All right, great. Let's go ahead and get started. Thanks for joining us here at the Leerink Partners Global Healthcare Conference. My name is Thomas Smith. I'm one of the senior biotech analysts here at Leerink. It's my pleasure to welcome our next company to the stage, Eledon Pharmaceuticals. Happy to be joined up here by President and CSO, Steven Perrin. Steven, thanks for joining us.
Thomas, thanks for having us.
Of course. Great. We are in a really exciting year of data for you with your CD40 ligand-targeted antibody, tegoprubart. We're looking for updates from a Phase 1b study in renal transplant, and then 1obviously the highly anticipated Phase 2 BESTOW data in the second half of the year. We'll hit on a lot of that in much greater detail. Steven, why don't you go ahead and kick us off with a little bit of a brief overview of Eledon and what you guys are working on these days?
Sure. Yeah, like you mentioned, it's a critical and exciting year for us. We have a lot of progress that we've made across our transplant studies. We'll talk more about the two kidney transplant studies, but we're also seeing progress in the xenotransplant space. As we announced recently, we did another patient at Massachusetts General Hospital for a xenokidney transplant study in collaboration with eGenesis. That patient's doing quite well, and we anticipate, after the announcements of both United Therapeutics and eGenesis, that they're on the path to a trial that will see some more activity in xenotransplant this year as well. In addition to that, we announced some early data from three patients in our islet cell study at University of Chicago. That's a study that Dr. Dixon Kaufman is being funded by JDRF. We're supplying tegoprubart for the prevention of islet cell rejection in that study.
We anticipate he's funded to enroll another handful of patients this year, so we should hopefully have another exciting data update from islet cell transplant. As you mentioned, our next data readout for our kidney transplant studies will be our Phase 1 study that will give an update of our data in August at the World Transplant Congress in Houston. That'll be a complete data refresher over what we presented a year ago at ATC. We will present all of the data on those 13 patients, as well as other subjects that we've enrolled since then. Very excitingly, it's going to be a really busy year to aggregate all of the data for our BESTOW study. That's our Phase 2 study that completed last patient of enrollment last September.
That last patient is now already six months out, and we're guiding to top-line data in Q4 of this year.
Great. Why don't we start just kind of high level? I think it's worth emphasizing the differences here between targeting CD40 ligand, which you're doing, and targeting CD40 receptor. Maybe just highlight why you feel like CD40 ligand targeting is the right way to go in renal transplant and maybe contrast it versus some of the historical approaches, what we've seen historically.
Sure. It's a great question. From a biological perspective, these are incredibly different targets, even though they're a ligand and a receptor pair. They were identified back in the 1980s, where the receptor was identified first being expressed on the cell surface of B cells. Today, we know that CD40 receptor is constitutively on the cell surface of all cells of the monocyte lineage, in addition to B cells, dendritic cells, macrophages, and other types of antigen-presenting cells. It's always on the cell surface, whether the target's engaged or not. That is very different than CD40 ligand, which is expressed on the cell surface of T cells primarily. It's only there transiently after costimulatory activation, and then there's negative feedback mechanisms that get it off the cell surface to protect uncontrolled autoimmune responses.
After the receptors were initially characterized, there was a lot of preclinical data, initially done in rodent models of autoimmunity, showing that blocking this pathway was incredibly robust at slowing down disease progression in animal models of multiple sclerosis, lupus nephritis, psoriasis, rheumatoid arthritis, and a host of others. Subsequent to that, it was shown that blocking this pathway was very potent at preventing transplant rejection in multiple different species: rats, mice, baboons, rhesus macaque, and cynos. To this day, blocking CD40 ligand in particular has been the most potent way to prevent transplant rejection in multiple species.
Great. You alluded to the most recent data update we've seen from your Phase 1b experience. Maybe just kind of level set us what you're seeing in that study versus what you historically see with tacrolimus-containing transplant regimens.
