I'm required to point out certain disclosures regarding the relationship between Piper and our next presenting company, InflaRx, at our post at the back of the room and also at the registration desk. So InflaRx is developing therapeutics targeting the C5a and C5a receptor signaling axis of the complement system. GOHIBIC, which is a brand name of vilobelimab, is available in the U.S. and just actually received a positive CHMP opinion in the U.S. for SARS-CoV-2-induced acute respiratory distress syndrome. The company is conducting a Phase III trial of vilobelimab in pyoderma gangrenosum, or PG as we will refer to it from here out as it's shortened, with an upcoming interim analysis. And it's also preparing to initiate a basket study, a Phase II study for their oral C5a inhibitor, INF904. And that would be in hidradenitis suppurativa and also chronic spontaneous urticaria.
Here from the company is founder and CEO, Professor Niels Riedemann, and also Jan Medina, who heads up IR. Thanks both for being with us today.
Thanks, Ted, for inviting us. Thanks, Ted.
So Niels, start off, if you would, at a high level, describing the complement pathway and specifically where C5a fits in.
Yeah, absolutely. Happy to do so. So as we know, there's great potential in complement. We've seen numerous great performing complement drugs in the complement cascade. So it's an important part of our innate immune defense system, if you will, the oldest part of it, right, the most preserved one. But we are targeting a very specific part of it, which is at the end of the cascade, and that's the C5a, C5aR signaling axis. Interestingly, it's one of the best researched parts, over 6,000 publications in various preclinical disease models, really a lot of knowledge around the mechanism of that pathway, but not many drugs. There's one approved drug in the C5aR space, and we're the first-in-class drug on the ligand on C5a.
So the one part I want to point out is that there is a frequent misperception that you can block this pathway adequately when you go to upstream available inhibitors, including inhibitors of C5 or C3. And that is because there's different ways that C5a can be generated that are outside the reach of the complement pathway. So that is very old knowledge, but not paid much attention to. So if you want to control that particular pathway that is very well researched and very important for pro-inflammatory action, you need targeted inhibition. We have two highly specific, highly active drugs. The ligand is blocked by vilobelimab, the C5a first-in-class monoclonal antibody. And the receptor, the main receptor, the signaling receptor C5aR1 is blocked by our new addition, INF904. You mentioned it. It's an oral chemical inhibitor that particularly targets this receptor.
You touched on this a little bit, but to get a little bit deeper into it, how do these compounds compare to Soliris and Ultomiris from AZ, you know, what used to be Alexion, and those other complement inhibitors that have gotten approved now at other intervention points? What's unique about kind of how you're going about it?
Right, so we have a unique strength and potency in really blocking that pathway. As I mentioned, C5a can be produced inside the complement pathways. That part is inhibited by, for example, Soliris, you mentioned it, C5 inhibitor. But it's also produced directly by enzymes through enzymatic cleavage. It's a mechanism that most cells in our body can do by themselves, and that is not blocked by, for example, Soliris. So what does that mean? How does it translate into action? These blockers cannot fully engage, fully control this pathway. But if this pathway is driving, for example, like in COVID, a death signal, then you want to block and control that path like as much as you can, and just a little bit of lowering or not even significantly lowering C5a with these upstream inhibitors will not cut it.
Yeah.
On the other side, these upstream inhibitors, talking about Soliris, block, for example, in this case, very specifically the C5b-9 pathway, which we leave untouched, that may have big merits in diseases like PNH, the first approved disease indication, where our drug would not work at all because we leave that intact. Now, the benefit of that is that an important immune defense mechanism, especially for bacterial defense. And that's why they have a black box warning. They need to vaccinate patients for meningococcal meningitis disease. And we don't have that. So that's a differentiator. But I would point most emphasis on targeted inhibition needed for controlling that pathway.
Yeah. So different diseases, but also you could have the benefit of lower infection risk. So that's really helpful. Did you get it? You mentioned, and I talked about GOHIBIC very briefly. Just remind us what benefit it showed in critically ill COVID patients in the PANAMA trial. And, you know, I know the market opportunity is sort of waning, but what does this demonstrate in terms of proof of concept, really, for you guys, for this mechanism?
