Eledon Pharmaceuticals, Inc. (ELDN) Earnings Call Transcript & Summary

Good morning. Thank you for joining us today, both live here in New York as well as online. I'm David-Alexandre Gros, and I'm the CEO of Eledon. Very excited to be here on our second ever R&D Day. We will be making forward-looking statements. So please read both the disclaimers here as well as on our publicly filed documents. Today, you will hear from a group of individuals that include both management as well as experts from outside the company. From the company side, I'll talk as well as our Chief Medical Officer, Eli Katz; and our Chief Scientific Officer and President, Steve Perrin. And from outside of the company, we'll be joined by Dr. Andrew Adams, who is the Head of Transplantation at the University of Minnesota and is working with us on both our clinical programs as well as some nonhuman primate work in liver transplant. We'll also hear from Bill Fitzsimmons. Bill spent a large part, majority of his career with Astellas working on tacrolimus, which we'll talk about today. And today is with the transplant consortium -- Transplant Therapeutics Consortium, which is in discussions with the FDA around the use of a new endpoint, which we'll discuss iBox as an endpoint in clinical trials. We'll also be joined by Dr. Piotr Witkowski. Dr. Witkowski chairs the division of pancreatic and islet cell transplant surgery at the University of Chicago and is doing and leading a lot of the work that -- with tegoprubart in that space. And finally, we'll also be joined by Dr. John Cleveland, from USC, who is going to talk about xeno and the work that he's doing in pediatric cardiac xeno. He is a pediatric cardiac surgeon. In terms of the day, I'll kick things off. I'll then turn things over to Steve to talk about the science behind our lead asset, tegoprubart. We'll then dive into solid organ transplantation, and that will be led by Dr. Adams. We'll then shift to talk about new endpoints in kidney transplantation, and that will be Dr. Fitzsimmons. Afterwards, Eli will come up to run through some of our data to date. And we'll then move into islet cell transplant first with Dr. Witkowski and then Steve to go through our data before diving into xeno. And ending with Dr. Cleveland and then ending the day with me talking about commercial opportunity as well as next steps and some catalysts. And at that time, we'll then open it up for any questions from the audience either here or online. It's been about -- we were talking about it last night, exactly 5 years or so since Steve and I started to work on what is today Eledon. And at the time, when we were looking at what we now know as tegoprubart and thinking about which indications would make the most natural sense for a small biotech to pursue, we chose to focus on transplant. And we did that for a number of reasons that all remain as valid today as they were then. The first one was the science. When we looked at the available science, the historical data, data from -- which Steve will go into looking at nonhuman primate work in transplant really across organ types, across species. We looked at the data that we had generated at the time with nonhuman primates in transplant, the use of anti-CD40 ligand became clear as the best way we believe to protect a transplanted organ. After the science, the second reason was the market itself. As we'll discuss, it was a proven blockbuster market. There had been multiple drugs that has achieved blockbuster sales in transplant, but it was one that hadn't seen much innovation in decades. And so there was this large need for newer drugs or a newer drug that could help resolve some of the issues that had been seen or were being seen with a historical standard of care with the calcineurin inhibitors. And the third reason had to do with ourselves as a smaller biotech. And this is a very concentrated market, as we'll discuss. And so this was one -- it's rare disease like in many ways. And so this was one where we, as a small biotech could undertake and could prosecute programs without needing to worry about the need for scale. Today, we are in multiple areas of transplantation. We have multiple trials going on in kidney transplant. We have trials going on in islet cell. We are IND ready for liver. And we've done work in xenotransplantation, which we'll discuss -- which we'll also discuss. Originally, the company was worked also on ALS. But right now, the program is on hold as we continue to look for nondilutive sources of financing ideally to keep moving it forward. In terms of today, I think we'll go through the full range of areas where Eledon is working on tegoprubart. We'll cover the need that I just discussed for a new standard of care after the calcineurin inhibitors in immunosuppression. In order to do that, we'll talk about some of the issues and the limitations that are being seen with calcineurin inhibitors and particularly tacrolimus, both -- and the impact that has, both in terms of how long organs can function, transplant organs can function, the impact on kidney function even in patients that haven't gotten a kidney transplant as well as the quality of life of the patients. Talking about kidney in particular, we'll focus on the importance of long-term graft survival. If we go back to when CNIs were first approved, it was the acute rejection, rejection in the first year that was of particular importance since organs often did not make it to 12 months. But today, what we're looking to do is extend the functional life of organs. So the question, the need is for organs that can go beyond the decade or so that we're seeing organs function today. In order to help predict how long organs and kidneys are likely to function, we can use eGFR, which is kidney function as one of the best single predictor, but we can get even more power in terms of predictability by using something called iBox, which we'll discuss. We believe that tegoprubart will be able to lead to better long-term outcomes, better protection of transplanted organs and in particular, kidneys, better tolerability for patients and as such, has the potential to replace tacrolimus as the cornerstone immunosuppressant in transplantation. Tegoprubart can also help unlock new markets, and that includes islet cell transplant and xenotransplantation as well. But even without those markets, as we'll discuss, just kidney transplantation by itself could be a large blockbuster size of market and one that has unique commercial dynamics because of how reimbursement is done as well as because of how concentrated a market this is. And finally, we'll finish talking about catalysts to expect from us in the next 6 and 12 months. So with that, let me turn the podium over to Steve to talk about the science of tegoprubart.

