Hansa Biopharma AB (publ) (24H.F) Earnings Call Transcript & Summary

Good morning, and welcome to the Hansa Biopharma virtual KOL event. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Hansa's website following the conclusion of the event. I'd now like to turn the call over to Renee Aguiar-Lucander, Chief Executive Officer of Hansa Biopharma. Please go ahead, Renee.

Thank you very much, Tara, and welcome, everybody, and thank you for attending this webinar on our recent Phase III trial data and for the discussion to follow. And obviously, a very special welcome to our highly distinguished guests, Professor Montgomery from New York Langone, in NYU Langone Transplant Institute and Professor Cooper from the Medical College of Wisconsin. Thank you both for taking time out of your very busy schedule to share your insights with us here today. Next page, please. I refer you to the fact that we may be providing forward-looking statements in this presentation. I ask you to refer to our documents on file. Next page, please. This is the agenda for this webinar. The presentation will take a total of about 15 minutes. It will be followed by around a 25-minute discussion with our distinguished guests, after which we will open up for Q&A. I will now give a very brief introduction to those of you who may not be that familiar with Hansa. Next page, please. Hansa is built around a novel, unique and first-in-class IgG-cleaving platform with a lead product candidate imlifidase as well as a next generation enzyme 5487. Imlifidase is extremely efficient at cleaving IgG both intravascular and extravascularly and reduces IgG by over 95% from baseline in just 2 to 6 hours from administration. It's highly selective with no identified off-target activity and is therefore very well adapted to address situations such as acute flares or exacerbations. Next page, please. The platform is uniquely positioned really to treat these serious immune-mediated diseases or challenges due to this very rapid IgG reduction. So in comparisons to FcRns, for example, these enzymes do provide this immediate and significant reduction that allows for both a faster and deeper impact on IgG. Obviously, antibodies level will recover after about a week from that kind of deep reduction. Next page, please. So Hansa is really presently pursuing some key rare indications where there are significant unmet medical need. This includes desensitization before kidney transplantation for highly sensitized patients as well as desensitization for patients eligible for gene therapy, but who might be excluded due to high levels of antibodies against AAV vectors. Finally, we've also generated highly promising Phase II data in IgG-mediated autoimmune diseases such as anti-GBM and Guillain-Barre syndrome and we are planning to read out top line data from our randomized controlled Phase III trial in anti-GBM later this year. We recently read out kind of positive Phase III data in our randomized controlled U.S. kidney trial with a p-value of 0.0001, and we plan to file a BLA before the end of this year with the FDA and building out our commercial presence, which we already have in Europe based on a conditional approval for highly sensitized patients. And we have a cash runway into 2027 following a successful capital raise recently. Next page, please. In terms of the actual kind of market opportunity with regards to kidney patients, highly sensitized patients in the U.S. face great difficulty in finding a matching organ due to their high levels of antibodies. And so there is a significant unmet medical need, which imlifidase hopes to address. Today, there are about 100,000 patients on the waiting list in the U.S. and about 15% of those, about 15,000 or so are categorized as being highly sensitized, which is then looking at a so-called CPRA score above 80%. In the study that we conducted, we conducted this in the very, very highly sensitized group with a CPRA score of over 99.9%. There are about 7,000 patients with the CPRA go over 98 and about 3,500 patients today on the waiting list with a CPRA score above 99.9%. So against this backdrop, obviously, these patients stay on the waiting list much longer than the average kind of patient on the waiting list. It can be up to 7 years for these highly sensitized patients. And we do know obviously, that the community is really looking for a solution for these patients because obviously, as we know, staying on dialysis for extended periods of time is a very difficult situation for a lot of these patients, obviously. So against this backdrop, I'm going to hand over to Dr. Richard Philipson, who is our CMO, who will take us through the results of the ConfIdeS trial and get some insights from our guests in the discussion to follow. Next page, please. Richard, over to you.

