An ability to start that trial before the year-end. Obviously, we'll also hope to present the phase 3 data at the American Transplant Congress in June.
Awesome.
Quite busy.
Yes, very busy. Let's start kind of high level setting, the product profile for imlifidase. I mean, one of the key differentiating aspects here is speed of onset. Maybe just walk us through why that matters in highly sensitized kidney transplant patients and guess how the onset compares to some of the other desensitization approaches, none of which are approved but are used in clinical practice?
Sure. Here, obviously, 80% of all kind of kidney transplants are done with donated donors, I mean, dead-- diseased donors, donor organs. That basically means that you have a limited amount of time to actually transplant the organ to keep it viable. This basically means that in this case, a lot of these patients who are considered to be highly sensitized, these are patients with a so-called CPRA score above 80. They a lot of times will be on dialysis on the wait list for very many years. The median kind of year that they're on wait list is seven. I mean, they wait for a very long period of time.
Quite a few of them also actually die on the wait list or get moved off the wait list because they are no longer transplantable. In this case, obviously, it's finding that it's for the actual kind of clinical trial we ran, these were really patients with a 0.01% chance of ever finding a kind of a natural match. As you can imagine, that's a, you know, very poor outlook for these patients. In this case, obviously, you don't have that much time, and you really, you know you have an organ, you're gonna call the patient, get them into the hospital, and you have a very limited time in order to actually do the transplantation in order to keep the organ viable.
In this case, imlifidase really kind of reduces IgG, all four classes, intravascularly, extravascularly, within two-six hours by more than 95% from baseline. You really kind of very, very quickly and rapidly cleave all IgG across all parts and actually kind of end up in a situation where you can turn that cross-match positive organ to a negative cross-match and thereby actually proceed with the transplantation. You cannot really proceed with a cross-match positive transplant, as that will kinda really have a hyperacute rejection. This is actually why it's very important in this case to be able to do this in a predictable, consistent, and safe way and very rapidly in order to enable this transplant to go ahead.
That makes a lot of sense. You mentioned the ConfIdeS pivotal data. Maybe just, touch on highlight like key takeaways from that data set, and what do you feel is the most underappreciated, part of that data readout?
That really goes back to part of your kind of question before, which is, so what is being used today? I think this control arm really shows that, you know, there is no real standard of care today. There is no way of really kind of desensitizing these patients. If you look at actually the control arm, physicians there could use pretty much anything that's available today, IVIG, Plex, Rituximab, Eculizumab, etc., to kind of like before or after, during. There was a fair amount of kind of, you know, ability for physicians to try to kind of have exploratory protocols. Out of those 32 patients in the control group, only three of them actually decided that they could progress to transplant at randomization.
You can imagine these are patients with a very low probability of ever getting an organ offer. They're on dialysis. Despite that, they're in a clinical trial, which we know also generate, you know, even higher kinda levels of kinda results generally. I think the fact that you only had three kind of out of 32 patients who did that despite being so highly kinda motivated, I think really shows that this is really something that is a significant unmet medical need, and there's really nothing out there today. If you look at the outcomes, 'cause obviously the primary endpoint was kidney function, at 12 months after randomization.
In this case, if you look at those 27 patients who actually all progressed to kinda transplant or randomization in the imlifidase arm, their eGFR was around 59.3 mils per minute at 12 months. Obviously, that would indicate that that was, you know, a very, very good performance from a kinda kidney function perspective. If you look at those three who basically kind of were randomized with other types of desensitization approaches, their eGFR was 23.1 mils per minute. I think the clinical point, trial points to two things. One is that, you know, there really is no standard of care. There's no kinda consistent, predictable, and safe way of doing this.
If you try to do some of these things, I think you run a high risk of having unsatisfactory outcomes. I think that really kind of points to both the unmet medical need as well as the, you know, significant opportunity that's out there for imlifidase.
I wanna follow up on the outcomes part of that story 'cause durability here is really important. This is a product that has been approved conditionally and used in Europe now for quite a while. Maybe just remind us of, I guess, the kinda the most important long-term follow-up evidence that you have that supports that treatment with imlifidase actually results in better long-term graft function and outcomes ultimately.
