All right, welcome everyone. I'm Josh Schimmer from the Cantor Fitzgerald Biotech Research Team. Very pleased to introduce the management of InflaRx. We have Nils Riedemann, Founder and Chief Executive Officer, and Jan Medina from the investor relations team. Maybe we could just start with a quick snapshot of the company, the key programs, and what we should be looking for in the next 12 to 18 months.
Yeah, happy to do that. Thanks for inviting us, Josh. Really, appreciate being here. We're a late-stage complement company with a key focus on immunoderm space. Within the complement space, we're focusing on a pretty unique part of the complement system, C5a and C5aR signaling. I think we're gonna speaking about that a bit later, but we got into this because the founders, Renfeng Guo and myself, worked as postdocs at the University of Michigan, really focusing on researching the role of C5a and C5aR in inflammation. And that's kind of the history here in the laboratory of Peter Ward, who's actually one of the godfathers of complement research. When it comes to the pipeline, we have a first-in-class monoclonal antibody called vilobelimab. Trade name is Gohibic.
It's commercially now available in the U.S. for certain severe COVID cases. We got an emergency use authorization there. But it's also in late-stage development in an interesting disease called pyoderma gangrenosum. It's a rare disease, but we believe it's a significant market opportunity. Also, it's a high unmet medical need. There's no approved drugs in Europe or in the U.S., and that's, you know, one of those derm diseases we're interested in. And then, we also have a new addition to our pipeline, which is INF904. That's a small oral molecule, chemical inhibitor of the C5a receptor, which we believe may have best-in-class potential as far as our phase I data show.
And this is moving into phase II studies, just towards the end of this year, which is in hidradenitis suppurativa and in another derm disease called chronic spontaneous urticaria, so significant market opportunities. When it comes to milestones, we're hoping to kick off the study, as I mentioned, with INF904 by the end of the year and read it out already, kind of in summer next year. So with that, that's gonna be very significant, and we're gonna get a lot of information on PK/PD and early signs of efficacy in these two studies. We are also having an important interim read with our PG phase III study, pyoderma gangrenosum phase III study with the antibody.
That occurs next year, and we hope to give more granularity of when exactly that will occur towards the end of this year. Our recruitment is going well, and we're on track. Then also, you know, we have recently been selected by the U.S. government under BARDA, Just Breathe program. It's going to be a national study in the U.S., very large ARDS trial. That's important for us, even though we are not investing in it, but the trial is supposed to kick off towards the end of the year. It's not under our control because the government is running it, but we've been selected in there as a promising target, and we hope that that will kick off soon as well.
So maybe you can explain where C5a and C5a receptors sit in the complement cascade? I've probably a little bit more familiarity with C3 and C5 as therapeutic targets. Where would you expect C5a targeting to have a therapeutic role?
Yeah. C5a, C5aR is a very well-researched space, basically, at the end of the complement cascade, but that's just if you think of it as a cascade and not three-dimensionally. It... When it comes to inflammation, this is a very central part of our immune response that drives it upstream of the cytokine cascade, and it drives various inflammatory pathways, including cytokine production of IL-6, IL-8, IL-17 pathway. It also has very unique functions that are not replicated by other mediators. That's why it's so abundantly present in our body and produced. That is, for example, the way it translates danger signals into immune cell responses.
So neutrophils, monocytes, macrophages, other cells can that express the receptor, can react to C5a, and you know, uniquely get attracted into the site of inflammation and then release mediators that can induce tissue damage, oxidative radicals, enzyme release. So that's very unique, and that's why it's researched in, I don't know, hundreds of disease indications preclinically, and there's over six thousand publications on this, so a very well-researched target. But I wanna, you know, also explain within the complement cascade that there's a common misperception that if you block something upstream, that you can control C5a or C5aR. That's not the case, and there's a reason for that. That's because the body found different ways to produce C5a.
One of them is through the complement cascades, through those, you know, mechanisms, and the other one is through direct cleavage from C5, which is through enzymes. They're abundantly present in inflammation, and it's now proven and published in peer review journals that you know, you can, for example, not block C5a in human disease with a C5 blocker that we all know, like Soliris or Ultomiris. Is this important? Yes, I think it's fundamentally important, and the ultimate proof was actually in COVID, when we basically had a head-to-head situation of our drug that we put into a global study in intubated COVID patients, and Alexion taking Soliris and then Ultomiris into a phase III attempt, pretty much copying the same study, and we predicted that if everything we know about the pathways is right, that drug cannot block C5a.