Thanks very much, Renee. So before we move on to the discussion with Dr. Cooper and Montgomery, I'm going to start by presenting a short summary of the efficacy and safety outcomes from the ConfIdeS Phase III study. This was an open-label randomized controlled study evaluating kidney function at 12 months as measured by estimated glomerular filtration rate or eGFR, in highly sensitized kidney transplant patients treated within imlifidase prior to transplantation compared to a control group. So I'll begin by just presenting a brief summary of the study design. Patients considered potential candidates for the study were consented and entered a prescreening period. One or more of the unacceptable antigens were delisted from the patient's HLA profile to increase the likelihood of the patient receiving an organ offer. When an organ offer was received, patients entered screening and underwent a final evaluation of eligibility. Eligible patients were then randomized to the imlifidase arm or the control arm in a 1:1 ratio. The period of follow-up in the study was 12 months from the time of randomization. Patients randomized to the imlifidase arm accepted the organ offer and were treated with imlifidase. If treatment resulted in crossmatch conversion from positive to negative, then patients were transplanted and entered follow-up. Patients randomized to the control arm either accepted the organ offer were treated with nonapproved desensitization and then proceeded to transplant or the organ offer was rejected and the patient waited for a more compatible organ offer or offers later in the 12-month follow-up period. A total of 64 patients were randomized in equal numbers to either treatment with imlifidase or the control arm. So there are 32 patients in each arm of the study. Two patients randomized to the imlifidase arm did not proceed to treatment. In one case, the organ offer was refused. In the other case, the patient withdrew consent to be treated with imlifidase. The overall rate of completion of the study was excellent, a total of 58 patients or just over 90% in the study completed the 12-month follow-up period. The treatment groups were balanced with respect to sex and age. Overall, there are almost equal numbers of males and females in the study, and the mean age of the study population was 45.3 years. The treatment groups are also balanced with respect to race and ethnicity and representative of a highly sensitized kidney transplant waitlist population. With respect to the primary efficacy outcome at 12 months, mean eGFR was 51.5 mls per minute in the imlifidase arm compared to 19.3 mls per minute in the control arm, with a statistically significant and clinically meaningful difference between the 2 groups of patients of 32.2 mls per minute with a p-value of less than 0.0001. This outcome reflects the excellent graft survival that was observed in the imlifidase arm. When looking at 2 of the supportive analyses of the primary end point, these provided outcomes consistent with the primary analysis. So when we performed an analysis of 12-month eGFR using a nonparametric test that does not assume normally distributed data, the outcome remains statistically significant. Similarly, when we look at 12-month eGFR in patients transplanted based on organ offer at randomization, again, the outcome remains statistically significant. These supportive analyses of the primary endpoint give us additional confidence in the robustness of the primary analysis. Also of note, a key secondary endpoint of dialysis dependency at 12 months was statistically significant with a p-value of 0.0007 in favor of imlifidase. In terms of the safety outcomes of the study, the tolerability of imlifidase was good. There was a low incidence of infusion reactions and no infusions were interrupted due to an infusion reaction. Infections observed in imlifidase-treated patients were typically not related to treatment and the adverse event and serious adverse event profile of imlifidase reflected a population of patients undergoing kidney transplantation with most serious adverse events considered unrelated to imlifidase treatment. So I'd now like to move on with -- following the conclusion of that presentation, I'd like to move on now and open up the discussion with Dr. Cooper and Dr. Montgomery. So perhaps I can open this discussion with you, Dr. Cooper. And I think it would be really helpful if you could first please describe what receiving a kidney transplant means for patients with end-stage kidney disease who are on dialysis, particularly in terms of the clinical outcomes, the quality of life changes and the long-term prognosis.

Thank you. First, let me start by saying I really appreciate this opportunity to be here. 25 years into the practice of transplant, I can say this is one of the most exciting potential opportunities that I've seen in my entire career and also a privilege to be here with Dr. Montgomery, who was one of my attendees when I started this field. So it's, again, very exciting. So to answer the question, I -- when describing to patients or to anyone who is interested in hearing about the kidney transplant and end-stage renal disease, I describe dialysis and transplant as the pure apples and oranges comparator. They really shouldn't be in the same sentence. Individuals and some of the data was shown will wait for years for a kidney transplant. Many of them will not receive a transplant. They'll continue to suffer the complications associated with what brought them to end-stage renal disease, most often as being diabetes and high blood pressure, increased risk of peripheral vascular disease of strokes and of heart attacks and then the ability to receive a kidney transplant, albeit in this highly sensitized patients, waiting sometimes for some up 5 to up to 8 years. I think most data would show. It is a really life-changing experience for them. Dialysis patients will tell you that their entire life revolves around either presenting to a dialysis center, so 3 times a week for 4 hours each session. Home dialysis or home peritoneal dialysis, all of that requires a significant demand, a significant change in lifestyle, challenges in holding steady and regular job, inability, for instance, to go on vacations, all the things that probably you and I may take for granted. But the transplant really gives people the opportunity to return back to life. The data would show that the 5-year survival on dialysis is around 45%. The survival with transplant, again, is so much better and the data -- early data in the imlifidase trial, which we'll talk about, begins to show that those same statistics. And so again, I think that this is really revolutionary for individuals who come to our transplant programs looking for an opportunity better than dialysis or the fear of dialysis. And for the longest time, the numbers and the percentages, and we can get into the CPRA would show that their opportunity for sensitized patients in identifying a suitable candidate donor organ is almost limited to really to none. And so again, this is a major change for us. It gives us a different way to converse with patients. It gives us hope to be able to tell people when they come to us that we're going to give them every opportunity to have a life free from dialysis. So apples and oranges, dialysis to transplant, highly sensitized our options in the past to what we have with imlifidase the same way. So very, very different.

Thanks very much. And I think that really paints the picture of the transformational impact of undergoing a transplant for patients who are on dialysis. So perhaps turning to you, Dr. Montgomery. Again, thinking of that kidney transplant setting, now turning our attention to highly sensitized patients. Can you just take a moment to describe how highly sensitized patients are waiting for kidney transplant, how these patients currently manage, what their treatment options are for desensitization and what the unmet needs are for these patients? You're on mute.

