It's my pleasure to welcome our next participating company, InflaRx, a company I've known for quite a while. It's a very interesting moment in time for the company, which we'll get into. Can't see you on the webinar. Riedemann, CFO, Thomas [inaudible] head of IR. I really look forward to the conversation. Maybe off the top, gentlemen, there's been, I don't know, I guess an evolution or a fairly major update to the strategy this year with the decision to advance development into ANCA vasculitis. It was always something that made sense, but now that's been a pretty assertive direction that InflaRx and avacopan, of course, that is being left already in Europe in its withdrawal from the market. If you could talk us through the state of affairs here, what ultimately drove your decision [inaudible] marketplace?
Absolutely. Well, first of all, thanks Steve, for inviting us. Really thrilled to be here. Great conference so far. Yeah, we did really make a therapeutic shift into the broader renal space with the key focus first and foremost on ANCA vasculitis, followed by some other indications. As you may recall, there was always an interest in ANCA vasculitis, and that is because the research very clearly indicates the role of C5a and C5aR1 in this disease. So there's quite good research. As you also alluded to, there's an accepted path that is used as an approved drug on the C5aR1 inhibition with avacopan. So that was all in the mix. But on top of it, actually Amgen was really also reporting quite good increasing sales, showing to the investors and to the street that this is a real market, which was always a bit in debate.
As you know, we had for a while in the making a new version of a C5aR1 inhibitor with izicopan, maybe to provide some solutions to some shortcomings that we spotted in avacopan. So this was all there, and all of a sudden, this disease popped back up with the announcement that we're all aware of around potential withdrawal. So we got a lot of interest back in the ANCA vasculitis space. I should let all of you guys here know that while we had done some early studies, phase II studies with vilobelimab, our antibody, we also have the licensed vilobelimab version in China called BDB-001, which is in phase III for non-inferiority pivotal trial. So there's interest. There's clear evidence that the pathway is important. Here we go. We have a very interesting C5aR1 inhibitor that has best-in-class potential. And we have a proven market.
And we have a situation where in some major markets the current competitor is already withdrawn or on hold and an unclear situation, but also with the situation in the U.S. where the FDA has recommended that withdrawal. So we don't know how this is going to play out, but completely independent of that, with the drug properties that we may speak about, we see either way, if the drug gets pulled or not, advantages, and even if it stays on the market, we think we have a really good competitive molecule to it.
Yeah. Niels, I want to put you on the spot as a pioneer and somebody who has been working in complement for a long time. I am finding that in my conversations with investors, there are a lot of people maybe that had not followed the development of avacopan and your work in ANCA vasculitis years ago as that was being moved towards market and some of the FDA interaction. They are visiting this space maybe with fresh eyes or even for the first time in many instances. I am sure you are having some similar interactions as you are broadening your conversations. So maybe from the highest level, remind us all why C5aR is the right target and is a proven target at this point in ANCA vasculitis, because I think there is some confusion as to why there is a controversy around avacopan.
It has a lot to do with data handling and trial design and features of that molecule that are specific to the molecule maybe. But I think the target is quite well-validated and certainly very rational in ANCA, but nobody better to articulate that than you. So would love to just put that over to you.
No, absolutely happy to cover that a bit. Actually it is also preclinically a very well-researched area. In ANCA vasculitis, ANCAs is an anti-neutrophil cytoplasmic antibodies. So the word ANCA implies that neutrophils are in the game. And in fact, these ANCA antibodies, they are different subtypes. They are directed against neutrophil structures that are usually inside the cell, but under certain conditions, like viral infections, that they can get on the surface of the cell. So these antibodies bind to these structures, for example, MPO, myeloperoxidase. And what happens when an antibody binds an antigen? Obviously, you activate complement. And you are doing that on the back of the very cell that has the highest density of C5a receptor 1 of all known cells. Plus, other cells have that, you monocytes, macrophages particularly.
So key cells of the immune response that actually drive damage because they have mechanisms to drive damage, like releasing granular enzymes that are very nonspecific, generating reactive oxygen species that can damage tissue, and undergoing NETosis, which is very well described in ANCA vasculitis. So that very cell gets activated by a mechanism on its back that generates more C5a. So ultimately, it is clear that everybody has almost the first go-tos, like, oh, okay, if you want to stop the damage, block the C5aR1 because neutrophils get excited, they will cause damage. They will cause damage right at the vasculature site where they get activated. And in all these preclinical models, it is very clear, for example, if you take C6 knockout mice that cannot assemble the MAC, they are not protected from damage. But if you take C5aR knockout mice, complete protection.