That's now been published in COVID. But it actually stopped for futility because they didn't see a mortality benefit and strongly increased infection rates. We saw the mortality benefit and no increase in infection rates, because I should mention, we do not touch the membrane attack complex formation, that other part that can be a problem in very rare diseases, but it can also be important to defend microorganisms.
Maybe, quickly on Gohibic, as you've mentioned that program, you do have emergency use authorization approval for COVID. COVID's not gone. You know, it's still in the news, if you look for it. There's still, you know, somewhat meaningful morbidity and even mortality associated with it. But I guess we haven't really seen commercial traction with Gohibic despite that. So what are some of the factors that might have limited the commercial traction, and is there potential for that to change?
That's absolutely true. I mean, when we saw COVID rates, death rates at the end of the pandemic, they were actually a bit lower than they are right now. It's not gone, and there's patients dying, and if anybody of us would say, "Hey, there's a new cancer that causes a thousand deaths per week," we would probably be all listening up. But in COVID, it's a bit different, but these patients still exist. When we got the emergency use authorization a bit over a year ago, we had the FDA saying, "Look, we want to make... You have to make the drug available, like, within four to six weeks," which we did, but we had to hire a small team. We had to, like, start from scratch.
So there was no pre-launch activities that we could finance or do. We have a very small but very experienced commercial team. So normally, you do a year and a year and a half, pre-marketing, work to get set up to do it. So we have, we had to do that, while we were already making the drug available. So there's two steps that make it a bit difficult, in the acute care setting. The one is you need to win P&T committee approvals or have, and/or have the drug being stocked in a hospital. Why is this important? 'Cause you want to get the drug into the patient immediately when you see one, and there's a time restriction within the 48 hours after intubation that you should give the drug. Now, that's, that's a hurdle because pharmacists watch their budget.
Hospitals are set up in a way to be very kind of defensive of new drugs, and that's because they have to watch their budgets. But for that, for example, we, you know, we're very inventive. We brought up a warranty program to say, "Look, if the patient dies on the ICU, we reimburse everything you gave, all the drugs we gave with our drug, I mean, all the doses you gave Gohibic." That has really caught interest. So in other words, you only have to pay for it if the patient survives the ICU stay.
The next hurdle is when you win a P&T committee, when you get the hospital to stock the drug at least and allow it in the hospital. The next hurdle is you need to train the staff, including the ICU nurses, because they're twenty-four/seven at the patient. But if you had, like, one big KOL knowing about the drug, liking it, that doesn't mean that the attending that night thinks of the drug. So we're making progress, but we can't and we haven't guided to sales because it's a difficult market segment.
But I would say it's fair to say that especially our recent data, the post-hoc data on the combination of standard, like when you include standard of care and give, like, baricitinib or tocilizumab, the patient still deteriorates, and then you add our drug, they show an 86% reduction in mortality, which is unheard of in ARDS setting. So we make a lot of progress in as much as US KOLs are getting behind the story, looking at the data, and we get a lot more traction with intensivists now.
Yeah.
You know, I think there is a market. It's definitely not easy to get to, but I always said, like, we're not making larger investments. We're making a very minimum investment to keep the drug available to patients. But if that drives upside in the future, it's upside for our investors.
You didn't see the opportunity for a strategic partner to help in the commercial side of Gohibic?
We definitely scouted to see.
Yeah.
But as I said, last year, everyone was a bit tired and done with COVID.
Yeah.
But, it's a problem that doesn't go away.
So we've also seen target validation for Tavneos in vasculitis. What are the hallmarks of an indication or disease where targeting C5a may be worthwhile?
So I think there's, there are different angles. There's the neutrophil angle, that's, it's very unique. Neutrophil and monocyte angle, as I mentioned, that's very unique feature of C5a and C5AR, where if you look at some of the diseases we're in, like pyoderma gangrenosum with the antibody and now HS with INF904, these are so-called neutrophilic skin diseases, so they're clustered in a basket. There's few other diseases in that basket, a handful, that are believed to be driven by neutrophil activation. So that's one of the mechanisms that go more to unique function. Then there's another area that we're very interested in, which is the allergic side of things. You know, his C5a was discovered and called, anaphylatoxin.