So first, I just want to say hello, and thank you all. And it's great to be here today to talk about something that I think is extremely important for our field and particularly for a group of patients that when I started working with these patients in the 1990s, we're essentially warehoused on lists with really no hope of getting a transplant. So you probably know that in 2014, we had a change in our allocation system that gave extra points, priority points to patients who were highly sensitized. So just to sort of get a nomenclature sort of wrinkle that I think a lot of people don't understand out of the way. If you are greater than 99.5% sensitized, you're referred to as being 100%, right? So it's -- we round up to 100%. So if you're 99.5% or less, you're 99%. So I think the important thing is to really focus on this group of patients. These 100%-ers are actually quite different in terms of how much the new allocation system, which is not so new anymore, has helped them. And we did a study published in 2019 Schinstock et al. in clinical transplantation, which really looked deeply at this because I think what happened was with the new kidney allocation system, most groups stopped doing desensitization because they thought that we had a solution to this problem. And in fact, when you really look at what's happened to these patients who were 99.5% and above, you will see that there really has not been a transformative change in their access to organs. And this is particularly true for the patients who were included in this study the FDA felt strongly that we should look at the most disadvantaged patients. These are the patients who are 99.9% or above. And as mentioned earlier, this is about 3,000, 3,500 patients. And on average, these patients will receive 1 organ offer every 10 years. So 0.1% -- or 0.1 offers per year. And really, for these patients, there -- the likelihood of getting a transplant is ridiculously low. If we drop down in each of the categories below that, down to 99.5%, you do see that the transplant rate increases a bit. But if you look at that whole group, the waitlist mortality at 5 years is 50%, and that has not changed. In fact, anybody with a CPRA of greater than 98% has had no improvement in waitlist mortality. So half the patients are dead at 5 years. And the other sad thing is we used to transplant a lot of these patients with living donor transplants. And we don't do that anymore, only 1.4% of the patients who were 99.5% or above got living donor transplants, the best quality transplant. So in conclusion, what I would tell you is the -- really, things have really not changed for this group of patients. And that's what's so exciting about this opportunity because we have the first drug that has been approved for getting these patients transplanted. And you can see that when you receive this drug, there's close to 100% chance that you're going to get a transplant. And that is a dramatic difference.

That's very helpful. And I think -- so I think we've kind of painted the picture of the positive -- many positive impacts of kidney transplantation and the very limited options there are for highly sensitized patients and how long they do remain on the waitlist waiting for a transplant. So maybe we can now turn to the results that are being presented today. And I'd like to ask each of you in turn what your key takeaways are as a transplant surgeon and clinician working in the field of kidney transplantation, what your key sort of takeaways are from these data. Perhaps I could start with you, Dr. Cooper.

So Dr. Montgomery outlined the problem extremely well. And like I said, having the privilege of working together at Johns Hopkins at the turn of the century trying to care for these patients with the nonapproved, and I think that's the right word, non-approved desensitization techniques that were available at that time. It was a very, very difficult road to travel with the patients, and that's an important piece. We, as clinicians want to do everything we can to provide patients the opportunity when they come to us. And so desensitization with interventions such as apheresis and excuse me, plasmapheresis and IVIg were very challenging and required significant follow-up and an appreciation that there was a high risk of complications, including antibody-mediated rejection. But certainly, as mentioned, that was the only option and we felt necessary to provide patients with that option, the results of this current study now allow me to say that there is a much better option for these very complicated patients that while still requires very close follow-up of these patients, and we can't ignore the fact that these individuals have a breadth of antibody that demands close follow-up after their successful procedure, but at the same time, also gives us a much clearer pathway into the operating room and immediately thereafter. So when I first look at the data, as mentioned, these are a group of patients that before the numbers of transplants would have been close to 0. And as our data demonstrates, the patients that were randomized to this arm of the trial, in fact, did receive a transplant. So number one, that's hope. And number two, we have now 1-year data that demonstrates not only are patients being transplanted, but the outcomes of those transplants are consistent with others who have received a deceased donor organ and with an eGFR that is comparable. And so we're not substituting poor outcomes for just the ability to transplant. We're not only transplanting, but we are seeing patients receive the benefit of that organ. And while these are early data, 1-year outcomes, there is, I think, significant data and significant publications that would say utilizing that 1-year eGFR is predictive of at least medium-term outcomes. And so I see this data as incredibly positive. It is something that, again, I'm very excited when individuals who come into my clinic, oftentimes having 1, 2, maybe 3 transplants that's recognized that one of the highest levels of sensitization is women with pregnancies. And so when I see those individuals come to my clinic and before I would panic like now let's see what their CPRA comes back, and I may have to have a totally different conversation with them about their opportunities. I don't feel I have to think that way anymore. I have something that regardless of what that antibody level comes back, I'm able to give them, I think, hope for which perhaps they've never felt in the past and may have been to other centers where they have given them that message. And so I'm encouraged by the fact that people are transplanted. I'm encouraged by the outcomes at 1 year, certainly a very -- I think a safety profile, which is non concerning to me. And like I say, this is an option which I never had before. So again, I'll reiterate, this is an incredibly exciting intervention that in my 25 years, I've never seen anything like this.