It is very well established, the role of these innate immune cells in the damage driving mechanism. There is some new research that also suggests an impact on antibody generation from plasma cells that there is new research out just very recently in the public domain. The mechanism could be even broader disease modifying. If you think of in the ANCA vasculitis space, there is always kind of two pillars. The one is contain the life-threatening damage right there that can kill your organ. For that, currently, we use mostly high-dose corticosteroids with terrible side effects. The other pillar is drive down this ANCA antibody production, which is, for example, rituximab targeting, and maybe also to a certain extent, the old drug cyclophosphamide. Until avacopan came around, there was really no alternative to high-dose corticosteroids. The drug is really used to drive down corticosteroids.
You hear and see that from the responses. We hear that with our KOLs, with our advisors. I think the mechanism is really ideal for a drug like ours. On top of it, I want to mention that the mechanism how renal damage is established by complement activation, there is a lot of good research pointing to C5aR driving that mechanism. It is a very recent publication that shows how acute kidney injury is driven by complement, particularly C5aR, and then how C5aR plays a key role in the transition to chronic renal disease, specifically by fibrosis induction.
This is measurable in ANCA vasculitis, presumably through the kidney function.
This is exactly the mechanism that patients suffer. They have this in ANCA, the acute kidney injury-
Yeah.
-that over time will translate into a chronic renal impact.
We will definitely circle back to that because that could be relevant in terms of how you are thinking about development strategy. But on the molecule itself, INF904, just in the context of some of the things the FDA in particular and EMA, I think we have similar visibility into some of the issues they have, things like hepatotoxicity they have been concerned about. Can you just highlight some of the pharmacologic advantages INF904 has over avacopan that you alluded to and how this molecule was designed in light of some of the learnings of the first-generation approaches?
Yeah, happy to do that. So one of the key design issues, and the key advantages that we wanted to cover is a better PK. So avacopan is a very good blocking molecule in vitro. Our molecule, by the way, has almost identical IC50 in vitro in different assays. But in vivo, the uptake in the gut into the system in animals, and in particular in humans seems to be quite difficult. The plasma presence is quite low at the beginning, and it then will, over time, reach steady state after 13 weeks. So we designed our drug to have a much better immediate plasma presence. We reported a tenfold area under the curve increase at the same dose compared to the reported data from avacopan at triple peak.
A very different presence of the drug, which we hope translates into an immediate efficacy signal block, meaning that you really have control over C5aR signaling and do not leave a gap. That was the initial driver, and we feel that our program so far has really exactly delivered that. As we saw evolving issues around the question of hepatotoxicity and the cases reported in Japan, including not just DILI cases, but also vanishing bile duct syndrome, some of them leading to death. We looked much more into that, and we found two key differences. By the changes and by our development, we created a molecule that is more three-dimensionally stable. We have an amorphous end-stage drug, not a crystalline, which may explain the better formulability and uptake. But we also have a metabolically more stable drug.
Our drug shows a magnitude difference in formation of so-called reactive metabolites. Normally, they are cracked down through the same mechanism called CYP3A4. That is a liver detoxifying engine. avacopan happens to be known to be a time-dependent inhibitor. If you imagine you are creating metabolites that could be damaging, and over time you are blocking that very mechanism that should build them down, you may have an accumulation. You may see, and that is a pure hypothesis, a drug-induced toxicity that comes from its own metabolites. That is a complete hypothesis. We are just saying we saw two differences, a magnitude difference in metabolic activity, so a more stable drug, which is derived from in vitro models that are commonly known to evaluate that, and we are not a time-dependent CYP3A4 inhibitor. We think that very meaningfully differentiates us. We have less concerns about drug-drug interactions because of that feature.
We have less concerns about creating metabolites that we cannot crack down. We have not seen in over 180 patients so far treated, I think it is close to 200 now, but just roughly, we have not seen any liver enzyme elevations. We have a very clean nine months non-human primate tox, GLP tox, so we have no liver signal. That at a pretty high exposure rate, granted only up to four weeks treatment so far. That all lets us to believe that also on the safety side, we may be meaningfully differentiated. Last but not least, the convenience side, we are packed at 30 mg per capsule, so we may have a more convenient dosing, and our modeling shows that you can switch that dosing also to QD dosing.