Thank you, DA, and thanks for everybody joining us today. It's been about 30 years since immunologists from around the world first started to elucidate and characterize the pathways that were required downstream of antigen presentation to elicit a full-blown immune response. And that seminal work really led to excitement in the field that if you could harness these pathways called costimulatory pathways, you might be able to really control and modulate full-blown immune responses, both to foreign antigens as well as to autoimmune indications. So that seminal work led by Randy Noelle, Jeff Ledbetter and others, started to show that there was interactions that were required between T cells and B cells to elicit that full-blown immune response. And the seminal work that started off was that if you co-culture these cells together, it took activated T cells to elicit B-cell maturation and B cell proliferation. And importantly, if they treated those cells with proteases prior to co-culturing them, all of a sudden activated T cells no longer resulted in proliferation of B cells. And that suggested that there were cell surface proteins or receptors on the surface of these cells that had to communicate and interact in order to elicit that immune response. And then finally, the last graph on the right just shows that if they treated these cells with enzymes that inhibited the ability of messenger RNA synthesis that again, the activated T cells no longer allowed B cells to mature. And this suggested that there was a signaling pathway downstream of these cell surface receptors. These co-stimulatory pathways that they were thinking about in these particular experiments, they still didn't know what the receptors were, but downstream from these elegant experiments they use technologies called expression cloning to clone those receptors, and they identified CD40 as the key receptor on B cells and subsequently CD40 ligand as the key receptor on activated T cells that interacted together to elicit this full-blown immune response. If you fast forward to today, antibodies were generated that could block these pathways. And it became really evident that the key signal downstream of antigen presentation to elicit a full-blown immune response and not have the cells actually apoptosis because they weren't recognizing that antigen were costimulatory pathways and the CD40 ligand CD40 pathway became one of the more prominently characterized pathways to elicit a full-blown immune response. Antibodies that blocked CD40, CD40 ligand, initially antibodies that worked to block rodent CD40 pathways and then subsequently, primate showed that if you treated preclinical models of autoimmunity that blocking this pathway had profound effects and ameliorating disease progression in animal models of rheumatoid arthritis, lupus nephritis, colitis, neurological indications like multiple sclerosis and ultimately demonstrated in ALS, potential to slow down and protect beta cells as a primary treatment for type 1 diabetes. And ultimately, as you'll see, really profound effects in multiple species to prevent transplant rejection with multiple organs as well as cells. That data led to companies focusing on CD40 ligand and bringing humanized antibodies into the clinic. And they focused on the ligand because in those preclinical experiments that I just described, blocking the ligand was more potent than blocking the receptor. Both Biogen and Idec brought antibodies forward in the '90s, focusing on lupus nephritis and an autoimmune indication called idiopathic thrombocytopenic purpura. These early Phase IIa programs looked very, very exciting, showing early efficacy in both programs. And unfortunately, we started to see platelet activation and thromboembolisms that were unexpected at the time when the programs were put on hold. It took 5 to 6 years subsequently to that to understand what was causing the platelet activation in those early antibodies that had full Fc IgG effector function. And it became apparent that CD40 ligand was expressed on the surface of platelets and that once an antibody bound to CD40 ligand on those platelets, the Fc interacted with Fc gamma receptors on the platelet causing platelet activation. Really elegant experiments on the right-hand graph showed that, that was Fc mediated and you could either cripple Fc effector function by making mutations in the Fc or if you completely cleaved off the Fc portion of an antibody, you could eliminate that Fc effector function mediated platelet activation. If you fast forward to today, 30 years later, CD40 ligand is an incredibly well-validated target. As you can see, there's multiple programs in multiple different companies, and we've seen positive clinical data, both Phase II and Phase III data from multiple companies. We have Amgen focusing on Sjögren's syndrome and rheumatoid arthritis showing positive Phase II data in both of those. More recently, Sanofi's presented positive data in multiple sclerosis and Biogen and UCB have shown positive data in their SLE program in Phase III. And as you'll see today, we're seeing very encouraging data with tegoprubart in the prevention of transplant rejection, both organ as well as cellular. So mechanistically, back when these molecules were first characterized, we didn't understand why blocking the ligand was more potent than blocking the receptor. Today, we have a better understanding of that biology, and it really comes down to 3 broad reasons why we think blocking the ligand is more potent. The first is that they're just very different targets. They're expressed on different cell types, and they're expressed in a different way. CD40 is expressed on cells of the monocyte lineage, including B cells, as I mentioned, where it was originally identified. It's also expressed on macrophages, dendritic cells, NK cells and specialized antigen-presenting cells in your organs such as your skin and your gut. And it's constitutively on the cell surface. It's always there whether the cell is activated or not. CD40 ligand on the other hand, is expressed on platelets, endothelial cells and activated T cells. And it's not constitutively on the cell surface. There's negative feedback mechanisms to get it off the cell surface after antigen presentation and pro-inflammatory activations either cleaved from the cell surface to become soluble CD40 ligand or it's internalized and degraded. So when you think about the biodistribution of antibodies and target engagement, these are 2 very different targets. The second thing is biologically, when people think about costimulatory activation with CD40 ligand, they think we only activate co-stimulatory activation through CD40, its receptor, but that's not true. CD40 ligand activates multiple different co-stimulatory pathways. One of the more better characterized in the last few years is activation of CD8-positive cytotoxic T cells through the MAC complex and binding to CD11. It also modulates T cell function by controlling T cell apoptosis. So when you block CD40 ligand, you're blocking multiple different costimulatory signals, not just one. And then the third one that's probably the most unique to CD40 ligand and probably the one that's most biologically fascinating is because it's expressed on CD4 positive T cells, when you block CD40 ligand on those cells, you not only block their pro-inflammatory differentiation, you actually convert them into regulatory T cells, which can create a tolerogenic environment. So that's why we think blocking the ligand is more potent than blocking the receptor. As I mentioned in the last slide, there's multiple different ways and the secret sauce of moving these molecules into the clinic was crippling Fc effector function. There's multiple different ways to do that. With the development of tegoprubart, we decided to make mutations in the Fc portion of the molecule to decrease Fc effector function and eliminate it. We chose that path because of the predictable manufacturability of antibodies, the better drug-like properties than other strategies and the fact that they tend to be very manufacturable and they typically don't have potent ADA responses. So how did we get there with the development of tegoprubart? Well, we started with the original molecule 5C that Biogen was developing in the clinic that I showed you. We showed and started playing with Fc effector function mutations that would eliminate the interaction with Fc gamma receptors. As you can see in the left-hand part of the slide, we compare binding to CD40 ligand. And as we made these mutations, we did not impact binding. But as you can see in that one graph with 5C8 that interacted quite potently with several different Fc gamma receptors, we don't see that with AT-1501 or tegoprubart. We've completely eliminated Fc gamma interactions with tego. More importantly, we wanted to show that if you crippled Fc effector function, did you eliminate platelet activation. We did this with FACS experiments showing that if you incubated platelets with immune complexes in an antibody, would you increase PAC1 expression, which is a protein on the surface of platelets that shows that they're activated. You can see in the left-hand graph, there's a little shift in the orange and pink when you incubate immune complexes with Biogen's original 5C8 molecule, and we completely have eliminated that with tegoprubart. So why did we start to focus on transplant as an indication, as DA indicated? Well, this is a meta-analysis of all of the nonhuman primate data going back 30 years, showing with monotherapy arms, how different types of drugs performed at preventing transplant rejection in nonhuman primates. And this is specifically kidney transplant rejection. So these are Kaplan-Meier plots, percent survival on the y-axis and days is on the x-axis. As you can see, not surprisingly with the black line, untreated animals pretty much lose their organs. If you don't immunosuppress at all, they lose their organs in a few days. Tacrolimus, the current standard of care as a monotherapy, as you can see, the gray line, it really doesn't do that well as monotherapy. Median survival is only a few days to a couple of weeks. Belatacept, which blocks a different costimulatory pathway than CD40 ligand does a little bit better than standard of care. That's the gold line. But again, as monotherapy doesn't do incredibly well at protecting organs. The blue line is 4 different anti-CD40 receptors, including the original iscalimab model. But you can see the orange line. That's 4 different anti-CD40 ligand antibodies. And you can see why we focused on transplant to this day, blocking CD40 ligand has been the most potent way to prevent transplant rejection, both acute and long term in multiple different species, rats, mice, nonhuman primates. And hopefully, that's going to translate here into humans. Similarly, this is work that was done by Andrew Adams lab. We'll talk a lot about xenotransplant today. The last slide showed allotransplant where you're transplanting monkey organs into other monkeys. Here, they were transplanting pig organs into nonhuman primates and really telling the same story. You can see that tac does not do as well at preventing xeno rejection in nonhuman primates compared to anti-CD40. But again, anti-CD40 ligand is clearly superior at preventing xeno rejection in nonhuman primates. And if it's one thing that the field has kind of coalesced on in the world of xenotransplant, if you're going to translate this into humans, blocking CD40 ligand is going to be a critical component to prevent xenotransplant rejection. And with that, I will introduce Andrew Adams.