Sure. The whole premise of what we're trying to do with tegoprubart in transplant is to replace the CNI, tacrolimus, which is the current foundation of standard of care. Tacrolimus really revolutionized transplant medicine 20 years ago, but there's been very little innovation since. It really changed the ability to do transplant and protect graft up to a year post-transplant. It also comes with some unfortunate toxicities and side effects, including nephrotoxicity. It's actually toxic to the actual kidney that it's trying to protect. It causes hypertension. It can induce new-onset diabetes in about a third of patients after exposure. From a quality of life perspective, it also induces tremors and brain fog, which over time, some patients just stop taking the immunosuppressive drugs, which leads to increased risks of subsequent transplant rejection.
The whole premise is to replace the CNI with tegoprubart and try to improve longer-term outcomes for patients. There are over 100,000 people on the transplant waiting list at any given time. Half of them will not get to an organ. There are only two ways to solve that problem: either make organs last longer post-transplant or find a new source of organs. Hence, xenotransplant is also a very exciting technology platform.
Yeah, that's great. In the phase IB, in those 13 patients, I know you have a lot of encouraging biomarker data. I know we've been focused on what you've been seeing on eGFR. Maybe you could just describe the experience that you're seeing there relative to TAC.
Yeah, so the most exciting data that we're seeing there is our eGFR. It's become apparent in the last five-plus years that eGFR is one of the best predictors of long-term kidney function and survival. On standard of care, there are large retrospective studies that suggest that after a year, your eGFR on the current standard of care with TAC is around low 50s. In our 13 patients that were reported, we're seeing mean eGFRs in the high 60s, which is a really significant clinical delta on predicting and suggesting longer-term graft function and survival. That data set that we presented last year of 13 patients was quite exciting to see eGFR levels as high as that.
How comparable is that? Are those 13 patients to your sort of typical renal transplant patient in terms of prognosis and outlook?
That is an open-label study. We have some of that data that we have already presented and published, but we are not cherry-picking the patients. These are pretty tough patients. The HLA mismatching tends to be a little bit higher than normal. We are excluding perfectly matched individuals by HLA. If you look at the mean age of the donors and recipients, they are a little bit higher than what we are typically seeing in standard studies. About the only thing that might favor a more favorable population in that study is we are seeing a little bit more living donor transplant than deceased, but that is kind of the nature of a small-centered open-label study. In the phase II BESTOW study, those variables are actually balanced between the study groups.
Got it. Yeah, that's really helpful. What have you seen? Obviously, you've also generated data outside of the renal transplant setting, but in terms of safety tolerability, maybe talk a little bit about what you've seen in the phase IB, but then also more broadly across the program, what are you seeing?
In the phase IB study, up to last year's data cut, which was around this time a year ago that we presented in May, the data cut happened sometime in late March. We had three people that had come out of the study. One, she just withdrew consent on her own, and it was completely unrelated to kidney function. Her eGFRs at the time, I think, were in the mid-70s, but she was having some alopecia or hair loss that she did not tolerate so well at day 200 and decided to switch over to TAC, which was unfortunate because her eGFRs went down to the 50s, but we could not let her back into the study. We had a second patient who I think the second patient that enrolled in the study withdrew at day 54 due to bacteremia.
The investigator, because our drug was so new, he didn't have a lot of experience on how to treat that at the time. He decided to switch the patient over to tacrolimus just so that he had a better understanding of how to manage the bacteremia at the time. The third patient that dropped out of the study did have a T cell-mediated rejection around day 217, and the investigator switched them over to tacrolimus because they wanted to add on some other drugs that we didn't allow on the protocol. Other than that, the rest of the subjects have either rolled over into the long-term extension study or they continue to be in the study and approaching probably a year.
As far as broader safety from not only our drug, but from the drug class as a whole, the typical things that you would look like for blocking this type of an immune receptor would be increases in opportunistic infections and malignancy. Not only are we not seeing that in our other studies where there were monotherapies, such as our ALS or IgAN study, we didn't see it in our healthy volunteer study either. Across the entire drug class with Sanofi's drug, Biogen, Amgen, the safety profile of the class so far has looked pretty good.