Okay. And perhaps turning to Dr. Montgomery, could I also ask for your reflections on the results that have been presented?

Sure. So as mentioned earlier, both Dr. Cooper and I got involved in trying to care for these really desperate patients who I've just shown you their outcomes are without being desensitized and transplanted are worse than most types of cancer. And we showed in a paper that was published in New England Journal of Medicine that just using plasmapheresis and low-dose IVIG, desensitizing the patients that we could and transplanting them, the difference was an 80% survival at 8 years versus a 30% survival if they waited on the list and most of them, 84% never got a transplant. And so we did what we could, and we transplanted about 700 incompatible patients during that period of time, 15 years or so, and we saw their lives transformed, but the techniques we're using weren't approved. And in many cases, we struggled to get them paid for. But that didn't stop people from all over the country to coming and trying to get some shot at a bit of hope. And so this is an incredible step forward to have a drug that I think based on these data that were shown today, has a significant likelihood of being FDA approved for this indication. It's going to be transformative. There's no question about it. And I think we'll be able to rapidly get those patients that have been sitting for a long time and just clear the patients who are 99.9% from this sort of hellish existence that they've had to live. So very excited about this, very excited about the future with this drug.

I wonder if I could just ask you a follow-up question, Dr. Montgomery. We saw the eGFR at 12 months in patients who received imlifidase, that was 51.5 mls per minute. I wonder if we could just -- I could just ask you to expand on taking what we see at 12 months, how we see that in terms of longer-term benefits. I wonder if you could just kind of reflect on that and expand on that a little.

Sure. So I think the FDA, for a long time, really didn't accept any surrogate endpoints in clinical trials and transplantation that really held our field back. But there's such convincing data now that endpoints like eGFR, like the iBox are extremely good at predicting the long-term function. And so eGFR now is the endpoint that's used in the majority of transplant trials of different new drugs. Now you might say, okay, well, this is a very unusual group of patients whose immune systems are highly primed to be responsive to other people's tissue. Is it relevant in these patients? Or are they going to have a different trajectory after a year? And I think the proof that that's not the case that these patients that EGFR is going to be just as predictive as in any other group comes from our 5-year study of the patients who were treated in the Phase IIa trial that we completed quite a few years ago. We were the highest enrollers in that trial. And so I, of course, continue to see those patients now. And there really wasn't a drop-off in graft survival and patient survival after a year in that group. So I think you can take this to the bank that what we're seeing in this trial is going to be predictive of the long-term outcomes in these patients.

So maybe I can turn back to you, Dr. Cooper and just perhaps begin to think about how you see this treatment being used in clinical practice. Could you perhaps expand on that, how do you see it being used and which patients might be eligible for treatment with imlifidase?

I began to hint at that when I've talked about patients that come into our clinic. They -- certainly, the inclusion criteria for our trial makes it clear that patients 99.9% CPRA are the individuals that, as Dr. Montgomery said, would benefit the most and sadly have been underrepresented in transplant populations. The way I think it could be used, should be used and has the opportunity to be used is that there are other individuals, certainly with perhaps not that degree of sensitization that could also benefit from this drug. So putting a couple of other numbers together. As mentioned, death on the waitlist is a real thing. It's unfortunately numbers that we don't follow. We are always excited about the numbers of people waiting for transplant, the numbers of folks that are transplanted, but we often forget the number of people who die waiting for that transplant. The fact of the matter is, as many patients, including and especially highly sensitized patients, often can't wait 5 years for a perfect organ or a compatible deceased donor organ to be available for them. And so even with lower levels of sensitization, there are patients at programs that may not ever get in a second offer, and there's been a lot of data, particularly published out of Columbia that shows patients who have an offer refused for them that maybe they never get the chance for that second offer. And so I think there's a lot of additional patients with lower levels of sensitization that could be -- that could benefit from this intervention as well. Now I think what is important and to add on to Dr. Montgomery's conversation about long-term outcomes, there does need to be a higher level of concern, a closer follow-up with these patients. Certainly, the 1-year data is encouraging, but that does demand the efforts to ensure that we are still following these patients greater than 365 days for instances such as antibody production, changes in GFR. We do have, I think, additional molecular techniques that allow us to follow these patients closer. We do have, I think, the expectation that we may need to biopsy these patients more often to identify things earlier than maybe we might have been in the past for non-sensitized patients. But I think overall, there's going to be a greater confidence in addressing sensitized patients in transplant programs around the country who -- let's be honest, that we're very uncomfortable approaching these patients at all. There were individuals who, like I said, remained on waiting list just expecting for that 1 in 1 million organ offer to come that we know never did. And so now I think transplant centers will have the ability to really to provide access for these patients regardless of their experience in desensitization that patients regardless of what they call their ZIP code, now have access to transplantation. And I think that's very important. We often want to say that patient should go to a center that has all this experience. And while I don't disagree that there are centers of excellence, Dr. Montgomery is one of those. There are some patients that just can't travel to New York City or to Wisconsin to be able to receive their transplant. And so this is really an opportunity to provide access for patients that have been -- perhaps their unappreciated lack of ability to receive these types of interventions have gone unnoticed. And so we're really opening up transplant for populations that really, I think, deserve equal access to therapies like this.