Yeah. So happy to go into that briefly. So obviously, we ran the so-called PANAMO Study. There was a rather global study in intubated patients with, so they suffered from an immune response to SARS-CoV-2, which we know can kill patients. And we exclusively, and that's probably the largest trial ever conducted in these patients, looked at patients that went over the edge, needed invasive mechanical ventilation or even lung replacement therapy known as ECMO. So we showed a 23.9% relative survival benefit, which is very remarkable because these patients fulfilled the oxygenation criteria for moderate to severe ARDS patients. And so there's no drug approved or authorized in the space of ARDS as of today. And there's been a lot of research on this immune response. So what does it mean to us? So first of all, it validates that this mechanism can be lifesaving.
That's an important validation for us. I should point out that we have an emergency use authorization, not a full approval in this country, in the U.S., and that means there needs to be more research done for full approval, but it also opens, you know, the gateway to maybe a broader ARDS label in the future once that research is done.
Even beyond COVID then.
Yes. And why is this important? And why do we believe there's upside value? Because, you know, we talk about pandemic preparedness. We talk about you want to have something on the shelf when a new virus hits. Ultimately, that would be the goal of that additional research to get to that point. Now, for the time being, we have clear authorization only in COVID-19. I don't want to stress that. But also there, we've seen waves. Right now, there's less patients dying in September, October. November, usually it starts picking up again. But for example, in the U.S., in the summer, I think in the month of August, there were reported roughly 4,700 deaths. You don't see that in influenza and flu viruses or RSV, but you do see it in COVID. So it reminds us that virus can always come. We make our drug available. We're commercially ready.
We learned a lot. We have a lot of engagement now with the research community. The data kind of made their way into the U.S. research community, and we want to keep that available for patients and make it accessible, and we've seen first treatments and have, of course, anecdotal, like really great stories that really make us feel good about keeping it available. At the same time, we are very cost-cautious and we're putting very limited resources into that.
Yeah, well, truthfully, I'm surprised it's not used more often. We won't spend too much time on this because obviously there's bigger opportunities here, but I'm honestly surprised it's not used more often, so I guess that's just about getting it in the hands of the right people, and hopefully it will because it is a lifesaving therapy.
Yeah. It has to do with the healthcare systems in our Western world, right? You need to first, in this country, get P&T Committee approval or at least get the pharmacist to agree that this can be ordered inside. So it's a multi-stage approach. And we kind of had to build the plane while we were flying it. So we got positively surprised by the EUA and then had to start all the activities that you usually do pre-launch.
Yeah.
You know, we don't guide to any sales at this point, but we think there's upside potential and we're very mindful in the resources we put in.
Moving on to some of the larger indications, walk us through the data you've reported on vilobelimab in other inflammatory conditions, and then we can get into the Phase III trial.
Yeah. We've conducted Phase II trials in various inflammatory conditions and gained like multiple efficacy signals. I don't want to go into all details because we want to focus on what we're doing. But the one area that we're conducting research in right now is pyoderma gangrenosum, PG. It's a very interesting immunodermatological neutrophilic skin disease. So that basket of neutrophilic skin diseases contains also diseases like HS, hidradenitis suppurativa. And so there's a common denominator that speaks or that kind of resonates with our mechanism of action for the drug. And we generated Phase II data in which the drug showed a very good response rate in terms of closing these ulcers. These patients suffer from very large ulcers. A patient representative that we worked with explained the feeling of having a PG disease as being skinned alive every day of your life.
It's much worse even than it looks on the ugly pictures for the patient's well-being. It's a significant need. There's nothing approved in the U.S. or in Europe. We're now conducting this study that we may be talking about a bit more in detail as a pivotal Phase III, which is the first really controlled study in this area. That's based on the very promising Phase II results from our open label.
Let's get right into that because it's kind of a unique adaptive design trial. Tell us about the design first. And then what should we be expecting or what are the potential outcomes from the upcoming interim analysis?
Sure. The trial design of the pivotal running Phase III is pretty straightforward, even though it took a while to put it together. You have two arms, a placebo arm and a treatment arm. Each arm is dosing placebo or treatment vilobelimab on top of standard of care, corticosteroids. There is no real standard of care, I should say, but corticosteroids are often used. Now, having a fully placebo-controlled trial would be unethical and patients would not be enrolled. So we had to dose it on, we had to construct the placebo arm such that it becomes ethically feasible. So we chose to work with the physicians in the U.S. and Europe and elsewhere to design the study to say we have a skin-active lower dose of corticosteroids that shouldn't result in meaningful responses, but should make it acceptable for patients.