Yeah. Okay, great. One of the other questions we get from investors quite frequently is to just kind of compare and contrast the experience with Novartis' CD40 receptor-targeted iscalimab, who also had a renal transplant program versus your program. Obviously, there are important compound differences there, but maybe you could talk about, I guess, the experience with iscalimab and why you continue to be quite confident in what you're seeing with the data generated with Tegoprubart.
The iscalimab study at the time Novartis was enrolling in multiple indications, including transplant, as well as Sjogren's syndrome. They've never published the results of their transplant studies, unfortunately. What you can glean from the data that's on clinicaltrials.gov would suggest that if they continued the study, that they actually would have hit statistical significance. This is based on their data, their analysis on clinicaltrials.gov. It would suggest that they possibly stopped their transplant indications to favor other indications where maybe they didn't want to see the safety profile that you might see in a transplant study because they were at that point in time enrolling in Sjogren's syndrome and one other. As far as the premise behind transplant, the non-clinical data going back to the 1980s would suggest that blocking the ligand is much more potent than blocking the receptor at preventing transplant rejection.
We certainly haven't lost our conviction that we think that we're a very differentiated target from CD40 receptor and that we should see better efficacy.
Got it. That makes sense. You have this major clinical data catalyst coming up with the BESTOW readout at the end of the year. Q4 is the timing that you've laid out. When you think about bar for success, maybe you can just help frame expectations, how you're thinking about bar for success and what investors can expect out of that readout.
Sure. This is the first study ever that's going head-to-head with an anti-CD40 ligand antibody compared to standard of care with tacrolimus. It's a well-designed and robust study. 120 subjects are randomized one-to-one. It has a much bigger global footprint for enrollment than our phase I study. We're enrolling the BESTOW study in the United States, Canada, Australia, several countries in Europe, as well as South America. It was designed as a superiority design, which is also quite unique. Most of the transplant studies tend to focus on a non-inferiority against the composite endpoint of graft function, graft survival, patient survival. We went after being able to do a superiority readout on eGFR. The study is powered to detect a nine-point difference with 80% power between the two groups.
We based that on the belatacept and iscalimab study designs as far as what power we would need to detect that difference. This is a really exciting study just as a superiority design. Obviously, we're collecting all of the other data that one would typically collect for the typical composite endpoint. We're also reading out secondary endpoints around other parameters of kidney function, such as DSA. We're tracking things that are associated with the toxicities of tacrolimus, including diabetes, tremors, brain fog, et cetera.
Great. Yeah, it sounds like that will be quite a robust data set for you. When you think about subsequent steps, I guess, engagement with regulators, what's sort of your base case for what a Phase 3 or potentially pivotal study would look like? I also have some questions around iBox and what could be maybe a bit more of a bull case or something above a base case. Just walk us through kind of your base case right now.
I mean, certainly, we are going to have to run a Phase 3 study. We get asked that question a lot. We will be designing a Phase 3 study after we get our phase II BESTOW readout. It's going to probably look a lot like the BESTOW study, but with a bigger footprint, more patients, more sites, probably a bigger global footprint as far as countries go. The key thing that maybe is an unknown until we have some discussions with the health authorities is endpoints. You brought up iBox, and that's probably the biggest unknown at this point. iBox was approved as a secondary endpoint in Europe a while back. It's currently under review at the FDA. It's unclear until we hear what they're thinking about, which they're guiding Q1 of next year, how a company could utilize iBox as an endpoint. Is it a co-primary endpoint?
Is it a key secondary endpoint? Do you have the flexibility to pick which one that is? Are they only going to allow a company to use full iBox, or can you use abbreviated iBox? Are there pluses and minuses to those two things? We have some thinking to do about how we may utilize iBox as an endpoint as we're going through our phase II design. Some of that depends upon what our phase II data looks like, which we're blinded to. We do not have any insight right now into what that data looks like.
