Good morning, everyone. My name is Yatin Suneja. I'm one of the biotech analysts here at Guggenheim. Welcome to our inaugural healthcare innovation conference. Our next presenting company is InflaRx. From the company, we have two executives. We have Niels, who's a good friend as well, CEO and founder. And then we have John Medina, who's VP and head of IR. We have about 25 minutes, but I'm gonna hand it over to Niels to just maybe give us a five-minute overview of the company, highlight some of the upcoming milestones, and then we'll go into the Q&A.
Yeah, thanks so much, first of all, for inviting us. Yatin, we feel great to be here, be part of this. InflaRx is about complement, complement in human disease, and we have a very specific focus on one part of the terminal complement cascade, which is C5a and its receptor C5aR. We have two assets in progressed clinical development, or one in early, I should say. We are very excited about those, because, you know, our lead drug, Vilobelimab, which is a first-in-class monoclonal IV-infused antibody against C5a, has shown great efficacy in COVID. It's been emergency use authorized for that as a life-saving effect. So it's an immunomodulator, if you will, of the C5a signaling cascade and it has life-saving potential that shows you the efficacy potential.
Now, one of the reasons why we feel great about that, we are also in phase 3 for pyoderma gangrenosum. We will have an interim read next year that is very important for us. That's coming up in Q2, which is a new guidance that we're a bit more concrete now on when this is going to happen. And we have also our C5a receptor chemical small molecule oral inhibitor, which is, you know, a best-in-class potential inhibitor. Some of you may be familiar with avacopan, which is approved. So it's the only class-approved drug.
And we believe that we saw a lot of opportunities to improve features for chemical inhibitor of C5aR. And we believe that INF904 can be that. And we are heading into a phase 2a study in two dermatologic indications, HS, hidradenitis suppurativa, and CSU, chronic spontaneous urticaria. Also for that, we will see first clinical efficacy data coming up in summer next year. So important year for us.
Very nice. Okay. So perhaps we'll start with the oral molecule first. Could you maybe help us understand the differentiation that this molecule has, how it might be better or superior to avacopan, what data you have generated so far to sort of prove that?
Yeah. So the opportunities we saw in this space, particularly with avacopan, is to improve the PK/PD features. You know, to be inhibiting C5aR, there is a pocket inside the receptor that ChemoCentryx back then found, an allosteric binding site, which means, you know, in order to have a fully inhibiting drug, you need to be very lipophilic to get into that pocket. And the problem that we saw with avacopan is in healthy humans that when they looked at their PK coverage, it was very low in plasma. And it also translated into a neutrophil inhibition or neutrophil excitation inhibition assay, I should say, that maybe after one week, dosing twice per day with that drug at trough levels could only inhibit about 50% of the signal. Now, that is healthy humans.
We know in complement human disease, you see a lot of turnover of complement activation products. We felt there's significant room to improve the PK and thereby improve the PD. Both of which we've been shown in the phase 1, single ascending, and then in the second, multiple ascending dose where we treated for two weeks with our drug that showed a multiple higher exposure. We had, you know, a much different plasma exposure up to 10x. We also saw that we can reach that exposure right away on day one if need be because we were able to updose our drug multiple times. Now, having said all of that, some of the extra features that we worked on is we have a very much lower 36x lower engagement with the liver enzyme apparatus, CYP3A4. This is preclinical in vitro data, I should say.
But that's important 'cause there is always the question for chemical inhibitors on liver tox. That's important that we don't block that enzyme apparatus. We've also shown in a preclinical model in hamster that these PK/PD features actually translate into 2x improved efficacy in a hamster model of neutropenia that we could reverse with our drug to 100% while avacopan was only able to do that with 50%. We believe, a long story short, that the data we've shown really can translate into a very much stronger, efficacious drug. I wanna reiterate, you know, avacopan is a good drug. You can reach that efficacy in vitro, but you need to dose it a lot higher.
Got it. One thing you didn't touch, what about the DDIs? I think avacopan does have an issue how it interacts with steroid. So how is your molecule different or similar?
Yeah. That's the liver enzyme apparatus. I mentioned is CYP3A4, which is, i t's the name of that liver detoxifying. That is actually responsible for breakdown of corticosteroids in the liver.
For no interaction.
Right? So if you block that significantly less, you don't block the metabolism of corticosteroids. Other drugs for that matter.
Yeah. So better exposure, better safety, no DDIs, obviously preclinical showing better data. Now, how do you expect that to translate in that into clinical? Like, would you be able to dose lower or can you dose higher and don't have that issue? Just, help us understand that dynamic?