That is also what we will test going forward now.
Interesting. The other sort of strategic decision, and you have alluded to it before, I think including on your earnings call about potentially also exploring testing of vilobelimab in ANCA vasculitis, just given the sort of void that could be left there and the data you have in hand from vilobelimab. Given everything you just articulated about INF904 and the advantages of it, I guess what would be additive from further development of vilobelimab in ANCA vasculitis, and what kind of angle does that provide the company?
So yeah, that for us creates a potential opportunity, particularly if avacopan was pulled from the market, because as you mentioned, we are quite progressed with vilobelimab. There's a few advantages. The strategy would not to do it instead of izicopan. That's still our key focus here. The idea would be that could be the fastest to market to bridge, and maybe even develop your own market later. That mechanism with a pretty safe, so far as we know, very safe antibody, doesn't bind to liver, shouldn't deliver any liver tox. Yes, it's IV every two weeks, so certainly not ideal for lifelong dosing. But if you just want to avoid high-dose corticosteroids during remission induction, that is an opportunity you would provide. From that angle, we also have the data in China that were only released high level in a press release from our partner.
But essentially what they did in phase II, which has never been done, at the day of initiation of dosing, this was a randomized study, but open label with a control arm. At the day of dosing initiation, they completely slashed the corticosteroids to zero. Now, in the western world, we usually like to taper them out fast because of adrenal insufficiency concerns. But these data sets where they did that happened to be numerically the best data. They went back to the Chinese FDA, and the current running trial there is for non-inferiority, a phase III trial to replace corticosteroids.
What I'm trying to say is we have already a good hint that this may work with this drug. We don't have safety concerns at this point in time. As you may know, the drug's approved in Europe and has gotten an EUA for different indication in this country. Major markets and regulators have looked at manufacturing market readiness. This is all checkbox.
Yep.
That doesn't require additional investments. It creates a certain opportunity if we don't find a very fast path with the izicopan to approval to say, well, maybe we have those three, four years to bridge where we have already a mechanism.
Yep.
We could pave the market for our oral then.
In Europe, of course, TAVNEOS is already pulled from market.
It's pulled, yes.
There is indeed a void there. That BDB-001 antibody in China that you mentioned on the data for, that basically is vilobelimab. I know it's not precisely a manufactured vilobelimab that's shipped over to your partner in China, but it's the same structure and same-
Yeah.
-cell line. Yeah.
Yeah. We licensed the cell line. It's produced with their own production facility and media.
Yeah.
But it's pretty much vilobelimab produced under their premises.
Yep. Okay. Let's talk about the clinical development strategy in ANCA in general, and this could be for, I guess for either vilobelimab or INF904. First, how much interaction have you had recently with the FDA about sort of some of the proposed clinical plans that you have and some of the possible trial designs?
Yeah. We have scheduled meetings with the FDA, and we are scheduling additional meetings with them. So really active because we have these two drugs. We have the ability to be in front of them a bit more than usual, which may also be important. We have informed the FDA that we have these two drugs that we would like to discuss very early in the process. This creates an opportunity to discuss more the need and what we're trying to get accomplished from the development path perspective. It helps us that vilobelimab is quite advanced, if you will. So you have a more mature database discussion. Yeah, I think one thing that is, for us, very important, and in that sense, the entire saga around avacopan is also helpful.
It's very clear to us, to the prescribing physicians, to KOLs, there's a huge need to reduce corticosteroids in this disease. You see that from the publicly filed patient responses to the wish to-
I think just the adoption of TAVNEOS, despite its limitations-
That itself
tells you that people are anything but steroids type mentality, right?
Yeah. That's absolutely true. The pathway is very well accepted.
Yeah.
There is a clear need for this, and we think we have, as far as we know today, a potentially very ideal drug for that.
One of the things that's always been a bugaboo in the space, and that the FDA is still taking issue with is the BVAS endpoint itself, BVAS remission endpoint, and it's complicated. It needs to be adjudicated. The adjudication is what got ChemoCentryx into trouble when they started manipulating and mishandling how that was happened, and concealing when things were blinded and unblinded. Just on BVAS itself, how can you make that more palatable to the FDA? I assume it needs to be adjudicated, but how can you make sure that you don't run into confusion or issues where too many patients have to be switched and all that.