Right. That makes sense. For those who are less familiar, maybe you could just elaborate on iBox, what goes into it. And then in terms of this pathway, what sort of visibility do we have, do you have into that regulatory path to maybe getting iBox accepted as a surrogate endpoint or as a potential use in either a primary, co-primary endpoint type of setting? Is that like a transparent process that we can kind of see the development as it moves along in the regulatory pathway, or is there a little bit less transparency around it?
I don't think we've seen much transparency to this point, so I'm guessing that we will not have a lot until we get our initial sense of what they're thinking about. I don't think we would hear much until Q1 is the guidance that we're hearing from them.
Okay. Yeah, I guess what drives that Q1 confidence on your part?
They're in the process of evaluating a massive submission. I mean, it was a huge amount of data that went into the initial consortium's evaluation of iBox and what the parameters might be that correlate with long-time graft survival and function. They did multiple validation sets across multiple other studies. They negotiated with the agency quite a bit about how one might utilize iBox in a clinical trial setting. I don't know that we're going to hear a lot about what that process is until Q1, if I had to guess.
Okay. Understood. The incorporation of that, I guess if I could just ask you to elaborate a little bit on how that could be that sort of bull case for a Phase 3 program for tegoprubart.
Sure. I mean, iBox is incredibly exciting. I'm not trying to give the impression we're really excited about the possibility of having a new endpoint to utilize for clinical studies in transplant. Again, there's been little innovation in the current endpoints for 20-plus years. iBox, depending upon how it's utilized, could be used for the first time as a superiority design. Right now, in Phase 3 studies, we're kind of hampered by the fact that in the first year, there's so few rejections on current standard of care that it's impossible to do anything except for a non-inferiority design unless you want to put 4,000 patients in each arm, which would be cost-prohibitive. iBox could give you the opportunity to actually think about a superiority design at 12 months or as a key secondary endpoint as well if you end up not doing it as a co-primary.
It has a lot of different moving parts to it, though. It's based on eight different parameters, which puts a lot of onus on the sponsor to make sure that you do an incredibly robust job with data collection because the way that the algorithm is utilized, it doesn't impute missing data. You can immediately start to lose lots of data at your endpoint if you're missing pieces of data. It's complicated. It's a combination of clinical data, such as time to transplant. eGFR is one of the major drivers of iBox out of the eight parameters. That's one of the ones that drives the algorithm quite high. There are four components around histology. You need biopsies from every single patient at 12 months, which was often sometimes not easy to get. Another parameter is DSA.
You have to make sure that you aggregate all of those collections from every patient in your study. You're going to lose power at the end of your study for iBox. How you utilize iBox, since nobody's done it yet, is also something you really have to think carefully about as part of your design.
Yeah. That makes sense. Okay. Let's spend a minute talking about the potential commercial opportunity in renal transplant. You alluded to the donor waiting list being 100,000 in the U.S. I think when most investors kind of think about kind of analogs or precedents in renal transplant, you have TAC, which is huge commercial success, I think unequivocal commercial success. You also have Bristol's belatacept on perhaps the other end of the spectrum. Maybe you could just high-level outline how you're thinking about the commercial opportunity here and sort of within the realm of those two analogs, like where is Tegoprubart going to really fit in there?
I mean, I think you have to frame transplant as a significant unmet need. There's around 25,000-27,000 transplants done per year in the U.S., an equal number in Europe, around 250,000 people with a transplant that's currently on CNIs, whereas we've alluded to that the long-term effects of tacrolimus on kidney function is not great. Belatacept has shown that even with not a greatly supported launch, they have about a 6% of the market share right now. We're estimating that they do about $600 million in the context of transplant rejection. TAC has been a generic drug for a long, long period of time, and yet sales are still at $1.6 billion. There's clearly an unmet need for innovation in transplant medicines. We think Tego can improve on both of those. We think certainly we're going to eliminate all of the CNI toxicities we've talked about.