That's, that's its original name, because it was discovered as being very important in anaphylactic reactions, as we see in Quincke's edema and others. So that's hence we came to see as chronic spontaneous urticaria. Its role in mast cells and histamine release in this disease has been well documented in preclinical science. And, we had, you know, a very strong supporter suggesting this to us with Marcus Maurer. We all know that he sadly passed away within a hiking accident, but he's been driving a lot of development in this disease, and, we feel even more prone to pushing it forward now since it was his baby.
You had evaluated vilobelimab, if I'm pronouncing it. I know, I'll go ahead, Gohibic 'cause it's much easier to pronounce.
Easier.
You had evaluated that in hidradenitis. I believe maybe you can share some of the experience and lessons from that program that you're applying to INF904.
Hidradenitis is a, as I mentioned, another neutrophilic skin disease, and there's some unique role, and it's been even now published in review articles, about what C5a does. It induces NETosis, neutrophil NETosis in this disease, which is believed to be a driver of later stage disease when you have, these draining tunnels. And it was not surprising that we saw a very strong reduction in draining tunnels. We also looked at DT100, meaning how many patients that had draining disease had no more draining disease, which was over 40%, and with a so far never reported delta to placebo of 3.1-fold. So there was a very intriguing, you know, signal also that we reduced all three inflammatory lesions.
All of that would have been significant, but we also learned that the currently used score that was originally constructed by AbbVie, called HiSCR, has its intricacies and difficulties, and that's because it's, you know, very susceptible to baseline abscess and nodule counts, the numbers, and also these are abscess and nodules are lesions that fluctuate a lot. So if you run small studies, and you don't cap the baseline abscess and nodule, you can fall into the problem that others have fallen after us, including anti-IL antibodies, like the IL-23 one that was supposed to be a big promise. So we know how to deal with that now. You need to have control over abscess and nodule counts at baseline and run large enough studies. That's a big learning.
And the last thing I would like to say is, HS is a disease where you really need to figure out your dosing. You know, that the approved drugs currently all are approved at double the dose from where they are usually approved, like adalimumab, secukinumab, and that's for a reason. This disease needs a lot more drug than usual. So our PK modeling showed that with the antibody, we did underdose, and the FDA agreed to a phase II program back then, where we used a higher dose that we suggested, that we had actually tested in phase II. And that's why we're so excited about INF904 . That's a small molecule, different tissue penetration, different, ability to up dose to a much higher PK than so far seen.
We really believe this will drive a signal that is providing a benefit to patients that is on a different mechanism than currently served. If we can bring that to the market as an oral with no known safety effects on inhibiting C5aR, obviously, the molecule still has to prove itself. That could be a significant value to patients.
Maybe you can describe the phase II-A program and more specifically, what it is we should be looking for next year.
Yeah, in the phase II-A, which is now again, our small molecule oral C5a receptor antagonist, we're going to have 45 patients in chronic spontaneous urticaria in three groups and 30 patients in HS in three groups. So the idea is to test different doses on a 4-week consecutive dosing up to a pretty high dosing to figure out PK to figure out safety, but also to scout efficacy. We are lining up all the preclinical studies to do indefinite dosing and longer long-term studies, which we will be there very soon, but we're making use of this time to scout this. In CSU, it's interesting because we're gonna add one group in these 45 patients.
That's 15 patients, where we use a pretty high dose, but we're exclusively looking at the so-called type IIb subtype, which is the one that is traditionally not served with drugs really well. It seems to be independent of the... so anti-IgE drugs don't work in this subgroup. That's one of the hallmarks, so obviously, something other than the IgE pathway drives histamine release, and we believe that's an ideal place. This was what Marcus Maurer always thought, that that's the strongest rationale. Aside from the fact that if you think about how many patients are not served with antihistamines or anti-IgE drugs, there must be a role for a known other pathway, and C5a has been well described for that.
I think Tavneos has been on the market for a couple of years, I wanna say now. Have there been any off-label use or publications of Tavneos, either in HS or CSU or even other indications that might give you clues in terms of what you might be interested in pursuing?
Yeah, that's a really good question. So obviously, Tavneos is approved for ANCA vasculitis, and we see the sales numbers go up, beating at least the expectations of the street, under Amgen's now premise. There have been actually quite a few. I sometimes call them breadcrumbs that have been published here and there, for example, some interesting signals in chronic kidney diseases, also in aHUS. Just happened to speak to an investigator that used this in one of these small studies at the European Meeting on Complement and Human Disease, and there is conviction in these. First of all, the data show efficacy. Obviously, that's too small to prove it, but at least these breadcrumbs show that the drug is active.