Thanks, Steve, and thanks for setting the stage. My task today really was to talk about the need. I'd say solid organ transplant, just as an overview is really a success story of medical innovation over the last kind of 50, 60 years, but there still is a long way to go to be able to go and transplant a patient, give them a new lease on life and say you've got the rest of your life to go ahead and live versus talking about the need for a transplant again in 10 or 12 years. And so kidney failure, just as an overview is a huge problem, not just in the U.S., but globally. And we think about the burden of disease of how many people are living with kidney disease or kidney failure, it's a huge number. And the mortality rate, we think about dialysis, the option for patients that have their kidneys failing as a real option for them to go ahead and live. And what I think is really untold or unrecognized is the mortality rate as they transition from their kidneys failing on to dialysis and then living on dialysis. While it does preserve life, it does -- it has many limitations. And then with liver failure, we talk about the burden of end-stage liver disease. When we think about the most productive years of life, kind of middle-aged life, 40s to 60s, it's the third most common cause of death. And so it's a growing indication for transplant. We see that in the number of transplants that are performed, the number of people that are diagnosed with liver disease. And that could be said also for cardiac and for lung transplant as well. There's a huge number of patients that are on the waiting list because the bulk of those are kidney or potential kidney transplant recipients, they are waiting on dialysis. The other organs aren't as fortunate to have that modality to kind of preserve them for a few years until they can get a transplant. And the number of transplants that we perform is really limited by the number of donors that we have right now. When thinking about the burden of end-stage renal disease or end-stage kidney disease, just the picture there from the paper on the left just shows the prediction from 2010 to 2030 of the increasing number of patients who are going to suffer from kidney disease and thus benefit from some form of kidney replacement therapy and the gold standard there is kidney transplant. It is a huge, as many of you know, piece of what we spend our health care budget on as Medicare covers most of these patients, and that's predicted to not to continue to increase over the coming years. So it's a huge burden on our health care system. With the rising tide of obesity as well as the comorbidities that go along with that, the predictions are that we're going to continue to have an increasing number of patients who will suffer from end-stage renal disease. This is also complicated by the fact, in some ways, we're -- we suffer from our own success. We're able to care for these patients better and better year after year. And so the aging population in the past may not have survived that long on dialysis and now we're able to help them over a number of years. And so the number of people that can benefit from transplant will continue to grow, especially in those categories that are in the higher decades. And this is just another graph to illustrate the increasing burden of liver disease here, looking at from the '90s out to now our time, the increasing number of patients that have been diagnosed with end-stage liver disease and cirrhosis. This is a nice article to illustrate the promise of organ replacement therapy. And this really sometimes we just look at the number of patients who are on the waiting list. But that is a very small subset of patients who might benefit from organ transplant. Because we have a limited resource right now with the number of organs that we're able to use, there could be many more patients that would benefit from transplant when some of these new therapies come through. And this is just to highlight that as they suggested that the true size of the organ shortage could be many times larger than is reflected by the waiting list that we currently see. When we look at the waiting list, again, around 100,000 patients, but when we kind of distill that down into the number of patients that we see day in and day out in the clinic that could benefit from transplant, the numbers are staggering. And the benefit comes as we develop new therapies. And that's why there's really a lot of excitement surrounding this pathway and this particular reagent to be able to prolong the life of the transplant that we give. Kidneys by far represent the largest number of patients who exist on the transplant waiting list. But you can see that the need far outstretches the demand -- or the demand far outstretches the number that we can transplant now. The need is very high. This is just to illustrate kind of increasing demand and limited supply. And some of that is that we have patients that get a transplant and then they need another transplant. If we can prolong the life of those transplants, we're able to then expand the number of people that can be transplanted. And then as we'll be talking about later, Dr. Cleveland and others talking about the really exciting therapies that may be emerging to be able to expand the number of patients who can benefit from transplant and the role that CD40 ligand therapy plays in being able to make that happen. So if you look over the years of the decades, the number of people on the top list, total number of transplants, transplants from the ceased donors and living donors increasing over time, but a limited number of transplants that we can do, some of that's based on the therapies that we have. But by far, kidney transplant is a much better -- has much better outcomes than dialysis. Again, dialysis is a good short-term therapy. It's not a great long-term therapy. And when people are able to access transplant, they live not just a better quality of life, but a longer life. But that life span of that kidney that's transplant is limited. We've done a very good job, and I'll show you in the next few slides of focusing on the early outcomes after transplant. Well, why was that? In the early stages of kidney transplant and organ transplant in general, the focus was on limiting acute rejection. We had very limited therapies to be able to treat that and rejection at that time meant kind of graft failure, again, in the '70s and the '80s. As new therapies emerged, initially the calcineurin inhibitors, cyclosporine in the '80s, tacrolimus in the '90s, this really did a good job at limiting early rejection rates. And so our 1-year rates there on the -- of survival are up into the 90% now. And so it's really a story of success. But when we look at the longer-term outcomes at 5 years, at 10 years, we start to see that those therapies are limited in their efficacy to the early short-term period and that the side effects that are associated with those therapies really limit the longevity of the transplant and in general, the longevity of the person receiving that transplant. And the focus now for our field has to turn not just from the first year or 2, but it has to turn to the first 10 years and 20 years. When we see patients in their young -- in their early 20s talking about getting a transplant, for them, 10, 15, 20 years, sure is much better than living on dialysis. But then they're looking at the need for having another transplant in their 30s, 40s, 50s, maybe a third transplant when they get into their 60s. And so what we need are new therapies that really preserve that function and give that patient a lifetime with their transplant without the side effects that are associated with calcineurin inhibitors. So this just illustrates in the '90s when this is when cyclosporine was used, tacrolimus was emerging, really the success that the field of transplant had was in limiting the rates of early rejection and early graft loss. Again, rejection in that period of time meant that the kidney failed it wasn't salvageable. With new treatments now, we can treat early cellular rejection and be able to benefit from the long-term effects of having better therapies. And that's what we've seen with this kind of class of agents of co-stimulation blockers of which tegoprubart is one of. And so this success in the '90s was really about limiting early acute rejection and the focus wasn't on long-term effects. And so -- but what we've started to find, we're talking to people, especially as they're receiving kidney transplant that might not be from ideal donors, older donors, donors that -- whose kidney function we might not expect to be that long. You can see that the half-life of those is not