We think it's going to improve long-term graft function and survival. Our eGFR data right now is suggesting that we're actually doing a little bit better than Bela.
That's great. Okay. Just one other one on commercial in terms of reimbursement environment and I guess ability to kind of price a drug within this regimen when we do have things like generic TAC that's available but maybe not being used. I guess how should we be thinking about, and it's too early for you guys, obviously, to comment specifically on tegoprubart pricing, but just getting a drug, getting access there and getting a drug paid for? Can you just talk through some of those dynamics?
Yeah. We haven't really guided that much on the topic, but you could envision that with the annual cost of Bela being $40,000-$50,000 per year, patients are on the drug chronically for the rest of their life, that this should be covered by insurance. All transplant medicines are now covered in the context of insurance providers. If Tegoprubart gets approved for prevention of de novo transplant, rejection should be covered by insurance.
Got it. Okay. Yeah. Let's switch gears and talk a little bit about some of the data that's coming out of the University of Chicago on the islet cell side. Maybe just talk about what you're seeing there. I think quite impressive results in the first three patients, but talk about what you've seen coming out of that study and I guess potential read-through to other transplant settings as well.
Sure. The data coming out of Chicago is absolutely fantastic. It's built on, again, a couple of decades of work. Some of the most amazing data that was originally discovered back in the 1990s with the first generation anti-CD40 ligand antibodies is the ability to induce tolerance in non-human primates. You could basically take non-human primate models of islet cell transplant, transplant in donor islets from another animal, treat them with an anti-CD40 ligand antibody for six months to a year, and then you could wean them slowly off drug, and they'd never reject their islets again. We saw that in a couple of our animals about 10 years ago with this particular drug, tegoprubart, in our non-human primate islet cell transplant study. Collaborating with Peter, this is not a trial sponsored by Eledon. It's an investigator-initiated study funded by the JDRF.
He launched the study about a year ago when he got his first three patients in. He got two of them off exogenous insulin with a single transplant. These are tough patients. They were fairly large body mass. They had had diabetes for decades on really high amounts of exogenous insulin and completely got their HbA1c normalized within 90 days post-transplant. Off exogenous insulin, it's pretty much a functional cure. To see that replicated from many years of animal data is absolutely amazing. It's a significant unmet need, albeit in a small percentage of the T1D population that have really uncontrolled hypoglycemic unawareness events. With additional safety and efficacy, it'd be interesting to see how that population expands a little bit outside that box. Peter's data is very, very encouraging.
Yeah. That's great. I know this is not an Eledon-sponsored study or supplying the drug product, but you don't necessarily control the timelines. You don't control the enrollment. Do we have a sense for are there expectations, I guess, for updated data from the three patients plus or minus some new patients in 2025?
We would anticipate that he'll present some data by the end of the year in one of the transplant conferences in the fall.
Okay. That's great. The total size of that co, I think you mentioned is nine.
He has support from JDRF to enroll up to nine.
Okay. Okay. That's great. Let's talk a little bit about Xeno. This is another one. It feels like periodically, but certainly more frequently, we've seen some very exciting headlines coming out from a number of programs. And Tegoprubart, you mentioned eGenesis. Maybe you could talk a little bit about your collaborative partners in this space and their choice of using Tegoprubart as their CD40 ligand of choice in these really groundbreaking xenotransplant settings.
Yeah. Xenotransplant is just an amazing technology platform. Right? If you'd asked most scientists 10 years ago, would you be able to induce 70 genetic mutations into an animal as a potential source for organs, we might have all kind of raised an eyebrow. To be where we are, even though it seems like a long time, it's actually in the context of science, really not that long. I think we saw a significant amount of progress in xenotransplant in a couple of ways this year. One is we obviously got compassionate use to do a few human subjects across multiple different types of organs. We did the cardiac transplant at University of Maryland. We've done a couple of kidney transplants at Massachusetts General Hospital. As a company, we're agnostic about the technology around the pigs.