Avacopan is approved at 30 mg twice per day. And we've shown that if we dose our drug INF904 at 30 mg twice per day in humans, we already have a multiple different efficacy. So one potential outcome is that at the same dose, we are seeing already quite a bit of difference in efficacy. However, what gets me personally, but also our entire team excited about that drug is what you couldn't do with avacopan. It has also to do with formulation. They have 10 mg per capsule. So at 30 mg twice per day, you're already swallowing six big capsules and all that. What gets me excited is that we can, from there on, even multiply that exposure.
We have, like, we went up to 240 mg dosing in single ascending dose and up to 90 mg twice per day. So 182 per day, multiple ascending dose, and why is this important? 'Cause we're looking at skin disease. We'll be talking about that. In skin, especially in disease like HS, if you had just dosed these diseases at the, you know, doses of drugs that have been later approved approved in other diseases like Humira, if you don't double that dose, you don't see efficacy. And so we think that in skin, that becomes particularly important to have the ability to updose from there.
Got it. One more preclinical question, and then we'll talk about the development plan. How translational are these, you know, neutrophil inhibition assay, you know, in terms of predicting activity in patient? Because I think you've generated some data with 904 there.
Yeah. I mean, in the end, you have to always prove it in patients. But I would say two things to this assay. First of all, it's the surface marker; it's called CD11b and is very sensitive. So if you show that you don't activate neutrophils, this assay shows it in human blood nicely.
I see.
Second thing is neutrophils have the highest density of the C5a receptor of all immune cells. The other cells have high densities too. But neutrophils constitutively, without exciting them, they already have a lot of receptors. So it's very sensitive, and in hamster, we've shown already how it translates into doubling the efficacy.
Got it.
So yeah.
Okay. All right. So now talk about the clinical development strategy. HS, I understand because there is already data on avacopan, also with your C5a antibody. How did you prioritize CSU? Help us understand the study design because these are shorter study. What should we learn, and the size of it?
Right. So in CSU, it's the mechanism is not neutrophil-driven disease, obviously. So in CSU, we're not going after the neutrophils. But of course, C5aR inhibition is much broader than on neutrophils. So, in CSU, particularly, the mast cells and the basophils start expressing, in these patients, the C5a receptor. And, it's actually a disease that was brought to us by our, you know, much esteemed former colleague, Marcus Maurer, who, as you know, deceased tragically. And he brought this disease to us because he was so convinced that it could be making a big difference to CSU patients. Why? Because there's the IgE cross-linking thing. We understand how you generate how you create mast cells, histamine release, right? But the other path that's long discovered and long described, hence the old name anaphylotoxin.
I see.
Of C5a is that C5a directly releases histamines in mast cells, particularly in basophils. So the next to the IgE cross-linking histamine release, you have C5a-driven histamine release. And the extent of histamine release is equally high. Now, you know that there are patients like this, the Type IIb subsetting that don't respond to anti-IgE treatment like Xolair. And for those patients, what else does make these patients have histamine-released symptoms? It was his conviction that it must be the C5a pathway 'cause it's known, it's shown.
And, so we're very excited about that. Now, if what we said is true for all patients, then you have a drug that could have the potential to also move into first-line treatment like Xolair because you may address equally a lot of patients with that. Always provided that it's safe and it would be great positive to have an oral safe drug with no bothering side effects.
Yeah. So you are running a 28-day study. What can we learn within 28 days in CSU?
Obviously, that's a short study. The reason why we're bridging the study towards a larger phase 2b is really because we were limited by the 28 days by the TOX program, which is now on the way to be fully completed here in due course. And we want to learn, are we getting a dose that shows us signals of efficacy and are we getting the right dose before we move into more meaningful trials? Now, in CSU, I think we have the chance. You will see, pretty much in one or two weeks, as it was what Marcus always told us, that whether a drug starts having an efficacy for the patient .
Obviously, there's also the question of placebo control. But I think that question can be partially answered by looking at patients with a response, meaning the UAS7 score of six and less, right? That's something that you wanna look at. And then you also wanna look at, you know, patients that have the refractory situation. The type IIb. So for those, it would be inherently meaningful to show something 'cause that's where usually placebo doesn't show big effects, right? So clearly, I think we can learn a lot from these 28 days, but that's just setting the stage for a larger study.
How many arms? And it seems like there is an arm for Xolair refractory patients.
