting research.
As I said, there's a lot of known, and people always ask us, "How do you know in four weeks if you have any efficacy?" We just want to remind that we used this slide, it is just a bit updated, but we used this slide before in our R&D day last year to say, "Look, how do the successful drugs look like with the primary endpoint, which is the urticaria activity score seven because it's always over seven days recorded?" When we say successful drugs, we mean drugs that successfully passed phase II into phase III or are already approved or on the way to approval. You see that the purple here, for example, is omalizumab, and then you have remibrutinib with the BTK inhibitor.
Most of these drugs show a substantial four-week reduction in the score already by a total of between, I would say, 14.8 and 20 points, absolute reduction points. You see that there is one exception, which is Dupixent, because it has a very different mechanism. It works very late. That one is known. Also, there is one other that comes up higher later, which is the anti-KIT antibody barzolvolimab. It is not the strongest at week four, but it keeps expanding until week 12. It has certain side effects and safety issues. That is why this is probably more of a last resort treatment, but it is very efficacious as far as the data go.
What I want to make, the point that I want to make here is really that what you see at week four is only incrementally changing for most drugs at week 12. You can actually tell drugs that are successful when they fall in this range. Now, there is a bit of a gray zone between 10-15, but certainly as 10 is sometimes reached by placebo, which you see on the left side already, that is a situation where you could argue whether this drug has activity. This is just as a comparator slide. With that, I want to just summarize the opportunity. We have an oral capsule that could be BID or even QD dosing. We are figuring that out. There is no known safety issue on that pathway. I want to reiterate.
It's a new mechanism, and that's really exciting us that is addressing the IgE-mediated and the type 2B autoimmune patients. Theoretically, we have to prove this, of course. If it really addresses both, that could be a big plus and could give that drug a space which could be used very much upstream in the cascade of where drugs are used in this disease. There is an excellent benefit-risk profile. We have a very fast onset of action potentially. That's something you want to see. These are opportunities. Durability of response would be a big opportunity. No black box warning is an opportunity if it plays out, as I mentioned, no other side effects like hair or skin discoloring. Also, no severe issues with neutropenia or thrombocytopenia. Ideally, no recurrence of urticaria.
There are still big opportunities, and we're hoping to address some of them, if not many or all of them with this drug. This is why we stood doing this study. Yeah, this is just summarizing this again. I think we alluded to that, so I can skip that slide here. I want to speak a bit about hidradenitis suppurativa, which is really a devastating, horrible skin disease where we had already experiences and where we have been quite involved in how the field progressed. These patients suffer from three main lesions: the abscesses, the nodules, and draining tunnels. Now, we want to start with the nodules because this is considered the most fluctuating lesion. These are actually deep-seated nodules that can cause quite a bit of pain and disturbance, and they can sometimes develop and ripen into an abscess.
These abscesses can break open and release odorous pus. They're extremely painful and extremely wearing on the patient because most of the time, the patients have these lesions in the axillary area or the groin area. They are affecting the social lives dramatically. As the disease progresses and abscesses become chronic, they can form very deep-seated, very large lesions in the skin that develop so-called draining tunnels. This is just what you see, sorry, what you see to the outside of the disease, but in fact, there's an inside large lesion. These draining tunnels can form up to a liter of pus. Recently, I came by a YouTube video where someone showed his own lesion draining a liter of pus. It's horrible. These patients develop these lesions. The epidemiology numbers are like they're varying quite a bit, but it's a large disease.
It's certainly probably affecting many more than 200,000 patients in the U.S. alone when we're talking about moderate to severe disease. The current treatment, there are treatment options. There are biologics aside from, of course, general anti-inflammatory measures and other treatment and care. The first biologic was Humira, and then there's the anti-IL-17s that have been quite successful, and there's other drugs in development. It's become a quite busy field, but there are also clear unmet needs. I'd say the biggest unmet need is the durability of the response because all of these other drugs, no matter how they show it, many of the patients start developing or start progressing with the disease despite so the effect wanes. The other thing is the draining tunnels. They're not really clearly addressed by most other drugs. New mechanisms are needed, particularly for these patients. I mentioned this already.
HS patients do have a preference for oral. They do not like to poke them. We already learned that. They sometimes even prefer an IV injection over poking themselves for some reasons. With an oral inhibitor that addresses a very different path here, that could be a very, very interesting value proposition for these patients. Niels, we have just a couple more minutes. Yeah. Yeah. I want to thank you for—I want to just reiterate there's already a lot of knowledge of C5a in here. These patients do have elevated C5a levels. That's also known. As far as science goes, more and more research suggests that C5aR is involved around all these lesions, particularly here the draining tunnels. You see that on the upper right side.
There is a mechanism called NETosis that is actually very uniquely C5a-driven, very much involved in the disease inflammatory progression. This has all been worked out. There have been two attempts for this pathway. We had our own experience with vilobelimab, and we saw various levels of efficacy of the drug. I am going to show you two or three sites. And avacopan, I am not going to speak about that today, but we gathered from the avacopan data that there is efficacy, except that it is a very low efficacy at that level and that it is a dosing question. Just to reiterate, we had shown various signs of efficacy with our anti-C5a approach. That was the IV antibody back then. There is clearly an effect on all these abscess nodules and draining tunnels. You see that on the left side, even a dose-dependent effect.
There's clearly an effect on other scores that are favored, for example, in Europe, the IHS4 score. That is an approvable score in Europe, interestingly. The FDA did not accept that as an endpoint for us. We had a very strong effect on draining tunnels. I want to reiterate that on the left side, you see the effect at our primary endpoint, week 16, in our phase 2b study back then. I also want to reiterate that this is something that was plotted recently by another company, the DT100 effect. I think nobody has ever shown this, and this is despite the fact that at 1200 mg, we underdosed the patients as we've shown in our PKPD modeling and as the FDA agreed when we back then decided to move this forward with 1600 milligrams. Very interesting effect.
A lot of patients lose their draining tunnels here, as you can see here with a very big X to difference to placebo. With that, I think we have learnings that we gathered into why we're moving back into this field now with an oral drug that is highly potent and can explore a broad range of efficacy. That is, there is a room for this mechanism in our eyes. Again, ideally, we can address the weaknesses of the past that you probably saw minimal effective dose with avacopan. We can reach just one last sentence here. We can reach the therapeutic dose level that they reach at week 13. We can reach that on day one with our drug. Okay. With that, we're at the end of the presentation.
I want to thank everyone for your attention, and we'll open this for a very short round of questions, I guess. Thank you. Okay. That doesn't seem to be the case, so we can move on, and I think we're already over time, so thank you.