just 10 years, but could be even less. And so what we really need are therapies that not only protect the graft early on and if we need to treat kind of early episodes of rejection, that's doable now with new therapies with -- that have come out in the interim period and really focus on long-term outcomes. And so this was work that was done by Ulf Meier-Kriesche, a nephrologist at the University of Florida at the time that really looked at when do grafts fail and what is the outcome of those grafts. So on the left hand there, you can see that over the period in the '80s and '90s into the early 2000s, that line that comes down from 20% down into the single digits was really the first year of survival and that's where the field focused on. The other lines were just look at 1 to 3 years, 3 to 5 years, 5 to 10 years, the longer-term outcomes are really flat. And that's where our field has been for many years since the advent of cyclosporine and tacrolimus. And then they started to focus on, well, why do those grafts fail in the longer term? Why patients needing to return to dialysis or the need for a retransplant. And much of it had to do with some of the effects that those particular molecules had, the cyclosporine and tacrolimus on the graft itself. To put this in perspective, some leaders in our field started to look at our outcomes, our longer-term outcomes on what it meant for a kidney transplant patient. And when you look at the survival rates on dialysis or on the wait list, over time, 5-year survival rates started to approach those that with other diseases, cancers, in fact, that we view as kind of morbid, so melanoma, colon cancer, kidney cancer, breast cancer, survival rates where we say those are really unacceptable. And what we in the field of transplant, although kind of our own making our own success thought, hey, we're doing really well with early 1- or 2-year survival rates of 90%. What we needed to focus on was now 5-, 10-, 15-, 20-year survival, where those rates really approach rates that in other fields were seen as unacceptable. And I think our field is finally coming to that realization over the last 10 years that we really need to focus on developing new drugs that will -- will enable people to live longer and their kidneys and other organs to survive longer. When we look at why kidney transplants fail and these different effects are also associated with other organ transplants. The vast majority or the majority, 50% die with a functioning graft. The other make up basically a compilation of what we call chronic rejection or immune-mediated effects or scarring on the kidney graft itself. And when we look at people who die with a functioning graft within that first kind of 6 months to year, over time, you see that a lot of that is due to cardiovascular effects. So increased rates of cardiovascular disease, high blood pressure, high cholesterol, et cetera, that we know are going to limit the lifespan of the individual receiving that and some of the nonspecific effects that we see with the current sets of immunosuppression. And so when we think about immunosuppression or drugs that limit the immune response because we have to do that to prevent rejection of an organ transplant, the ones that we use today, cyclosporine and mainly tacrolimus, along with other an antimetabolite or steroids or rapamycin, which is another class of agents, they have targets not just within the immune system. So they don't just inhibit T cell or B cell function. We also see those side effects where they're inhibiting pathways that are in other cell types within the body. Many people suffer from tremors, from seizures, neurotoxicity. That's not an uncommon thing to see in the hospital for patients that have been transplanted. Again, I mentioned the cardiovascular risk that increases with these agents. We know that they have higher rates of high blood pressure, high cholesterol. There's a higher rate of diabetes in these patients. And more importantly, these can have direct effects on kidney function, not just in patients who receive a kidney transplant, but those that receive a liver or a heart or a lung transplant. These drugs that we use to limit early rejection have long-term effects on the patient's overall health. And this is just another paper in the early 2000s to illustrate that fact where they looked at patients who received something other than a kidney transplant, a lung transplant, a heart transplant, a liver transplant and looked at rates of in this case, kidney failure over time and in large part due to the medications that we're giving them to limit that early rejection. You can see for liver transplant, for example, up to 20%, 25% of patients at 10 years develop kidney failure because in large part of the medicines that they're using to protect the liver transplant that they received. And we see that not uncommonly patients coming back in now needing a kidney transplant in large part because they're on tacrolimus or cyclosporine, and that has had negative effects on their kidney function. In fact, this is a colleague, Dr. Flavio Vincenti that's UCSF and a nephrologist. And this is looking at kidney transplants over time and looking at the effects of CNIs on those kidney transplants. And by 10 years, almost all of those kidney transplants have pathologic evidence of CNI toxicity scarring on the kidney due to the effects of the drugs that we're giving them to prevent rejection. This is a real problem that we see, not just scarring on the kidney, but the other effects that limit the lifespan of the transplant and limit the lifespan of the individual receiving that. So what we need is really targeted immunosuppression, molecules that are mostly restricted to the immune response itself. And that's where this whole field of co-stimulation blockade or co-stimulatory molecules that were discovered in the antibodies like tegoprubart were developed to finally kind of tune the immune response to accept a graft, but not have the widespread effects that we see with CNIs. So the promise of targeted immunosuppression is really less medication-related side effects, a better cardiovascular profile, like I mentioned. It's been seen in other trials and proven to have lower rates of diabetes, less high blood pressure, less medications for that, lower rates of neurologic side effects. And then most importantly, in kidney transplant, better kidney function over time. And so despite even seeing early rates of rejection that can be easily treated nowadays, with new therapies, we don't see the long-term effects that we've seen when we see rejection on CNIs. The most important part of that is antibody formation. And Steve talked about the key role that CD40 ligand and CD40 play in activating B cells and ultimately developing antibody. And I think one of the best properties of this molecule is limiting antibody. The antibodies are what cause long-term damage to the kidney transplant as well as other organs. And that is really the more difficult type of rejection to treat. If we can prevent them from forming to begin with, we don't need to treat them later and less scar formation directly from those drugs. And then it really opens up the opportunities for many other indications like what we talked about xenotransplant and others and the potential for drug minimization in the long term where there's less polypharmacy, less side effects. And so I think the promise of having a targeted pathway like tegoprubart is really exciting for our field, exciting for our patients and seeing the progress forward in the trial. And I think as Steve kind of illustrated, the CD40 pathway really is the most important pathway that we've seen in preclinical work, both in animal models and now kind of moving forward into humans. If you -- as his graph illustrated there at the end, it is probably the most important pathway to prolonged graft survival. We prioritize long-term survival now, moving away from focusing on the first year after transplant to focusing on 10, 20 years or more. Really needs a new class of medications to be successful there to increase and maintain kidney function and limit those cardiovascular effects that really patients end up dying from because of the mix of medications that we're giving. And as I kind of detailed previously, the really most effective part of that is preventing anti-donor -- antibodies to the donor and preventing that damage that can occur long term and limit the graft survival. And then opening the door for new therapies in xeno, bioengineered organs, immune tolerance, all of those are coming and CD40 ligand plays a key role in the success of those opportunities. And with that, I'll hand it over to Bill.