I want to maybe just high level explain that in a simple manner.
Please.
If you're a patient that has absolutely no symptoms left, it's easy, you're BVAS 0.
Yeah.
If you're a patient that has new symptoms or a clear worsening of symptoms, it's easy, it's clearly defined. You get scores, and you will have a score for that, so you're not BVAS 0. But then what people always maybe not fully appreciate or know, there's a certain number, and we cannot exactly quantify how many patients, but probably in the range of up to 30%, 35% or so that have remaining symptoms after three months of a major flare. The score clearly says after three months, remaining symptoms should no longer be scored with BVAS. They should be moved to damage, meaning you assess them in the damage index or somewhere else, but you don't give them scores in the BVAS score unless the investigator judges them as being due to active ongoing vasculitis.
That creates the ambiguity because the one investigator may say, "Oh, I have hematuria a little bit here. That's clearly for me always a sign that there's smoldering disease. I score it." The next one says, "No, no, it's three months. I move it to damage." Patients that have remaining symptoms, and they're probably one-third or so of them after six months, create that ambiguity where you want to have a consistent way to assess this, and that's why adjudication committees are used. Hopefully, that's helpful to slot it a bit in. There is a variability. It doesn't come so much just from the score but from that judgment call. Do you have that symptom because of active vasculitis or not? It's important to understand that. It's also important to understand it has been used for approval.
Disease control as measured by BVAS 0 is something accepted by the FDA, and we do anticipate that this will remain the case for the time being.
Got it.
The question is, do you show a BVAS non-inferiority plus other signals of your drug working if your attempt is to replace a drug or to create a new alternative? Or do you attempt to show superiority on BVAS itself? That's a different ballgame because, as I mentioned-
Can you expand on how you're thinking about that currently? Because obviously there's different risk levels and there's different things you can do, and there's different endpoints that you could see-
Right.
-superiority on. What's your current sort of thinking?
Yeah. I share with you a few current sources. The BVAS superiority signal that ChemoCentryx attempted to show at week 52 is a very tough one because if you think of the definition of sustained remission means you have reached BVAS 0 at week 26, and you maintain that until one year, week 52, without having a relapse in between. Now you have to first appreciate that there's not that many patients that come and lose their response. There are some, but in that trial was roughly around 10%. The world's best ideal drug that prevents any kind of relapse would bring it back to the same level at week 26, and that's just 10% delta. Week 26 is always roughly around 70%. You can do the math, like 60 versus 70, that's a 10% delta.
For a superiority powering, you would need roughly including 10% overallotment, a bit over 1,000 patients, 1,052 patients. That's unfeasible to do. I think we recently learned that they must have been powered for something like 18%. That is if you ask that to show from any company, very unlikely to happen just because of the numbers. We have to first appreciate rituximab is very good maintenance drug. Clearly, the currently used combination of corticosteroids with rituximab is yielding very high response rates. I found a famous rheumatologist who said we don't have any drug that exceeds 80% in rheumatology. These are multifactorial diseases. You don't find me any drug that gets response rates over 80%.
If you think 80% is the maximum or 70% is the maximum, you have very little chances to show on that endpoint with the ambiguity explained really a clear plus. But that's also not what the physicians and the patients need. They need to reach a good response without having to take toxic drugs.
But the conundrum is the FDA doesn't seem to see it this way always, right? And they want superiority on BVAS. That's what they've said at times.
To be-
So how do you navigate that?
Yeah, good point. To be fair to the FDA, at least from what we learned for the filings, I don't think they demanded that it has to be BVAS-
Right.
-superiority at a special week. They made several suggestions including, for example, time to BVAS.
Yep. Okay.
Since we have a very fast onset drug, there may be room to play and we're taking this renal angle here.
Yeah, tell me about that.
That there was a pretty good signal for patients that had renal involvement, which is like 70%, in this case, I think 80% of all patients in their avacopan trials that showed a renal involvement. They had a pretty good eGFR signal at week 52 at I think over 7 overall milliliter per square meter, 1.73 sq m delta. So that delta is meaningful, in the eyes of, for example, nephrologists and nephrology division. Drugs have gotten approval in the nephrology space on such deltas at week 52. If you think of IgAN, you think of C3G. So that's a possibility to say, look, we reached disease control with BVAS as shown by non-inferiority. But we may have the ability to show you activity on top. If that's really what you need, you could do it as a key powered secondary or as a co-primary.