The company's run, you know, like 10 different kinda clinical studies prior to this. Quite a lot of kinda smaller phase 2 trials. If you actually pool those patients, they were pooled and followed for a five-year period. What actually that shows is that in terms of performance, this is virtually identical to the performance that we would expect for, you know, a non-highly sensitized or natural matched kinda transplant patient. There's really no difference in terms of the long-term outcome for these patients compared to those who find a natural match, which I think is very important. We know that obviously in nephrology in general, you would say that actually the 12-month eGFR has a you know, very, very high level of predictability in terms of long-term outcomes, and that's exactly what we've seen here as well.
In terms of the actual kind of, ConfIdeS trial, we will obviously continue to follow all these patients up until five years, but we feel very confident about that long-term outcome, considering the excellent kinda 12-month data that we saw in the trial.
Great. I wanna talk for a minute about regulatory and, obviously, the FDA, we've all seen the headlines. It seems to be fairly tumultuous environment at the moment. Maybe, just high level, just describe, like, your regulatory interactions, I guess level of alignment with the agency around ConfIdeS and approvability.
Sure. The trial was actually I think the FDA was very influential in terms of designing this trial. Obviously, I wasn't here, but just Lick, Licken can kind of have the history and the minutes. There was quite a lot of debate, particularly with KOLs in the area, who felt that having a control arm when there is no standard of care that's accepted, was kind of a very odd choice. There was quite a lot of conversations about this. I think the FDA was very adamant about the fact that there needed to be a control arm.
I would say that actually this is something where the FDA has, you know, consistently been very engaged in this, and I think has had a very kind of strong voice in terms of how they wanted this kind of clinical trial to be run, and designed. I think what we've certainly found in the very kind of, you know, the interactions that we've had, you know, recently, I would say that those interactions have been very positive. I think it is, you know, so far, I think all that we've heard from the agencies that they're very supportive and they are, you know, they're impressed by the results that, you know, the clinical study has generated.
Got it. We submitted the BLA. We learned on, I think it was February 18th, BLA acceptance.
Mm-hmm.
I think you learned with your day 74 letter, standard review versus priority review. Maybe you could talk about, like, I guess, like, any insights into why we landed with standard review rather than priority review.
I think we don't know exactly. I mean, I do think that it was clear kind of at the day 60 that, you know, there was clearly some conversations ongoing internally in the actual FDA. I think that, you know, the fact is what they were not really willing to be drawn either way on whether they had decided on what kind of, you know, review kind of pathway. I think it's clear to us that there was some internal debate and discussion. Why and how and what that related to is a little bit unclear to us. I think that, you know, they have kinda kept on, you know, it reiterating to us that, you know, they want to try to be as collaborative and helpful as possible.
They wanna maximize the chances for this drug to be approved. We don't really have any reason or any kind of information to believe that this has anything to do with the clinical package or anything that we've seen. You know, we don't really know.
Right
I guess, is the answer.
Okay, that's fair. One of the other things we typically learn with BLA acceptance and subsequent communication is whether they intend to convene an AdCom, I guess, like any indication from the agency that they would like to form an AdCom to discuss the application.
They have made it clear on the letter that they do not foresee the need for an AdCom.
Okay.
We do not expect that.
Okay, cool. Let's talk about commercial opportunity. You've highlighted a relatively concentrated set of centers in the U.S. that we could initially target that do a high volume of kidney transplants. How do you think about, I guess, like, initial launch footprint and resourcing around the launch?
Do you wanna take that?
Sure. In the U.S., we have roughly 200 centers that do adult kidney transplants. Out of those 200 centers, 100 centers represent 80% of the volume. If you think from that perspective, it's a very concentrated coal point that we estimate would require sort of a field team of 15-20 people on the commercial side. The other thing I would highlight is that among those 100 centers, 25 of those participated in the ConfIdeS trial that Renée just described. There's a high level of clinical knowledge and clinical experience of the product, of the mode of action, of how to treat these highly sensitized patients.
That's great. Maybe if you could just walk through some of your other pre-commercial activities, payer engagement.
Yeah.
How are we thinking about the potential to price, I guess, within the procedure code? There's obviously, add-on payment.
Yeah
...potential. Yeah, like, walk us through the other work that you've done preparing for a commercial launch.
Sure. The pre-commercial work is really focused on the medical affairs aspect and the market access work that we're doing. From a medical affairs perspective, we're focusing on identifying who are the stakeholders within each of these centers, particularly the top 100 centers, and getting to know the multidisciplinary team that will take care of these patients, you know, once the product hopefully is approved. From a market access perspective, we know that this is an inpatient treatment, kidney transplant is a DRG code today. What the transplant centers do is that they also submit them for outlier payments to CMS if there's anything in addition to that, what the DRG code is covering. We expect that we will be treated the same way to fall into that DRG code and outlier payment.