Thank you, Andrew, and good morning. As DA indicated, I'm Bill Fitzsimmons, and I spent most of my career, 29 years at Astellas Pharma, first heading the development of tacrolimus in transplantation and retiring from there as the Head of Global Regulatory Affairs. But since leaving Astellas, I've also been working in a public-private partnership, the Transplant Therapeutics Consortium in order to advance innovative tools that we can use in kidney transplantation to bring new therapies in this space in a precompetitive way. So I'm going to highlight some of those. So it shifts kind of from the field and some of the science you've heard about now to the regulatory science in this area. So I'm really going to focus on the kind of endpoints we use when we're studying new immunosuppressants in kidney transplantation. And if we go back to 30 years to when this all started, it was when we were working on agents like tacrolimus and MMF. And at that time, it was decided through the discussions with the FDA that the primary endpoint in this area for pivotal trials would be something we call efficacy failure, a composite that includes biopsy-proven acute rejection, death, graft loss and loss to follow-up. And really, the reason why we made it into a composite was not because we valued death the same as acute rejection. We were really looking to say, if we're going to measure acute rejection as the effect of the drug, how do we do that without sensoring for events that can occur before rejection happens. That's how we ended up with the composite. And as you've seen over time with the current standard of care, those acute rejection rates and efficacy failure rates have continued to fall so that now we have acute rejection rates after kidney transplant in the first year that are less than 10%. So all of our studies that we do now tend to be non-inferiority trials because we can't show improvements over that less than 10% acute rejection rate. And all of our drugs have the indication from the FDA of prophylaxis for organ rejection. But no therapy is improved for what Dr. Adams just described as the real need for improving long-term graft survival. And the other problem that we have is even if we can show an effect on acute rejection, that endpoint, and I'll show you some data on this, actually is poorly prognostic for long-term survival and is clearly not predictive from the standpoint of a treatment effect. So this was really our call from the Transplant Therapeutics Consortium to say, how can we do better to bring an endpoint that actually addresses this issue of improving long-term survival after transplant without causing us to do studies that we have to wait for 5 years or 10 years to know that it will do that. So that led to the introduction of a surrogate endpoint that we call iBox as a surrogate endpoint that we could measure at 1 year post transplant that is prognostic and predictive of the long-term survival of that organ. And iBox is a composite biomarker. So it's all biomarkers that currently exist today. We're not measuring something that isn't measured in clinical practice currently. but we're simply taking those factors and combining them into a composite biomarker. So the iBox consists of measures of kidney function, eGFR as well as proteinuria, measures of the immunologic response of the recipient to the graft, mainly the donor-specific antibody or DSA to the HLA antigens in the blood. And then we can add in a biopsy performed by -- at 1 year, a protocol or surveillance biopsy, if we would like to enhance the scoring. But you don't have to have a biopsy at 1 year. So we have 2 forms of the iBox, one that we call the full iBox, and I'll show you the data on that, which means you have performed the biopsy at 1 year, you have those data and one that simply uses the blood and urine components, that being the abbreviated iBox that has eGFR, proteinuria and DSA included in it. Now the origin of the iBox goes back to Loupy [ et al. ] in the Paris Transplant Group, and he published a seminal paper in the British Medical Journal in 2019 in 4,000 kidney transplant recipients, really showing the ability of the iBox to be prognostic for a given patient for their long-term survival of their graft. And the intention at this time was to use it in patients to help predict what would happen and intervene if there's -- there were long-term negative consequences of their current state. But we looked at that iBox and said, we can change that into an endpoint by not measuring it at any time post transplant, but fixing it at the 1-year post-transplant time point. So we took Loupy's original work and then with a 4,000-patient derivation data set that you see here. And we then validated it in 4 independent groups of kidney transplant patients. 2 from single centers, Mayo Clinic in Rochester as well as Helsinki and 2 from prospective randomized Phase III trials from Bristol-Myers Squibb, their BENEFIT and their BENEFIT-EXT studies, both of which included belatacept in a non-CNI regimen compared to a CNI-based control arm of cyclosporine. So we have a derivation group and then 4 external validation groups that we're looking at. Now by having this degree of variability in terms of the data that we assess, we're really able to say how does the iBox perform with all available immunosuppressive mechanisms. So we have in this data set, lots of CNI-based patients more tacrolimus than we have cyclosporine, but we have both. We have belatacept-based regimens. So we're looking at non-CNI regimens that hit the co-stimulatory pathway. And we have mTOR, both sirolimus and everolimus treated patients. So basically, all the immunosuppressive regimens we have, we've tested the iBox across these 5 data sets. Now I'll be -- we've looked at this in a number of different ways trying to say how does the iBox perform in terms of predicting graft loss. And we are looking at graft loss prediction at 5 years post transplant, but we actually could predict at other times if we wanted to, but we've picked the 1-year measurement to predict 5 years. And one of the metrics that we use is a C statistic for discrimination. And just to give a quick primer on that, on the C statistics, you're basically looking at the area under the ROC curve that's the trade-off between sensitivity and specificity, where on the X-axis is minus your specificity and on the Y-axis is your sensitivity. So the further the curve is up into the upper left-hand corner, the better it is. So a perfect test for discriminating would be one that had a C statistic of 1.0, which would mean it has 100% sensitivity and 100% specificity. Of course, no test has that, but that would be perfect. And one that's not very useful or pretty much useless just by random chance, has a C statistic of 0.5, meaning for every trade-off of specificity, you lose sensitivity or vice versa. So it's been defined that a good test is a 0.7 or greater and a very strong test in terms of its discrimination is 0.8 or greater. So if you can put those numbers kind of in your mind as we look at some of the data on the iBox. So these are the data from our qualification package that has been submitted to the FDA. Again, looking at the iBox at 1 year post transplant as a predictor of 5-year graft loss. And then we have the 5 data sets that I've just described. So on the right side of the screen is the C statistic for the abbreviated iBox. Again, that's without a biopsy, just kidney function and DSA. And if you look at the iBox at 1 year in our 4 validation data sets, you see that all of them perform at least in good. Actually, in the Mayo Clinic, it's very strong at 0.84. So we have 0.7 to 0.84 in 4 independent external validation data sets for kidney transplants in terms of predicting that 5-year graft