That's very helpful. And I think turning back to Dr. Montgomery. Perhaps it's a related question, but good to hear your thoughts on this. I mean, obviously, we need to go through an approval process for imlifidase. But if it is approved, how do you think it is going to impact the care of highly sensitized kidney transplant patients?

Well, I think it's going to be a game changer. I think that we -- I think the important thing to point out is that we had really good results with plasmapheresis and low-dose IVIg. But the problem was it is a totally inefficient way to remove antibody because it only removed antibody from the intravascular space, as we make IgG. And so it's -- you had to know when the transplant was going to occur because you had to start the treatments in advance of the transplant. And oftentimes, those treatments would need to occur over a period of 1 week or 2 weeks. And we could only reach the patients that had low enough levels of antibody that this very inefficient way of removing it was capable of getting them to a safe level at the time of transplant. Imlifidase gets rid of all the antibody in the body within 2 to 4 hours. There's nothing that we have had that is anywhere near that. So it works across the interstitium, across the vascular space. You don't have to remove it from -- like we did with plasmapheresis, remove the antibody from the intravascular space, wait 2 days for it to reequilibrate and then remove a little more. So in terms of its ability to get rid of antibody, it is incredible. And now that opens it up to anyone, right? So we can have -- we can get an organ offer for somebody on the deceased donor list, bring them in, give them the drug and transplant them. And that's exactly what we did in this trial. So I think it's going to completely change our approach. I agree with Dr. Cooper that it is going to be something that will really help change some of those numbers that I mentioned earlier. And those numbers aren't just about the 99.9%-ers and they're really about anybody over 99.5% in terms of their survival rate waiting and so on. So I think that it's -- that we're -- we have to do what's right for the patients to save their lives. So I think you're going to see this drug really changing the whole landscape in this field.

Okay. So maybe in the last minute or 2, just before we then turn it over to some questions from our audience, perhaps I can ask Dr. Cooper to reflect on that. Maybe you can just in a minute or 2 just kind of tell us how this is going to change your conversations with patients waiting for a transplant?

A minute or 2 is important. So again, I'll say that this has allowed me to approach really every patient that I think now who walks into the clinic a little bit differently. So as I said, that you can't help but be concerned when an individual who has a complicated comorbid history, particularly those as we're seeing now with the success of kidney transplant, second, third, fourth transplant, multiple pregnancies, you can't help but worry about their access to deceased donor transplantation with the statistics as they are. And so now I think we're able to really look at every patient truly as someone who has equal access to a life sustaining or life-improving organ as we talked about, quality of life can't be undervalued in all this. And the one thing we didn't and can't spend a lot of time about, there's also opportunities for living donation here, too. I mean there's individuals who come in with a living donor with which they may be sensitized. And in the past, it's almost difficult to imagine we would say, despite how difficult it was to identify a living donor, you may have to go out and find someone else. And so again, some of these highest-quality organs now with the use of imlifidase, they could proceed the transplant. And so it really shines a light on many more opportunities for patients when they come into. And so I think I'm able to more positively give people confidence that we have options available for them and not pretend, particularly for the highly sensitized that they're going to have a very, very difficult time of receiving an organ transplant. So it's just again, a different conversation, we expected to be a very difficult conversation with people when they come.

Okay. Well, thank you. You managed to do that in 2 minutes. So I appreciate it. And so I think we'll move from a very, very insightful discussion. I'm going to hand it over to Tara, who's going to moderate the Q&A from our audience.

[Operator Instructions] So our first question comes from Farzin Haque at Jefferies.

The doctors, both of you mentioned the PLEX and IVIgs, but curious on your thoughts on where imlifidase fits relative to, say, anti-FcRn agents, CD38 like daratumumab and other complement inhibitors that could come up as alternatives?

Well, first of all, most of what the drugs that you mentioned are not -- they don't reduce soluble antibody, which is what the problem is in patients who are highly sensitized. Now they are drugs that target plasma cells, which make those antibodies and also can reduce the B-cell compartment so that those aren't replenished as readily. And those drugs, I think, are going to be important in the story because once we have an approved drug that gets rid of the soluble antibody, that is what puts the organ in jeopardy when you do a transplant, we can start to use those other drugs to prevent any rebound of antibody afterwards. And I think that's what you're going to see happening over the next few years. All the drugs that we've been using have been off label. A lot of them are drugs that are used for hematologic malignancies. And so having a drug that's approved I think will make some additional trials enabled because the FDA in the past has been really hesitant to combine drugs at all, particularly unapproved drugs in clinical trials. And so I think you will see clinical trials using some of those drugs that you mentioned that target plasma cells and B cells along with imlifidase to reduce the likelihood of rebound, which occurs somewhere around 40% of the patients will get a significant rebound. So this is only going to get better as time goes on. And I think the use of imlifidase will only improve. Plasmapheresis and IVIg, as I mentioned earlier, so inefficient at getting the job done, I think that's going to disappear. And any setting that you could think of where you would use that for HLA antibodies or ABO isohemagglutinins you're going to use imlifidase instead.