The other thing that we are doing is that we are applying for, we will apply for NTAP, New Technology Add-on Payment, later this year. You know, we think we have a great chance of getting that if you look at the criteria for NTAP. That will then give these transplant centers an additional reimbursement, in addition to the DRG code.
Awesome. Okay. Wanna come back to the conditional approval in Europe, maybe you could just comment on some of the learnings from that initial commercial experience. It's obviously, it's very different. This would be, you know, not conditional-
Yeah
...approval.
Yeah
...in the U.S. Just talk about some learnings from the Europe commercialization, how you plan to apply that.
Sure. I think there's some structures in Europe that were quite different. I'll have Maria address kind of the learnings that we can draw. I think, you know, what you have to remember in Europe was that when the company took this to EMA, it was basically on the basis of a single arm, open-label 14 - 16 patient trial. Only two centers in Europe were actually kinda ever involved in kinda phase 2 trials, and the rest was kinda really in the U.S. There was very, very limited clinical experience and clinical understanding because you really hadn't involved. There was no kind of European KOL advisory board or kinda that clinical understanding. This is obviously a patient population, as we've just shown in ConfIdeS, that, you know, physicians don't really have an opportunity to treat these patients today.
It's a little bit like you're trying almost to avoid doing this because there really is no way of doing this safely. It's a new kinda way of really kind of addressing a patient population with kind of a high unmet need. Generally, what you would expect is that you'd have some fairly robust clinical data in order to kind of, you know, convince physicians and have them had gone through that kinda clinical experience. It's kind of an unusual setup from that perspective. I think the company's done a great job in terms of creating guidelines, getting reimbursement, very broadly reimbursed in Europe. You know, the list price in Europe is about $350,000 per treatment.
I think that from that perspective, you know, the revenues that have been generated in Europe to date over the last three years, I would say is more like a pre-launch or kind of a soft launch, because really you know, the clinicians really learned about the product through the phase 3 trial. That was really kind of the first time that they were often introduced to the drug or used the drug, and that trial was fully recruited in March of last year and will read out in the middle of this year. I think it's a little bit of an unusual kind of setup in Europe, to say the least. We have certainly some learnings from there.
Yeah. I think one of the key learnings is that clinical experience matters. As Renée mentioned, there were two centers in Europe that had experience when we got conditional approval many years ago, and that's quite different compared to the situation in the U.S. today. The 25 centers that have been participating in ConfIdeS, they represent 25% of the transplant volume in the U.S. You already have a lot of clinical experience, not only with the surgeons, but with that multidisciplinary team that includes your nurses, nephrologists, HLA directors, and I think that puts us in a better position compared to the situation in Europe.
I would say the other thing relates to reimbursement, and we all know how fragmented Europe is and the challenges, and the company's done an excellent job in terms of gaining reimbursement and actually proving that it is cost-effective or cost-neutral in many cases to use imlifidase in this population. The difference in the U.S. is although pricing and reimbursement, all this is complex, it's, you know, it's in the U.S., it's covered through Medicare. It's a DRG code. We know that that pathway has been well established with other inpatient drugs before, such as Tecartus. We feel sort of confident from market access perspective and the clinical experience perspective that we are in a better position in the U.S.
I would say the third thing is also, as Renée said, you know, since both of us joined, we brought in people in the U.S. organization that have experience, that have recently launched in the U.S., that have transplant experience, that have experience in nephrology. I have many members of my team that have actually worked in a transplant center, have been doing this job on the other side. I think that is gonna help us as we look to bring EMFLAZA to the U.S. market.
That makes a lot of sense. Wanna come back to the confirmatory study that you mentioned that reads out in the middle of the year. Maybe just remind us of the design of that study and help kind of set expectations ahead of that readout.
Sure. It is a single arm. Basically it's say 50 patient transplant across Europe. It's about 23 centers, mainly our large academic institutions in Europe. EMA really required this to be a pan-European study, with 50 patients being transplanted that are highly sensitized. There isn't a particular cutoff in this, in this trial. It's really up to each center and each to kinda like to practice medicine, and to include those patients who they think, you know, would warrant to be included and transplanted. In that way, slightly different clearly from the US trial. It doesn't have a control arm. It doesn't have any specificity in terms of exactly what kind of patients need to be included.