Yeah. There's one arm for, and I should have mentioned that there's one arm for Xolair refractory studies only treated with the high dose. And then there is the all-comers that we are treating with two different doses, a low dose and a high dose.
Okay, so the study starts soon. We get data in summer.
Yes.
Right. Short enough, short study, but disease is such that within 28 days, you should get some sort of a sense of h ow the drug is behaving. Okay. What about HS? How is that study set up? I mean, that's a very tough disease to treat in the short duration. I mean, even in the longer duration, it has a higher placebo. So how should we think about that study because it's also open-label and short-term?
Yeah. We discussed, of course, a lot, should we do a short-term HS study? That's not necessarily preferable unless you wanna really understand your PK and your dosing. And we do, we really wanna do that. So in HS, we have three study arms with three different doses, low, medium, and high. And we wanna understand that vis-à-vis CSU, which gives us additional information about skin disease dosing. HS is a disease that probably needs a lot of drug.
And of course, we are not comparing four-week data to, like, let's say, on the HiSCR level where you see a huge variability, a lot of placebo responses. But what we're really looking for is can we already reduce the lesion counts significantly in a way that not statistically significantly, in a way that there's a very good likelihood? And is there a dose response, which we believe there is a good likelihood? You're right. These are low patient numbers. So we are really looking less at a very variable endpoint like HiSCR at four weeks. We're looking at are the lesions coming down? Is the drainage coming down? Does the patient report an improvement? And that would be very encouraging, especially with a high dose. We have high hopes that that is something we can see already.
Got it. For both, so both these studies are under one protocol. And then what is the status for the IND? When do we expect these studies to start, being active and start enrolling patients?
We are on track to start this still this year. So everything is going smoothly so far, so no, no stopping signals. It's under one protocol really for speed reasons because, you know, obviously these are a bit different patients, but they're sometimes treated in the same centers, sometimes different centers. We will be setting this up in enough centers so we get data next year as d iscussed. Everything's on track. No blocking elements so far. We're very happy with that. We should be seeing, you know, this kicking off very soon here.
So in HS study, at least in HS, you also looking at the PK because I understand in HS particularly, you do see higher doses being used across other antibodies.
Right.
More of a PK, not just the safety study.
Absolutely. It's really understanding our PK in these patients because we have a good situation in HS in as much as avacopan has been tested in this disease with the 30 mg, which we felt is considerably underdosed.
Yeah.
And we can compare it to what has been shown about that drug versus ours. So PK is really one of the key learnings we wanna have.
Got it. All right. Maybe moving on to vilobelimab. What is the status of the PG study? I think you made some announcement last week that you have achieved a certain threshold of patient that triggers an intent and just walk us through where the asset is, what's going on, what are the next steps.
Absolutely. Yeah. Vilobelimab is also our IV antibody directed against C5a. PG, pyoderma gangrenosum, is a rare disease. I just wanted to add that to your question. Obviously, it's a phase three pivotal study. There's nothing approved in Europe or in the US for this disease. There's never been a placebo-controlled or anyways a real controlled study. So it's kind of a bit of a groundbreaking situation. We have just recently reached the minimum number for interim enrollment, which was 30 patients. So, and we'll be more concrete on expecting the interim read in Q2 next year. What is this read? This means the IDMC is unblinded to the data, can compare the groups, sees the response rates, sees the differences, and will only further the study to between 50 and 100 patients if they see, you know, a benefit of the drug versus the placebo arm.
We don't further specify what that benefit concretely means, but you can, obviously we have capped the study at about 100 patients 'cause that will be a significantly large study in this indication, and obviously, you cannot show minor differences between two arms with 100 patients on a P-value positive pivotal study. So in other words, you have to have the trust that you see a clear difference and the placebo arm largely not bringing patients to close their wounds, and the second conviction you have to have is that your drug can do something clearly differentiated, so with that, any non-stop for futility is a positive for us.
We will let you know. We will not be unblinded. So the study is blinded. It's just the IDMCs that they can see the data. They can see the patients, the ulcer size at baseline, which is very important. You have to take lots of factors into consideration, but we will share with you the outcome of the recommendation, and we will share with the public where we are with enrollment. It's because we're not stopping enrollment, it could be that at the readout of the interim that we are, you know, have progressed with an enrollment that we are almost done or close to full completion depending on the adaptation. But it could be that it is within several months, and then, you know, it shouldn't be too long after the last patient in, six months treatment t o see the trial.
So the study size is 50 or 100?
That's within the adaptation realm.
So they can tell you to add 20 more or add 70 more, right?