Makes sense. And one more question. EGFR data is certainly very compelling, but what are your views on potential impact of the open-label design, heterogeneous control arm for the FDA approval process? Are there risks to it?

I mean we would have liked to have not seen a control arm, quite honestly. I was involved in the advisory boards and also spoke to the FDA as an expert about this. And for these 99.9% patients, I don't think there is a control group that you could really imagine that where you would do a transplant without first being able to reduce the antibody burden. And the risk of having a bad outcome would just be too great. Now the FDA felt very strongly about this, and we came up, I think, with the best possible control group. And I think you see the results that for the vast majority of those patients in the control group, there are only 3 where the team decided to move forward by probably doing a couple of plasmapheresis treatments or whatever their local antibody reduction method was or they just got lucky with the organ offer and there happened to be only low-level antibody. But I think the data -- the fact that this trial was able to be accomplished with a control group, I think, is an extraordinary thing because most people did not feel that there could be a control group for this group of patients.

And just to add, I completely agree that kind of fortunate to have 3 patients that were enrolled in the trial, one of which was at the control arm and you had a very difficult decision in front of you, knowing, as Dr. Montgomery described, our past history of what was successful but was very, very difficult, very, very challenging and the immunosuppressive in and of itself. There was a number of patients who we had challenges even getting into the operating room. And so finding even a control arm is you're really spectacular, but many of us felt it was unsafe to move forward with the way that the trial was designed. But I think what your question asks is, as we've sort of said throughout that there are patients well below the 99.9% that could benefit from this trial. Not every sensitized patient is going to need this. Certainly, there will be based upon the genetic frequencies and unavoidable antigens at opportunities for people, but there is a significant number beyond those 32 that received the drug in this Phase III trial that will certainly benefit in a more open label opportunity for enrollees.

I think one thing that people don't realize is that people become sensitized to common antigens. Common antigens are common in the population. And so in these highly sensitized patients, they're competing with each other for the same rare genotypes because their sensitization is very similar. And so that's why when you're highly sensitized, it is so unlikely to receive a transplant because these rare genotypes that do become available that could match highly sensitized patients, they're kind of good for everybody. And so maybe 1 person benefits from that.

Our next question comes from Tom Smith at Leerink.

For both doctors, Montgomery and Cooper, I was just wondering if you could expand on some of your comments regarding the nonapproved alternatives here PLEX and IVIg? And maybe talk a little bit about how often you're using these in clinical practice today and how effective they are in terms of desensitizing patients and actually getting patients to transplant.

I could start, Tom, that's okay. So again, we're actually using it, apheresis and IVIg that is very rarely at this point, to be frank. The reality and the truth is, is that the data has shown, yes, to be desensitized and transplant is better than remaining on dialysis, as I said, apples and oranges. But the long-term outcomes have not been as positive as we would have wished or have thought. And quite honestly, I'll be frank saying that I've followed this molecule, I followed this company for many, many, many years. And knowing where we were going, where this clinical trial, early phase data and now this Phase III trial was going, I quite frankly, have felt more comfortable saying, I would like to see this drug approved and give patients who are currently highly sensitized on my list the opportunity to receive imlifidase with the data that was demonstrated at the beginning of this presentation. So we're using very little of it occasionally with a highly sensitized patient and the living donor with which they are sensitized, we may use a combined paired exchange model and desensitization, knowing again that, that perhaps is the only way in which they will be transplanted as well. But from a deceased donor standpoint, recognize much of which the success of Dr. Montgomery and his program was with living donors and the ability to have multiple sections. So apheresis, IVIg, we don't have that benefit of time with deceased donor offer. So we get a phone call, maybe we have 24 hours before the organ is procured from a deceased donor, it arrives in our operating room and we're able to perform the procedure. 24 hours is not a lot of time, and it certainly isn't how we've been able to demonstrate success in a living donor population. So we're doing very, very, very little of it. And oftentimes, it's in combination with a paired kidney exchange and living donor.