I think there's already recognition in Europe of the fact that there is a high unmet medical need here. What the other thing is, though, that there is a kind of collection of data at the same centers of other transplant patients who are not highly sensitized. It's a bit of an unmatched kind of. There is data for the EMA to look at in terms of kinda what's been the outcomes in general in kinda transplant for these centers. There is something for them to compare to, but it's not kind of a matched arm, I would say. There'll be about 100 patients in that kind of data collection. The endpoint is very similar to that of the one in the U.S.
It's basically graft failure, free survival or eGFR at 12 months. Obviously, to the extent that if you think about the US trial, to the extent that patients were on dialysis in either arm, but in that trial, that would be counted as zero, right? That would basically kinda say that, you know, obviously, if your graft wasn't working, or you had graft failure, then obviously you'd be back on dialysis, and that would be counted as zero. In this case, it's very similar, and that's kinda again, that kinda 12-month period, when they're looking at kinda graft free, failure, graft failure free-
Interesting.
which is the same really as eGFR.
It's essentially, like a non-inferiority margin versus the external control or like.
Because it's not a matched kind of.
Yeah
They haven't really kinda set it up in terms of. It's more kind of a, as a reference, I would say.
Mm-hmm.
That EMA is looking at it as a kinda reference to kinda look at risk-benefit broadly across the two groups. There's no kind of exact number that, you know, needs to be reached because it's not, it's more... Yeah, it's not like a matched-arm, if that makes any sense.
It makes sense. Okay. Wanted to ask about potential use outside of kidney transplant. You, you had, I think with the last earnings call, a very interesting anecdote of use. I believe it was a lung transplant patient.
Yeah.
Maybe you could just talk about, I guess, your expectations for use kinda outside of this core kidney transplant setting and how you think, particularly in the U.S., where it seems like transplant centers have quite a bit of freedom in terms of how they manage their patients.
Yeah.
Like, how should we be thinking about potential use in, like outside of kidney?
Yeah. It's interesting now because there has been kind of case studies that have also been published, both in lung and in heart and liver kind of transplants, because obviously the drug per se is obviously organ agnostic. There's nothing that makes this drug specific to one solid organ transplant versus another. This drug only does one thing. It very efficiently cleaves IgG very rapidly. I think that's why what we've seen is we've seen kind of compassionate use requests, and we've seen kind of physicians who've published case studies on other kind of solid organ transplants. In Europe, there was some of these kind of In France, I would say they were one of the two centers that were part of the phase 2.
They had, was one of the countries that actually had some clinical experience early on. What we've seen is that that country is one of the ones who clearly has a very broad use of the drug for the reason that they felt already quite comfortable to actually use the drug and knew how it worked. We've had kind of physicians there who've been conducting lung transplants, and they actually independently went to the French government because obviously this is a socialized medicine structure. They went to the government to actually ask for full reimbursement of imlifidase to be used in lung transplants as well. The French government granted this in November of last year.
It's almost like, you know, the government is actually kind of fully reimbursing lung transplants as well, being, you know, in the use with the use of imlifidase. That will obviously be very interesting to follow, because that will obviously also be, you know, will be tracked by the government there. You know, they will know exactly how much they're spending on lung transplants as well. I think that that is something that's not so surprising. Obviously, we've had also here kind of, you know, compassionate use requests for other kind of solid organ transplants.
We've also had, the company previously ran an investigative study in AMR, so antibody-mediated rejection, which again I think is something that we get a lot of questions from physicians in terms of if you have something where you have a transplant, you have a patient, and you're seeing that this is running a high risk of antibody-mediated rejection, would you then actually use this drug to kinda control that patient, preserve the organ, and actually kinda have a higher probability of retaining that kind of graft? I think that there are quite a lot of kind of different areas where this could be used, but obviously our focus at the moment is to get this approved in kidney.
Once we have that approved, we can have plans to go back to the FDA and explore with them what would they require for us to potentially have a label expansion into other solid organs. You know, we have to take one step at a time, obviously. There's clearly a lot of requests coming to the company at this point in time, so.
Yeah. That's great. Makes sense.
Mm-hmm.
Let's switch gears and talk about your next-gen IgG protease, HNSA-5487. You've generated some phase I data. Maybe just kinda remind us of the TPP product goal for this next-gen candidate and then what you saw out of the phase I experience.