No, as a total of 100. So the 30.
30 plus.
70 more is the maximum. Yeah. Or 20 more, right?
That's how it goes.
Exactly.
Okay. So there are basically three outcomes for this interim, you know, futility stop, one, two, go, you know, as it is. Now, if they say just go as it is, what is the end? Is it 50 or 100?
Oh, 50.
Is it 50?
50. Yeah. Roughly.
Or you increase
Which is basically 100. Somewhere within, but that really is depending on their conviction level and what they see.
What have you shown in the previous experiment with vilo in PG? Then I understand you are not gonna disclose the data because you can, but at least from a threshold that you have established for this interim, can you articulate like what is, how should we think about that threshold? It's an easy threshold. Like what percentage you are looking at from wound closure standpoint?
Yeah. So, first of all, what have we shown in the phase II study that was a study with 19 patients, 17 available? We had a dose-response relationship in a way that the high dose produced the highest responses. We called response a PGA score of one or less, but we also photodocumented and confirmed that a lot of these patients reached ulcer closure. Now, target ulcer closure defined in the pivotal phase III here is on two consecutive visits, and closure meaning full epithelialization of the wound or scarring, but it has to be closed. Right? And it's a physician call, but we will also photodocument that. Now that's a very tough endpoint and a very high hurdle, and that is what the FDA recommended.
So it's since no one has done the study, for us, it's not clear to say this is how placebo will react in such a yeah. Obviously, as I mentioned, you in order to succeed, you need a p-value positive trial with a single-sided alpha of 0.025. You know the drill. So you can do almost backwards the numbers, what you need as a difference, but then we don't know, like, where the whole thing plays out. So if there is absolutely no difference between the two groups, it's pretty much. Unreasonable to assume you can still have a positive trial if you add, let's say, you double the patients, right?
What was the ulcer closure percentage for those 17 patients?
Yeah. We had overall over 50% ulcer closure. And in the high-dose group, we had 86%, but that again, this is low patient numbers. One patient numbers.
Is the steroid tapering and use the same or?
In both arms, yes.
Both arms.
And it's really meant to make the trial ethically and acceptable for patients to enroll. It's still tough because the dose we give is not a treatment dose, right? The treatment dose is usually multiple milligrams or up to a gram per day, multiple milligrams per kilogram body weight. So that's not what we're giving these patients, but it's at the same time, you need a skin-active dose so that they're accepting this to be on there.
So my question was the way you calculated the 86% ulcer closure at the high dose in phase II, is the same methodology you're using in phase three or are there differences?
No, we would not go with that super ambitious 86% closure rate, right? Because again, closure is defined a bit different. You need two consecutive visits. You need, like, a full epithelialization or scarring. So that creates small differences that can make impact that we don't fully understand yet.
Okay.
So the question is not do we reach, so we also did not set up the trial planning with 86. That, that's clear. So but the question is more, what's the difference to placebo, right? And that's something that the outcome will in the end show. But there needs to be a difference at interim for us to not stop for futility.
Got it. What is the commercial opportunity in PG? How big is that, indication? Is Humira used at all or?
I should say Humira is actually label approved in Japan, with a 20-patient trial, a bit over 20, 21, 22-patient trial, open label as an extension to their labels in Japan. That was several years ago. There's no movement and there's no development in PG in Europe or in the U.S. Is it used? Everything and nothing is used because there's no established standard of care. Some patients are being treated in centers that actually use combinations right away. So they give you cocktails off-label. So, Humira could be one of them. Other anti-interleukins are tried, but all off-label just because it's a pretty desperate situation. Some patients do respond anecdotally to corticosteroids and do relapse again. Some patients don't. So it's unclear what the responses look like, and there's no fully established standard of care.
Got it. Very good.
The market should say it's actually a significant opportunity at a premium price. You see a market of triple-digit million at peak, high triple-digit up to 1 billion. That's the external research that we conducted. I think it's a significant opportunity. It's a pretty rare disease, but with roughly 20,000 patients in the US and 30,000 in Europe, it is an opportunity.
Did you have buy-in from the European regulators in the study design or?
We didn't double, because the FDA was already putting the most conservative approach on us. So,
Once you have data, you probably go and sort of.
Yes.
Figure out from them. All right. Very good. I think that's all I had for you. Seems like the next, you know, 18 months or 12 months is gonna be pretty, pretty exciting.
Absolutely. We are very excited. Thank you.
Very good, Niels. Thank you, John.
Yep. Thank you.