Yes. I mean I think just as Dr. Cooper said, this worked plasmapheresis, low-dose IVIG worked well in the right hands and groups that really devoted a huge amount of resources and had great experience. It worked well, but only for a living donor, only for patients who had a living donor, that's only 20% of the transplants in the U.S. every year. So that was the big limiter. And I have to say we even stopped doing that for the most part because the thing was that we were very reliant on patients either being self-referred or other doctors referring to us from other parts of the country because these patients are spread out all over all the transplant centers. But once the new kidney allocation system came in, everybody thought we had solved the problem. And it was one of the biggest really misunderstandings. And so we stopped getting patients referred. And yet they just sat on everybody else's, list, believing, it's sort of like traveling in the past week. What I went through 2 days ago, getting on a plane and then taking us back off the plane and sitting for 17 hours in an airport. That's what these patients do every day of their lives. And they get false hope. Sometimes they told there was an offer and they come in and I really opine on their life during that 17 hours I was waiting for an airplane. And so imagine that being all you do all day, every day. It's a really terrible existence.

Understood. That's super helpful context. I appreciate the insights. And then if I could just ask a follow-up on -- as we think about perhaps that 3,500 patient waiting list for transplant, like those patients who are highly sensitized, greater than 99.9% CPRA. Just maybe you could just help us think through the potential uptake and how imlifidase might be used initially, meaning if approved, how many patients do you expect could get an organ transplant in the subsequent 12 to 24 months because we have this therapy available?

I think it's going to be adopted very rapidly. I think it doesn't require the infrastructure investment that plasmapheresis and IVIg and required. So I think that people will do this pretty quickly and patients can get transplanted in their own area, and they don't have to travel. We had a large number of centers that were enrolled in this trial. So they all have experience now. And so they're going to be probably the first group to just very rapidly start using it and get these patients transplant. I think it will be fast.

Sure. So one thing I want to add and give credit to what it does require is a close working relationship with your HLA lab director. These individuals in many ways, are unsung heroes of transplant programs in general. But in this trial, for sure, it required a close collaboration and the ability to delist unacceptable antigens as we talked about to get patients even offers to begin with. And then it required a collaboration with, again, immediate return once drug was administered to ensure a negative cross match and then post-transplant to be able to get data. And so having that -- and that was certainly an encouraging, I think, component of this intervention was to ensure that the HLA lab directors were appreciative of their role in all this. So that certainly is going to be something that's necessary for transplant to happen is to have that relationship with HLA.

I think there are probably a lot of patients out there who never get listed who are highly sensitized because people just say it's -- for you to get listed. So it's probably more than the 3,500 that are -- who will suddenly have an option.

Our next question comes from Matthew Phipps at William Blair.

Dr. Montgomery, you mentioned, obviously, the FDA wanted to look at 99.9% CPRA, 99.5%, you essentially round up anyways, but also 98% even having very low transplant success rates. So I guess what is the cutoff where imlifidase could really help in your practice? And then do you expect maybe your P&T committee or payers to set their own restrictions on CPRA cutoffs? And then for maybe both docs, obviously, in 2014 with the allocation system, trying to prioritize these highly sensitized patients, giving them more points in the scoring system. Is there something that needs to change in that pointing system with the introduction of imlifidase since you can kind of delist some of that sensitization?

Well, I mean, I think, first of all, the patients do need to get offers, right? So as things stand right now, if you start to delist their unacceptable antigens, you do make it more likely for them to get an offer. And so the problem is that if we had -- if we were going to make a change in the system, I think that you would want to not make it less likely for somebody if you delist their unacceptables to a level where they lose that point advantage then they actually end up not benefiting as much as they could. I mean I almost think that with this drug, we'll have to see what happens, but that the -- you still would want these patients to see all of the kidneys that are coming available at a national level, right? Because, again, they're searching for that rare genotype. It's very unlikely they're going to get it locally. So I think just wherever you draw the line, giving these patients access to all the organs that they could get a match with is going to be important in addition to having this drug available and not penalizing them if they fall below those advantaged areas. So I think we're going to have to rethink the whole allocation system for highly sensitized patients to make it more friendly to being able to use this drug along with it.

Yes, I agree with Dr. Montgomery. And Matt, just to quickly answer, I think, 2 other questions you had there. So I'm an unapologetic optimist, but I also am a realist when it comes to insurance companies. The data would show that it's cheaper to get someone transplanted to be on dialysis. That's always an important data point with which we bring to our P&T committee. And with this early 1-year data to demonstrate the success of that intervention, I think, is additional value add to insurance payer. I think in terms of a P&T committee, what this is absolutely going to require is a physician champion individuals like you see on the screen who are very committed, demonstrate, are able to show the return on the investment for these patients. And as an academic transplant center, our job is to find answers for patients who come to us. So I don't at all believe that a P&T committee is going to demand that it only be used at a certain PRA to your question. I think we have to be responsible in both looking at quality and looking at the financial decision-making around an institution, but I don't see this as being a problem as long as there's a champion who is able to verbalize the value add to having this seen on a formulary.

I know it's -- can I ask one quick follow-up? I know it's a little off topic, but would you look to use imlifidase for the treatment of AMR. That's obviously a -- they've generated data there, but it would be off label. Just curious your thoughts.

I mean so many of the drugs that we use in transplantation are off label. And I think the limiter has always been whether you can get it paid for, right? So I think that we would certainly try to help our patients in whatever way we can. So if that means they develop AMR to try to convince our pharmacy committee that it's a drug that will be very effective in treating that, I think we'll have success.