loss. When you then add in the biopsy into that assessment, which is the middle column of the full iBox, you can see that numerically in some of the data sets, you do improve that C statistic. It's kind of marked in the Mayo Clinic data set and not so much in others. Some actually don't move. But the bottom line is we have a good to strong predictor of 5-year graft loss with or without a biopsy by using the iBox assessment at 1 year. Now you might say, what's important in that iBox in terms of the components. And we know historically that 12-month eGFR is the single best predictor of long-term graft loss. So I'll look at first at some papers that were describing that on the left side, here's a relatively recent paper from Jesse Schold and others, where they actually took more than 32,000 U.S. kidney transplant patients, both disease donor living donor. And their goal was to say there's a lot of intercurrent events that happened in the first year post transplant, acute rejection, cardiovascular events, infections. How are they at predicting long-term graft survival compared to the 12-month eGFR. And what they found is even if you control for all of those intercurrent events, including acute rejection, the most dominant driver of graft failure is that 12-month eGFR. So we know from other independent work that the 12-month eGFR is really an important driver even if you control for acute rejection. And that relationship as shown on the right side, as the eGFR goes down at 1 year, the hazard ratio goes up. So the lower your eGFR at 1 year, the more important that hazard ratio is, and it's in a log linear fashion. So if you looked at this in a linear fashion, it drops very quickly and then kind of flattens out as you get to 50, 60, 70 ml per minute of eGFR at 1 year. So we know that historically. So then we want to look more specifically at the iBox data. So we kind of parsed out the iBox to say, all right, people will say, you really don't need this, why don't you just use eGFR or why don't you just use proteinuria. So we kind of took it apart in the pieces. So again, starting at the far right, we said, what if you took the iBox and only put eGFR in it. That's the only component, what would the C-statistic look like? And you can see that they're actually still pretty good. There's one data set from BENEFIT RCT that doesn't reach your 0.7 as a threshold for even a good C-statistic, but we're getting 0.7 in the other 3 external validation data sets with eGFR alone. So it tells you eGFR is doing a lot. It's still the primary driver here in the calculation. And then the iBox continues to get better, you can see numerically as you add other components. So you add proteinuria into this, which is, again, a continuous measure that we know is associated with graft loss, you get a little bit better iBox score in most data sets. Then you add the DSA, which is a relatively infrequent event. But if it occurs, it's a very bad prognostic factor. So if you add DSA into it, meaning the abbreviated iBox, the C statistics even get stronger. And then as I showed before, what happens with the full iBox compared to the abbreviated. So this really shows you, again, the iBox is more than eGFR alone, even though eGFR is the primary and predominant driver of that calculation. And then you can ask yourself, well, you've got the data, and this is what we are kind of wondering about, how does actually the iBox compared to acute rejection in the exact same data sets, right? Because people tended not to do this, they compare across publications. So what we did was we took all those 4 external validation data sets where we had acute rejection rates. We had all the iBox comparisons, including the biopsies at 1 year and said, what would the C statistics look like if we compare acute rejection, which people historically have said is associated with, is correlated with graft loss, which it is. It's associated and correlated statistically, but it's really a poor prognostic factor. You can see BPAR in this analysis has a C statistic of 0.57. So I don't think any of us would say a 0.57 C statistic for BPAR is a great one for predicting 5-year graft loss, definitely not. And you compare that to the combined validation data sets where the full and abbreviated iBox are 0.81 and 0.80. So we have very strong predictors from the iBox with or without the biopsy and a very poor predictor from acute rejection alone. And both of those are highly statistically significant in terms of comparing iBox to BPAR for a C statistic. So again, we were able to show in the same data, we're doing a lot better for predicting 5-year graft loss with using the iBox compared to just looking at acute rejection, which has been our historical precedent. Now when we -- we're in the process of regulatory validation and qualification of the iBox. And one of the questions that the FDA asked us along the way, and we actually had it in our qualification plan, but they wanted more detail on it was what's the minimal clinically important difference in the iBox because their concern is you're using a continuous measure you might be able to find a statistical significant difference that's clinically irrelevant, right? A small difference in iBox that reaches a P less than 0.05, but it really doesn't mean much in terms of its ability to predict long-term graft survival. So when you look at these MCIDs, you typically look at the totality of evidence. There isn't one calculation that gives you the number. But what you want to do is look at both what's called distribution-based and anchor-based methodologies for determining the MCID. So I'm showing you both here. So the distribution-based method says, what is the variability of this measurement in just various populations tested and take 0.5 of the standard deviation. So when you do that distribution-wise, you get a range of MCID 0.38 to 0.45, depending on which group you look at. Then if you look at anchor base, what you're basically saying is we know that there are factors that are really important in terms of prognosis of graft loss and what it would be the iBox if you saw those. So if you look at eGFR at minimum MCID of 5 up to 10, it's 0.23 to 0.46. If you look at the most prognostic bad biopsy lesion that you see, which is the transplant glomerulopathy or C score, CG score, that's 0.38. And going from virtually no trace to 0 proteinuria up to moderate proteinuria is 0.45. So we get an overall MCID that we've proposed the FDA of 0.4. And that 0.4 translates into a 4% to 5% difference in graft loss at 5 years post transplant. So you might say, what's that mean, 0.4 or 4% to 5% difference in graft loss. If you look at what Dr. Adams presented, there's 27,000-plus kidney transplants a year. If we can improve the survival at 5 years by 4% to 5% that's 1,200 to 1,500 additional grafts that are functioning at 5 years and then continuing every year on. Those 1,000-plus patients not only have a functioning graft, they're not getting on the retransplant list. Those organs are going to other people who are waiting on the list. So it can be a big population impact. For a given patient, that difference is about a 1.5, if not greater, reduced risk of graft loss at 0.4. So if you said to someone, I can show you a result that's going to reduce your risk of losing your graft at 5 years by 1.5x, that's -- we think that's very clinically important. And frankly, no drug has ever shown statistical significance on endpoint for long-term graft survival for immunosuppression. So we know that this is an important difference. So where are we at in terms of the regulatory qualification? First, starting with the European Medicines Agency. We took that route first. The EMA has qualified the iBox, both abbreviated and full as a secondary endpoint