We've worked with both United Therapeutics animals with the heart transplant as well as eGenesis with the kidney transplant. We're trying to be collaborative because there is some consensus that translating the technology from non-human primates into humans is going to require inhibition of CD40 ligand signaling. That seems to be one of the key immunosuppressive drugs that needs to be part of that cocktail. The other piece that I think was exciting that we saw in the second half of last year was that they're kind of transitioning from these compassionate use one-off studies to approved clinical studies for both companies. That really needs to happen with a really truly designed protocol where there is some consistency and we can get some better idea about what are the best methodologies to protect these organs post-transplant because they're very different than what we see for allograft transplant.
Yeah. No, that's great. I want to also ask you about it, maybe in a similar vein because we now have, as you alluded to, multi-organ experience on the xeno side. We think about potentially scaling tegoprubart use beyond renal transplant into other solid organ transplant settings. How are you guys as a company thinking about that and approaching that? What would be required? What data do you have to generate?
I mean, kidney transplant was our initial focus. It's the biggest market. It's where most transplants are done. There's more kidney transplants done than any other organ. In theory, based on just the process of the prevention of rejection, the processes are kind of the same. One can envision expanding into other organs, be it cardiac, be it liver. You could also envision going after other unmet needs where the mechanism of action of blocking CD40 ligand makes sense. You could think about antibody-mediated rejection where there's a significant unmet need in treating that. Blocking CD40 ligand prevents B-cell maturation, prevents the formation of mature IgGs, and could be a very good solution or at least potential treatment for antibody-mediated rejection. Much like Bella use has really picked up in the concept of conversion off of CNIs, especially in cases where people have CNI intolerability.
That could be a really great indication once we get further along to test tegoprubart as well.
That's great. I wanted to ask you also about potential use of CD40 ligand outside of transplant setting because there's another I feel like the news flow over the last 12 months has been quite strong for other compounds. I'm thinking UCB, Biogen's dapirolizumab in lupus. I'm thinking frexalimab in multiple sclerosis. How are you guys thinking about potential indication expansion and, I guess, strategic value and read-through from what you're seeing from some of these other large autoimmune indications?
I mean, I have a personal bias with the answer to that question because I was at Biogen in the 1990s when the first anti-CD40 ligand antibodies ended up getting halted during clinical development due to platelet activation. It's really great as a scientist 30 years later to see all of these assets doing well in multiple different indications. The world is your oyster with this particular target as far as where you want to go. The preclinical data is really exciting. I think companies are picking the right indications. The preclinical data in lupus animal models was absolutely fantastic. It was great to see Biogen's positive readout. The data in animal models of rheumatoid arthritis was very, very good back in the 1980s. It is great to see people focusing there.
Some of the other exciting ones that people maybe are just starting to think about probing the biology is the related kidney diseases. The IgA nephropathy, the FSGSs, glomerulonephritises, things like that. I think there's an opportunity there based on the animal data.
Yeah. Okay. Just maybe in the last 30 seconds or so that we have, I think you guys are working on a subcutaneous formulation of Tegoprubart. What's the latest on that? I guess I can envision a world in which that becomes a very interesting lifecycle management strategy and other strategy for maybe getting into some of these large autoimmune indications. What's the latest on the subQ?
Yeah. We have non-human primate data from a subQ. We have GMP-manufactured product. The next step would be a healthy phase one volunteer type study before we go into a patient population. We have not really prioritized it at this point because we kind of like the IV infusion and our clinical trials to support that. This patient population has been on dialysis for long periods of time, going to clinics every couple of days. Having to go every three weeks for a one-hour infusion is not really that problematic from a lifestyle perspective for them. The doctors know they are getting their meds, which also gives them some comfort. We have not really prioritized it at this point as far as a need to get into the clinic, even possibly during phase three, but we are poised to do so should we want to.
Got it. All right. Unfortunately, we're up against time, but thank you, Steven, for joining us. An exciting year for Eledon. We'll stay tuned for the data.
Thanks, Thomas. Appreciate it. Thank you.