Our final question comes from Doug Tsao at H.C. Wainwright.

So again, just to sort of follow up on the point or the question earlier in terms of trying to interpret the data in the context of the placebo arm and what that -- how the agency might view that? I guess I have a couple of questions. One, so is it fair to say your perspective would be that while there can be patients successfully transplanted using plasmapheresis, IVIg, et cetera, that is not necessarily a fair representation of sort of the clinical utility just because what imlifidase offers in terms of the speed of onset is so much greater, right, just given the availability of donors kind of often being a last-minute occurrence. And so that perhaps sort of understates the clinical utility and the control arm maybe oversimplifies the -- or the results from the placebo arm or control arm oversimplifies the sort of medical reality that you're dealing with as transplant surgeons?

I'm going to have to drop off because we're after 10, but I'll -- Matt can certainly answer that question well. So I'm going to say thank you and sign off.

Thank you so much for attending.

I think it's an incredibly insightful question. I'll say I refer back to the primary endpoint. So the fact that patients were transplanted in that control arm was a very rare event and then their outcomes were significantly worse than those that received the intervention with imlifidase. To me, again, demonstrates, as we said before, it was very, very difficult to even identify a potential comparator arm. But the reality is, is that, as stated, it's not realistic, particularly now looking at the data to say that those are equal options for a patient who is highly sensitized. And so I think regardless of how the trial was designed and the agency's expectation that we have a control arm, real-world evidence and real-world expectation, I go back to my apples and oranges. Just look at the data. Very few people got transplanted on the control arm, and those that did get transplanted did poorly. And so it's not just about getting someone transplanted, Douglas. I think we have to say how well do they do after the transplant. And so that's certainly the message that I think the team at Hansa is going to take to the agency despite the fact that there is a need for a control arm, it quite frankly, was trying to create something that isn't a fair comparator.

And I think as a follow-up, it was Dr. Montgomery who said he would have not had a control arm, but obviously, the agency had a different view. And I don't know, Dr. Cooper, if you were part of the discussions or sort of heard what the agency's view in terms of wanting a control arm. I mean, obviously, we know randomized controlled studies is kind of the gold standard, but there's certainly exceptions when need -- when warranted. And so what was it that made them think that they would want a control arm, especially given the fact that they probably knew there'd be some heterogeneity?

Sorry, it wasn't part of those discussions, Douglas. But as you mentioned, the gold standard is the gold standard. There was conversations about looking to use historical controls as the comparator. But I think the FDA, certainly, with the importance of how this drug was brought to them, and the value add to highly sensitized patients. This was thought, I think, not only to be the best way to study it, but also to provide the scientific community with, like we said, the gold label effort and the comparator was something that they expected.

And so I guess the final point I would just say is -- so it sounds like from your perspective, the sort of the speed and reliability of the sort of treatment effect or sort of the real value adds that imlifidase offers, especially relative to some of the other alternative methods.

No question. Just the ability to be able to transplant someone within 4 to 6 hours, unheard of in this patient population in the past and unable to be achieved in previous non-approved desensitization methods. And then again, the success and the reliability of antibody reduction, the ability to get someone through the transplant without evidence of hyperacute rejection. And now we have the data that shows that the follow-up at 1 year is, as I say, comparable to a non-sensitized cohort. So all outstanding pieces along the continuum of care that we provide.

And I know we're in stoppage time, but if I can just ask a quick one, real quick. So when we think about the alternative methods of desensitization, you sort of mentioned hours with imlifidase, right, which we know from the data. Typically, how long previously would it take if you were to use IVIg or plasmapheresis? What's that time course that you're looking for to potentially prepare a patient for transplant?

So I think -- so it depends upon the level of sensitization. And so we would often do dilutions to be able to determine the number of apheresis sessions that were necessary. So in the living donor scenarios, as we described earlier. We would often demand sometimes 3 to 5 plasmapheresis sessions done on an every other day basis with IVIg, allowing for the re-equilibration and the binding of antibody for the apheresis to be successful. So within, again, a deceased donor population, deceased donor offer, you'd have the ability to do perhaps pheresis with the IVIG and maybe add an additional complement anybody, which again is demonstrated in multiple clinical trials have found to be unsuccessful. If we go from needing sometimes a week of therapy to be able to move forward with transplant to only having 24 hours. It really isn't going to happen.

To plasmapheresis and...

Doug, I think we're going to have to kind of actually finish here. I'm sorry, because we're actually way over the time. And I know that Dr. Cooper also has other things he needs to kind of attend to. So I think we're going to have to finish here. Thank you very much for -- to everyone who's listened into the webinar. Thank you so much, obviously, to Dr. Cooper, Dr. Montgomery. I think that your perspectives have been incredibly insightful, really, really helpful. And I just want to thank you very much for taking the time.

Yes. Pleasure. Really thrilled for this opportunity, really excited for the future of Hansa and imlifidase.

Great. Thank you very much.