I don't anticipate that the FDA will drop BVAS, right? That's the path that has been used for approval and is established as disease control. But if the opinion remains, you have to show efficacy on top. Then that could be a fallback. Now we will argue why non-inferiority is actually the right thing to look at, and the right precedence. But yeah, can't promise. We move into interesting discussions here.
What about just the use of izicopan, probably not vilobelimab, again, as you mentioned, just given the IV administration, but izicopan as a maintenance or sort of chronic dosing to prevent flares. Is there a possible path forward there? I know with RITUXAN, for instance, it was sort of like a staggered approval where it was initially developed for induction, and then they ran a two-year maintenance study, and came back to that application. But it seems like there's a clear use case for maintenance treatment, especially if it's not steroids and if it's replacing steroids.
Absolutely. That's the point I'm trying to make. Oftentimes when patients are in remission and now they're getting active again, they have what people classify as minor flare. So they have minor BVAS items, not just a life-threatening major organ item first. Okay, or as we talked to saying, a minor relapse is a major one caught early. We'll develop further, but the current treatment for minor relapse, also guideline recommendations, is give 20 mgs or a bit more, so an active dose of corticosteroids over a few weeks, try to taper it out. There are data suggesting that that leads to a high remission rate for these minor relapses. So patients continue to get corticosteroids as maintenance.
Whenever there's a little bubbling, flaring, they get more corticosteroids. So if you could show that you can avoid that over time, that would also mean you avoid flares just like corticosteroids do, or you could even treat minor flares with corticosteroids. So instead of with corticosteroids, izicopan. So there's a clear need beyond the remission induction. The question is how do you get to that label approval for remission maintenance? This will be ongoing discussions, but clearly you mentioned the need.
Beyond ANCA, because over the years you've done a lot of exploring in different indications and complement, including the C5aR C5a axis. What excites you about izicopan and some possibilities beyond ANCA that you could explore?
I think what excites us about izicopan, I start with the broader renal space is this is a space where complement inhibitors have been approved. Factor B, C3, right? So the renal space clearly shows complement is involved. We believe much of the damage, if not the key damage coming from C5aR. People always think of the pathway, but this happens in seconds, right? So the effector when you block upstream may be C5aR. And what would excite us about it, and there's reasons to believe that that's true. Avacopan was tested in C3G, small studies, but still good signal on UPCR, was tested in IgAN, also signals. What excites us is we're providing an oral option without the need for vaccination, and as of today, we do not believe we drive meaningfully up like an infection risk. That's also true for C5a, our antibodies.
All of a sudden, you don't need to vaccinate anymore. All of a sudden, vaccination doesn't prevent the additional risk of infections outside the vaccination space, which is still existing. So you could have, if you will, the best of a complement inhibition, leaving the bacterial defense fully intact. And that would be a big advancement, even in spaces where there were renal drugs approved. Now, you know I have a passion beyond C5aR inhibition in the renal space. We had some very interesting early data sets in CSU, particularly in HS.
We are pausing this right now. We focus clearly on renal, but we believe the drug is very active. The pain signal, for example, we got in HS, I don't think has ever been shown to that extent.
We hear that back from patients that have been dosed and tested. I think there is a clear broader I&I game, but we need to bring this drug to first approval, and I think ANCA is such an established path already with a big enough market already shown that that seems to be ideal and a bit de-risked compared to the other.
Yep. What about near-term sort of timelines and guidance that you're setting for phase II? When can some of these programs kick off?
Our base case, that is a phase II study, if we cannot get to a faster, seamless, or direct to phase III approach. That's already ongoing. We're choosing CRO, doing all the prep work, and we said we would like to initiate first sites and so on early next year.
Okay.
That's all going on. The base case is running. We're also working towards a small aHUS study, which is an interesting paradigm shift. Again, what is the effector damage function? Is it the MAC or is it maybe C5a, C5aR platelet aggregation and vascular damage? We believe that could be. And we talked about a renal basket, which we haven't fully defined yet. There will be data coming. But of course, the most pressing part is to get the ANCA development going, get it going and start the trial.
Terrific. Well, we'll look forward to that progress. And Niels and team, thanks so much for the conversation. Appreciate having you at the conference this year, and thanks to everyone for listening in.
Thanks so much for having us.
Thanks.
Thank you very much for having us.