to use both in Phase II and Phase III trials. And this is the first time the EMA qualified a transplant endpoint. Now the reason why it's not used in other applications there is they don't have an accelerated approval program using reasonably likely surrogates the way the FDA does. So it's a much more rigorous process with the FDA. The FDA is a reasonably likely surrogate. We're proposing it as a co-primary with efficacy failure in the accelerated approval format. So we have been working very diligently over the years. We have an accepted letter of intent, accepted qualification plan from the FDA. At the end of February, we submitted our full qualification package. That's the last of the 3 steps to get iBox qualified as an endpoint to use an accelerated approvals in the U.S. And just 2 weeks ago, we received a notification from the FDA that, that FQP has been accepted for review, which puts us on a 10-month review clock. So we're feeling very good, fingers crossed in terms of the ongoing review of the FQP with the FDA. And you might say, what can that do in terms of getting a surrogate endpoint that's reasonably likely and use an accelerated approval, what can it do for innovative therapies in the field? We know historically what's happened in HIV and oncology with accelerated approvals. It's revolutionized the introduction of innovative therapies. But even more recently, if you look at IgA nephropathy, something closer to us. Back in 2017, there were no approved therapies. It was the first time the FDA at end of Phase II meeting said the sponsors will accept proteinuria as a reasonably likely surrogate endpoint and use it an accelerated approval. That started the Phase III development. And over the last 4 years, there's been 4 new therapies that have been approved using accelerated approval with proteinuria as a reasonably likely surrogate for IgA nephropathy. There's an additional BLA currently under review taking the same approach and lots of drugs in Phase III development. This has changed IgA nephropathy from a field that was dead in terms of new therapies to being one of the most innovative in terms of renal disease. That's what can happen if you have the FDA partner with you to get the endpoint and the accelerated approval pathway. So with that, to conclude, the iBox we see, it's certainly the only endpoint from transplantation that's in the FDA qualification program that's addressing what patients want, which is one graft for life, more tolerable immunosuppression, better safety profile. What regulators want, we're using it in a co-primary endpoint and what clinicians need and bringing new therapies that really are prognostic for long-term survival. And we can claim superiority. We're stuck in this noninferiority conundrum with the current endpoint of efficacy failure. This opens it up and opens up the ability to have an indication in our label that's not just prophylaxis of rejection. And doing that using the FDA accelerated approval pathway that doesn't preclude us from using the traditional efficacy failure non-inferiority endpoint if we don't hit superiority on iBox. So I think it brings a lot to the table, and I'm really looking forward to further discussion and the full qualification of this endpoint. Thank you.

Good morning. I'm really excited to be here today and to see all of you here and people online. I've been in transplantation for the last 30 years in different roles in clinical transplantation and in drug development. I had the privilege to work on another CD40 ligand blocker in the previous company. So I was very, very excited when I was able to join Eledon about 1.5 years ago and work on the development of tegoprubart, which I think is a very promising new immunosuppressive drug. So I would like to review with you our development plan. It's composed of three studies that run parallel. The first one that started also chronologically was a Phase Ib study that composed of single-arm treatment of about 12 to 14 patients per cohort. And we are going to present to you a little bit later some data of 13 patients from this Ib study. We're testing different tuning of immunosuppression on this different cohort and more data will come in the future. The core immunosuppression for this is only tegoprubart with the standard of care MMF and steroid and induction with Thymoglobulin. The Phase II study, the BESTOW study is actually the first ever randomized controlled study that was put CD40 ligand tegoprubart against tacrolimus. It's a randomized study that enrolled about 120 patients equally randomized between the two arms. And the two arms is, as I said, tegoprubart versus tacrolimus with the standard of care associated immunosuppression, MMF, steroids and ATG induction. The third study, which we are running is extension study, which means every patient from the Phase Ib of the BESTOW study who reached the 12 months' time point, have the ability to enroll to the extension study and continue therapy with tegoprubart. This is the design in more details of the Phase Ib study. As you see, it's a 1-year study. Patients started with only tegoprubart in combination with MMF. Steroids is being withdrawn until 5 milligram a day at about day 30 and continue to the end of the study. All of them are with induction with ATG. At the Cohort 1, we had ATG up to 6 milligram per kilogram. In Cohort 2, it's up -- it's a 4.5 milligram per kilogram. All of them getting MMF from the day 1 continue up to month 12. Some of the results related to coming from a 13 patients in the Phase Ib. So this is demographic. And although you see some difference between living donation and deceased donor that has to do probably with logistics issues that it's easier for investigator to enroll living donation. However, in spite of this more living donation donor versus deceased donors, if you look at the main parameters that usually indicate high-risk population, our median recipient age is 59, pretty old compared to median overall of 51. Our median donor age is 49 compared to about 44. And our mean HLA matching is 4.4, which indicates to you that in spite of the high rate so-called of living donation in this population, we are actually enrolling this study pretty medium to high-risk patient population. So we are not -- didn't select the best patients for the study. This is some of the safety outcome, and it's important to note that there was no cases of hyperglycemia, new onset of diabetes mellitus or tremor. So we free from all the major side effect that we see with tacrolimus or with cyclosporin. Of the 13 patients, 1 patient was discontinuation -- discontinue because of alopecia and fatigue. The patient decided he doesn't want to continue. The other patient who discontinue was due to BK viremia at day 54. And the last patient out of the three were discontinue -- we discontinued due to rejection at day 176. It was a Banff 2b rejection. Other than that, if you look at the overall distribution of different side effects or adverse events, there is nothing here that really stand out different from what you see usually in a population post kidney transplantation. So we're pretty satisfied with the safety of tegoprubart in this kidney transplant patient population. Going back to what we discussed already previously about eGFR. eGFR is the gold standard to assess kidney function. It estimated glomerular filtration rate. It basically represents how much blood is filtrated through the kidney in any particular minute. This what you see here is a result of about 5,000 patients looking at their eGFR over time. The left graph shows you the first 48 to 50 days, and you see the difference between deceased donor and living donor. However, they all stabilized at around the 50 ml per minute. Just to give you the sense of relation