Interesting side remark, the long-term kidney data in the ANCA studies was what a lot of rheumatologists got excited about because they showed an improvement. And then we mentioned HS. In HS, they ran a study. It fell short on the HiSCR in the entire data set, but. It showed an effect in the early stage three patients. Interesting that that effect only showed late between the last two time points, week eight and week twelve. And when you look back into the PK filings from the ANCA approval data, they, the drug had an accumulation pattern where it took thirteen weeks to reach kind of steady state. So it falls exactly in the steep curve of that accumulation, meaning all these weeks before, you don't have plasma levels.
You don't have a situation where you control the signal. You just see starting signal, good enough to drive HiSCR, but only when it accumulates. So we think this reiterates that dosing, and of course, the ability to up dose in HS is very important. And INF904, at least from the phase I data, shows clearly this ability, to be able to do that.
Maybe we can turn to pyoderma gangrenosum, which I think is a condition for which investors are a little less familiar. So maybe you can describe what it is, some of its etiology, incidence, and prevalence, and how it's currently managed.
Yeah, thank you for that question. So pyoderma gangrenosum is actually a disease that one of the patient advocates that we've been working with described as, imagine you're being skinned alive. It is usually a hallmark of that disease that you develop one or more very large ulcers. They start small, but they grow, and they're extraordinarily painful, and they do not heal upon all the usual wound treatment, right? All the sophisticated wound treatment out there. Of course, antibiotics are tried first. People think that could be a different ulcer, then you exclude the common ulcer causes. And finally, you may be doing biopsies to exclude some more rare things, and you come to the diagnosis of pyoderma gangrenosum.
And at that stage, this diagnosis is made by specialists in burn centers, and at that stage, your experimental journey starts as a patient because you've already suffered a lot and nothing worked, but there is no standard of care established, no drug approved. So there are centers that starts throwing very high dose corticosteroids on these patients, and in some patients that works, even though from what we hear, and that's more anecdotal than proof, the relapse rate is very high. We've seen also patients in our phase II trials that had failed on multiple attempts, and some other centers start right away with off-label combination therapy of corticosteroids with biologics or even two biologics at once. So every center has its magic potion. Many try corticosteroids first, but that is not even established in a consensus guideline.
So in other words, there's a big suffering. It's an interesting market, about 20,000 total number in the U.S. That's our estimate, according to our external research, and about 30,000 in Europe. In this case, it's worth mentioning Europe, 'cause there's nothing approved in Europe as well. So it's one of the, I would say, rare situations where in a rare disease, and we have orphan drug status in both, U.S. and in Europe, where there's nothing approved, you can still actually see a credible market. So it's interesting. It's a big unmet need. We see a market potential that leads up to a high triple-digit, maybe even up to $1 billion, in the U.S. as peak sales. So also there's always the question, is it underdiagnosed, because there's no treatment?
We see that in other diseases. Once a treatment is available, you may see a bit more diagnosis. So certainly, I mentioned it's one of the neutrophilic skin diseases, certainly a high unmet need. Nothing is perceived as really working in these patients. It's more like a trial and error. I meant I didn't mention it, but our phase II results were quite promising. We showed a high 86% ulcer closure rate in the high-dose group. Now, that was open label, I should mention that. That's not a controlled study, but there hasn't been any controlled studies. We are right now running the only placebo-controlled study, which the FDA insisted on, and we had to be creative to design it.
Do we know what the etiology of the condition is, and what is the evidence that supports a role for C5a?
So the etiology is, like, oftentimes not fully clear in this kind of, especially in the neutrophilic skin diseases like HS, PG, and others. But we know that from new work from Alex Ortega, who was the PI, for us, at the West Coast here in the US, and his group, that there is NETosis staining around these ulcers. So again, NETosis is a function that neutrophils go into, a cell death, C5a induced, throwing out extra to the extracellular space, some yeah traps forming RNA nets and others that can be a very strong inflammatory stimulus. So that's new research. Also, they measured C5a levels in certain lesions and found increased C5a levels.
What it encourages me is that in our phase II study, we went to a very high dose, not used in any other disease for us. That the dose that controlled C5a levels long term was the only one that showed a significant ulcer healing rate. So the lower doses could not come to the same control of C5a levels. Now, again, the numbers were small, so I don't want to overplay the numbers, but that was a very encouraging thing for us.
Maybe you can elaborate a little bit more on what you did see in terms of wound healing and, you know, what gives you the confidence that that was a treatment effect as opposed to maybe a spontaneous improvement?