We're tapering this corticosteroid dose out within the first six to eight weeks. There's a concrete tapering design, which happens automatically, so it's not up to the physician. If you are at certain control points not responding and as much as your ulcers are reducing in size and you're benefiting, you're forced out as a non-responder. Primary endpoint is target ulcer closure, full target ulcer closure on two consecutive visits. That's important. Theoretically, if you're not showing benefit, you should be transitioning out of the trial early. That was the trial design that we worked out with the FDA. It's on the one hand very straightforward, but it took a while to figure out what's the right way to do it.
We have an interim coming up in Q2 next year, which is based on the first 30 patients reaching their primary endpoint, which is a maximum of six months treatment. We are going to be blinded to these results, but the IDMC is going to be non-blinded so they can see the results on a patient level, and the interim read will either lead to a stop of futility or to an adaptation of the trial between 50 and maximum 100 patients. We blocked it at 100 patients because that's a very meaningful, one of the largest studies ever conducted in PG. If we go to 100 patients, so it is in this rare disease meaningfully large, but at the same time, you need to have efficacy signals at interim to get that conviction that you get a positive trial with that maximum of 100 patients.
That's on the first 30 patients or so. The full, if you don't adjust the trial, it's around 100 patients or 90 patients?
So if we don't adjust, it's only roughly 50.
Okay.
And we can adjust it up to 100. So I should say that we don't stop enrollment currently. We've voiced that we reached the enrollment already and we keep enrolling. So at the time we read the interim, we will have more patients in the study, maybe already close to the lower edge or, you know, even in the middle. So we will at that stage guide the public further on when we expect final full enrollment if it's not stop of futility, of course.
Yeah, and let's assume it's positive. So if it's, it could be that it just doesn't change and you keep going to the full 50, right? That could be, that's sort of best case scenario.
Yeah.
No change, not futile, not adding patients. And if that's the case, could we get data next year? And what are your guys' regulatory plans?
Yeah.
We have not granted that. What are your regulatory plans when it gets, assuming and hoping it turns out positive?
Right. So we think it's a significant market opportunity. There's nothing approved. It's orphan. We have an orphan disease designation in the U.S. and in Europe. We have fast track designation in the U.S. So if the trial is positive, of course, we're going to discuss approval scenarios with the FDA next. We can't guide on concrete timing. We see any non-stop for futility as really positive because through the capping, you need to have that meaningful conviction level at interim.
So that even an upside is viewed as positive. Yeah. I agree with that.
Really positive. Yeah.
I agree with that. Yeah. Awesome. Well, good luck. We're excited to see that data.
Thank you.
So switching gears, I think the biggest focus now is really on the oral compound INF904. And I appreciate it's already in the clinic, but maybe you can start off by just kind of reminding us of how that differs and walk us through some of the preclinical data you've reported. And I think recently it was at a European complement meeting. So maybe you can just sort of put that package together and we'll get into the clinical data you've reported.
Happy to do so. The other founder and I, Renfeng and myself, researched this target in very great detail 24 years ago at the University of Michigan. We love the target. It's just a tricky target, not easy to target with an antibody. A lot of companies have tried to bring oral inhibitors in the late 1990s, early 2000s. It was mostly peptides, cyclic peptides, but they're very toxic, so they didn't make it. There's one approved, now approved drug that made it. It's a chemical inhibitor, which was giving a lot of hope. It's known as avacopan. It's been acquired by Amgen. As oftentimes when you have a first-in-class drug, there are still opportunities to improve, right?
And we saw a significant opportunity for improvement because the major limitation of that drug was its PK profile that led probably to the fact that when looking at how much of the signal you can even in a healthy human control, that we didn't see much more than 50% control. So in a complement-driven disease where you have a lot of complement turnover, you need a tighter control. And we designed INF904 on the backbone of that knowledge that was created around avacopan, where there was IP freedom to operate, and spent five years with exceptional medicinal chemists and a great team engagement on can we fill that gap. And preclinically, we were very successful. All the data, the animal data showed the differentiation in PK profile.