Sure. This is an enzyme that's derived from a non-human host, therefore significantly less immunogenic, which means that there is far less ADAs being generated and also that it can cleave through, you know. It's also more potent and durable, so it can actually cleave through very high levels of titers. This was really developed with a view to, you know, having that kind of less immunogenic profile. What we can see in the actual phase 1b trial that was run is that, you know, after administration, it was actually effectively cleaving through. After six months or so, it was actually cleaving through effectively 100% of all ADAs, so it would enable that redosing potential.
I think that originally when this was kind of designed, I think this was obviously before you ended up having quite a lot of maintenance-related treatments in some of those kind of crisis and flare-type autoimmune diseases. I think that was probably the original kind of thought of this profile. I think what we're actually doing now is we're taking this into rare autoimmune diseases with a focus on neurology. Starting with Guillain-Barré, where there's a significant unmet medical need, and there's really nothing approved today. It's a fairly substantial rare disease. This obviously gives us kind of, you know, another enzyme with those kind of characteristics that provides us with an ability to build a completely separate franchise from imlifidase.
So keeping imlifidase really in the kind of kidney transplant and gene therapy space, and really kind of creating a separate, kind of with different IP, different pricing abilities, different partnering opportunities in kind of, you know, neurology and rare disease. I think that from a kind of market, kind of addressable market situation, obviously with 100,000 patients on the waiting list in the U.S., out of which about 15,000 are, you know, highly sensitized. Imlifidase as a kind of standalone market opportunity is obviously very substantial just in kind of kidney transplant. If you can think about, you know, that type of, you know, pricing per treatment with these type of kind of, patient numbers, that is already, I mean, I think, a very substantial kind of product opportunity.
Instead of just having it kind of be, you know, broader, we've just chosen to kind of create a different franchise with more kind of flexibility and partnering opportunities in autoimmune disease.
That makes sense. You have some experience with imlifidase and Guillain-Barré.
Yes.
I guess in this engagement with FDA that we're expecting next quarter, like, is there a potential for a more streamlined development path? thinking about in this construct of trying to get novel therapies in the hands of rare disease patients, and maybe only one study-
Yep
... needed for approval. Like, how are you thinking about the path forward?
I think, I mean, because we have had that kind of strong proof of concept already in a phase 2, and we've obviously had quite a lot of kind of KOLs who are very supportive of this mode of action and the safety profile that they've seen in that study, they've been extremely kind of helpful in terms of trying to really help us design a trial that is as kind of streamlined and kind of, you know, constructive as possible. It'll be very interesting to see kind of what the FDA's feedback is. In light of a lot of these kind of discussions and things that we hear from the FDA, I don't really know if that's gonna translate into actual action from the FDA.
This will be an interesting kind of, you know, case to see what kind of feedback we get and if they are indeed willing to kind of support what I think is, you know, an innovative and an interesting kind of design. We will know more, yeah, in next quarter, we will know more from that feedback and interaction.
Yep. We'll stay tuned on that front. Maybe just in the last 30 seconds or so, you're also exploring imlifidase in a gene therapy-enabling-
Mm-hmm
... setting. You have a number of different partnerships. Maybe you could just give us quick soundbite update on that aspect of the imlifidase program.
Sure. This, again, is the same thing obviously. It's the imlifidase cleaves kind of very rapidly you know, down to less than kind of 5% of those existing AAV antibodies, which is a challenge for a lot of gene therapy companies, particularly on the AAV8 - AAV9 kind of areas, which really prevents them from kind of including patients in clinical trials or actually having a full kind of commercial opportunity, because there's a high percentage of patients, you know, whose antibody profile really, you know, prevents that and they ends up being excluded. We have some clinical data towards the end of last year with our partners, both of our partnerships, Sarepta and Genethon.
I think actually what we're seeing is as these gene therapy companies get kind of closer to, you know, kind of bigger trials, phase 2 trials, to becoming like bigger into kind of commercial, there is a lot of interest to try and obviously make sure that they can reach these patients, both in a clinical setting as well as in a commercial setting. There are quite a lot of kind of conversations ongoing, and I think that will to some extent also be driven by, you know, how the regulatory environment ends up for these companies in gene therapy. I think we're certainly having quite a lot of conversations and would hope to, you know, during this year, hopefully kind of strike some more partnerships in the gene therapy space.
That's great. All right. Perfect. Well, we're up against time.
Yeah
thank you.
Yeah
... Renée and Maria for joining us and sharing the insights. We'll be tuned in here in 2026. Exciting year.
Great. Thank you.