Yeah, so I mean, first of all, many of these patients had a history that showed that wound healing did, despite all efforts, despite corticosteroids, despite other drugs, did not work. So there were only a few newcomers. Most of them had already relapsed, had already failed. So, you know, when you have a patient that has an increasing large ulcer, and in our phase II study, we allowed all size of ulcers, which, you know, can go to amputation status, when the skin is lost around the whole leg. So we healed a few, also pretty large ulcers, especially one that we healed upon up-dosing. So it showed a response, but it didn't heal. But when we up-dosed that patient to the highest dose, we showed a very fast healing.
There was another case that's just been published in the JAMA Dermatology this summer, that, developed PG under adalimumab treatment for psoriasis. So the patient was on adalimumab for psoriasis, and developed PG ulcer, and was an extremely fast healer upon our induction therapy. So there, you know, I think the question is valid. I mentioned it's an open-label study. It has drawbacks. You always, always wonder, you know, is this just good wound care that does it? But given the history and given how these patients come to a diagnosis, I would say, you can at least, guess that this is kind of a smaller risk. But in the end, we're running this phase III study now to show that versus placebo.
How many patients were in the phase II, and what % did show wound healing?
In phase II? So it's 19 patients. Among the available patients, two had an early drop, which was during the pandemic, was a bit tough to enroll. But, in the high-dose group, we saw the highest rate with 86%. Overall, in the study, 53% showed a complete ulcer closure. But one thing that's also comforting to us, all the patients, all the available patients, I should say, which was 17 in the trial, showed a response in a way that they showed a shrinkage of the ulcer. So we didn't have any patient in the trial that showed nothing but, you know, but the wound healing was overall a bit over 50%.
I guess there, there's just no good natural history data that gives you greater confidence that that's a clear therapeutic. It gives a... Sounds quite encouraging.
Yeah, we are very encouraged about it. I mean, it's the best you could do. Placebo-controlled studies were considered unethical. We had one of the patient advocacy group leaders with us at the FDA meeting, and she described that she would not go into a placebo-controlled study. So we had to be creative. We are doing this phase III study with a placebo control, but in both arms, patients will receive a skin-active dose of corticosteroids. Now, not a very high dose, but a skin-active dose to make that at least ethically acceptable, and then we have patient-level stopping criteria. So if you suffer too much after six weeks and we don't see an improvement, you're gonna drop out.
Got it. How large is the phase III, and what is the interim design to assess?
The total study will be between 50 and 100 because there's an adaptive element built in. We kept it at a little bit below 100 just because that's going to be one of the largest studies ever conducted if it is 100. The interim will occur after 30 patients. It's going to be a 1-to-1 randomized study until the interim, so just placebo arm versus vilobelimab arm. Both receive corticosteroids, as I mentioned. The interim will occur after 15 patients in each arm. For that unblinded IDMC, the study will be blinded, but the IDMC will assess whether there is a difference that would allow the study to proceed, and will then make a suggestion to adapt anywhere between, as I mentioned, around 50 to just below 100.
So if that reads positive, that means there's a signal that gives us, gives the IDMC confidence enough that there's a chance to reach a difference. Remember, you need an adequately powered study for one clinical phase III trial, so you have to have a difference that is meaningful between the two arms.
So it sounds like it'll be a go, no-go, and if it is a go, it'll determine the trial size. Is there any... So it sounds like there's a scenario where it may stop for futility.
Yes.
Could it stop for overwhelming efficacy at that point, or, or not?
No.
Okay.
It could not stop for overwhelming efficacy, just because we don't stop enrollment. So like the, should have mentioned, it's a six-month readout. So let's say we recruited the thirty patients on time point X, that means plus six month, unless the last patient drops out earlier or is done earlier, with the wound healing. And then you just clean up the data you need for the IDMC and that the IDMC need. But what it also means is while we don't stop for overwhelming efficacy, there's a likelihood that we're very close to to full enrollment at the time we read the interim.
Okay.
So it could, in an ideal scenario, mean we read positive, we don't stop for futility. That's a possibility, of course. But we're already done with enrollment.
Okay, and
As Nils said, by the end of this year, we hope to provide a better granularity on the 2025 timeline of that event. Right now, we're just saying next year
Okay.
But we'll give you more details by next year.
All right, excellent. I think we're out of time. Thank you so much for joining. Looking forward to some of these important updates from InflaRx. Thanks, everyone.
Thanks for having us.