That, for example, we did a head-to-head with avacopan, with the exact same formulation, with the exact same dosing in animals, and could show that because of the different profile of INF904, we doubled efficacy in that model. And so we also have a 36x less engagement with the liver enzyme apparatus, CYP3A4/5. This is important for drug-drug interactions and, you know, because this enzymatic apparatus clears a lot of other drugs, including also corticosteroids. So that's great. We don't have any greater safety signals of concern. We may speak about the clinical data. So preclinically, we were finally able to design a molecule that can fill that gap. And why are we doing that? Because we are very strongly convinced that in complement diseases, you need to have close to 100% inhibitor potential. We think INF904 can get there.
That will ultimately, that's the hope, but also our hypothesis, you know, lead to greater clinical efficacy.
Even with the weaknesses in Tavneos, ChemoCentryx was still acquired by Amgen for $4 billion. It shows the real potential here. With that background, which was super helpful, walk us through the clinical data you've reported on 904 to date, and then we'll discuss the Phase II.
Yeah. Happy to do so. We did a Phase I single ascending dose and a multiple ascending dose, so two study parts, and both were completed. We reported data. We showed a very differentiated PK profile from the reported data from avacopan. So in fact, these Phase I data really like fulfilled and exceeded our best case expectations. There was no safety signal of concern whatsoever. The PK profile ended up with a 10x improved area under the curve at same dosing compared to the reported data of avacopan. And when looking at the PD marker, where they showed about 50% inhibition, we really reached 100 at even higher doses of C5a engagement. So we are very, very happy with the data. And why is that? Because we can reach therapeutic exposure as fast as day one.
The reported data from avacopan show a 13-week accumulation pattern before reaching steady state. So the fact that not only we can reach therapeutic exposure levels very fast on day one if need be, but within a week in any case, even at lower doses, with the fact that we could dose multiple higher, we went above the 30 mg, we went up to 240 mg. So that gives us the freedom to explore efficacy, which when talking about skin diseases where you need a lot of dose, as we've seen in all the other drugs, they're approved at double dose, et cetera. So that gives us the freedom to explore that where they may be scratching minimal efficacy, we can push to see what is the pathway really generating a signal when we block it.
Yep. That's awesome. And then tell us about the Phase IIa study that you guys are working on in both HS and CSU. And you know, tell us about the trial design and when do you think we might get some data readout from that?
Yeah. So we are guiding through and we're confident that we can initiate the study still this year. We're on track with that so far, but also guided that we will have key data, top line data in summer next year. This is, if you will, a PK, PD oriented, fast, short-term exposure study, which should prepare a meaningful Phase IIb study in both indications i.e. So it's a four-week exposure. It's open label. It's different doses. We really want to understand PK. For chronic spontaneous urticaria, this was brought to us by my dear colleague and really great scientist, Marcus Maurer, who, you know, had a fatal accident. But he was behind this. He was suggesting this development to us. He used to work about a two-hour drive away from where I live.
And he was very engaged because he felt that's the second pillar not yet addressed by drugs in CSU. Like we know the IgE cross-linking leading to histamine release. The other way that's been shown in mast cells, basophils, is C5a. So there's comps of all the other drugs at four weeks. In CSU, you get a fast feeling for whether the drug is active or not. You have comps with placebo. You want to be away from that. So we hopefully get the right conviction level to start a real good, meaningful study that gives us more of a de-risking answer and then also that we know the right dose to move into. In HS, we have a lot of knowledge from our work previously in this. We gained a lot. Avacopan was tested in HS. So we have comps there as well.
And we know quite well what we want to see in terms of efficacy signals. So if you will, this is a preparatory study to get the conviction level and understand the right dose to move forward.
Awesome. We'll be excited to hear more about that next summer. You're right. Avacopan, I remember we used to cover ChemoCentryx. It showed some activity in HS, but it really, I think it was only the highest or the sickest patient. There it wasn't all that great. There's, just as you keep saying, there's room for improvement over that first drug in the class. You guys ended the third quarter with about 62 million EUR. I think that's about $65 million U.S. if Google conversion, you know, told me correctly. How long does this fund the company? Really, what's it enable you guys to accomplish?
Sure. Yeah. So that is EUR 62 million and we don't forecast exchange rates here, and that does get us into 2026. That's what we've indicated, so it's enough to, as Neil has been saying, for the interim analysis in PG2Q and also the Phase IIa data in 904 during the summer of next year.
Awesome. Well, guys, it's going to be an exciting year. So thank you for being with us. We look forward to all the data next year.
Thanks so much for having us.
Thanks.
Thanks.