in a normal person, like hopefully, all of us here, eGFR is about 120, 110 ml per minute. And as you get into kidney disease, it starts to go down and of course, getting to a level of 20 or less, it's end-stage renal disease. Here, what you see here that after liver transplantation, liver -- sorry, after kidney transplantation, you have an average of about 53 ml per minute. So it's about less than half of what normal should be. And this is after kidney and the difference between deceased and living is kind of get disappeared after about 30 days to 40 days after transplantation. Also and very importantly, if you look at the right side of the graph, you see over the years, what happened between patients who are on calcineurin inhibition like tacrolimus or cyclosporin versus patients who are CNI-free. So although both of them started around the 50-something ml per minute, you see that those who are on free CNI-free regimen it's -- they continue to be stable at around the 50, 53 ml per minute. However, over time, over the first few years, those who are on calcineurin inhibition, a significant drop in eGFR as time is going forward. And as we just heard from Bill, eGFR is a very strong predictor overall of graft survival. So coming to our study, this is the first 13 patients. You see here, this is the average mean of eGFR in the first year in our Ib, Phase Ib study. And if you see here that we are -- the overall mean eGFR of all reported time is about 70.5 ml per minute, which is significantly higher than what I just showed you about around the 53 ml per minute. And at all time points, we have eGFR above 60. The red line here is the one that reminds you of what I just saw you in the previous slide of about 53 average in this study of about 5,000 patients. So we are pretty encouraged by this eGFR performance of our first 13 patients in this Ib study. We are going to report a larger patient population from our Ib study, about 30 patients in the upcoming World Transplant Congress in San Francisco beginning of next month. This is going to be a report of 30 patients and is going to happen, if you're interested, in August 6 in the morning, and Dr. John Gill from University of British Columbia in Vancouver will present the data. Going into phase -- our Phase II, the BESTOW study. I'm not going to talk about results because the study is ongoing, and we don't have the results yet. But as far as the design of the study, as I said earlier, it's a randomized 1:1 study stratified for type of donor age and HLA. Patients are randomized either to tegoprubart that start at day 1 and then given at day 3, 7, 14, 21, 28 and then every 21 days in combination with induction therapy with ATG, MMF and steroids. The control arm is tacrolimus, again, start from the beginning with combination of corticosteroid and MMF. The endpoints are at month 12 and the endpoint for this study is powered for superiority of eGFR. So we expect hopefully to show eGFR -- significant eGFR difference between the two arms. Something to note is that our enrollment of the BESTOW study was completed about four months ahead of schedule. We saw a lot of enthusiasm and excitement with the physician and the transplant centers, and it was reflected in the way that this study was enrolled. The other thing to note, I think it's important is I mentioned the extension study, the patients are moving at the end -- coming to the month 12, they can move into extension study. We have now about 60 patients now in the extension study, and the conversion rate, if you look -- try to assess how many of those eligible are moving into is about 90%, which for us is an indication that the patients and the physicians are feeling good about the treatment, trust the treatment and willing to continue on the same regimen. What happened this year is going to be very exciting. We have -- as I mentioned, we present our Phase Ib study in the WTC in beginning of August. We're going to have our last patient, last visit for the BESTOW study, the Phase II study in September. And we're hoping to present the top line results in first week of November in Houston in the Kidney Week meeting. So we are looking forward to all that. This represent two kidney transplant catalysts, the data from both Ib study and Phase II study that are expected to come in the next few months and each really mark a keystone in advancing tegoprubart for patients in need. So we are very excited and looking forward to that. So, thank you, and I will welcome Dr. Witkowski into the stage.

Thank you. Good morning. Thank you very much for the invitation and opportunity to present. So I will present today results of our pilot study on three patients with tegoprubart and islet transplantation to treat type 1 diabetes. The study has been supported by the research foundation by The Cure Alliance and Breakthrough T1D and Eledon provided medication, tegoprubart free of charge. So this is some background information. So as we know, type 1 diabetes is autoimmune disease that destroys insulin-producing cells of the pancreas that's causing high sugar, hyperglycemia and related health complications. There's over 2 million Americans who live with type 1 diabetes. Insulin injection still remains as a standard of care therapy, but maintaining optimal blood glucose remains difficult despite technological and medical advances. As we know, now we have closed loops, insulin pumps and continuous glucose monitoring, which help patients, but they're still not perfect. There is over 80% of patients with type 1 diabetes who has hemoglobin A1c above 7%, which reflects inadequate blood glucose control, still despite the best technology. 33% of patients report impaired awareness of hypoglycemia and 10% experienced life-threatening severe hypoglycemic episode severely compromising their life. 5% to 8% of adults with type 1 diabetes experience diabetic ketoacidosis, which require hospitalization. So definitely, there is a need for improvement. And whole pancreas transplantation can -- allows patients for normal glucose control, but it requires major surgery and has some risk of complications. So islet transplantation has been developed as an alternative and a minimally invasive alternative for whole pancreas transplant, but it still requires the same immunosuppression, which we need for any other organ transplant. So how we do islet transplant. We take the deceased donor pancreas and instead of transplanting this as a whole organ, we take it through our laboratory and we isolate the islets, the cells. And then we put them in the solution and then we put them in the infusion and we just infuse the islets into the -- through the small catheter placed under local anesthesia by interventional radiologists through the skin into the liver, and we infuse the islets into the liver. It's -- there is no surgery, just the infusion. So one option is to get the islets from the deceased donor pancreas. Another option, new option is that the islets can be manufactured from the stem cells as we heard recently from the results in the -- from the Vertex trial, which were published in New England Journal of Medicine recently. So the new options are coming. And the advantage of having islets is manufactured from the stem cells, the cell product can be available off-shelf in unlimited amount in contrast to islets from deceased donors. So the field is progressing. But definitely, there is still need for better or less toxic immunosuppression to protect the islets from rejection. So this is design of our pilot study. Instead of tacrolimus, which is standard of care and has toxicity about -- we heard about. Now we're using tegoprubart together with Myfortic the oral medication for induction. We use the same Thymoglobulin, which we use for any other transplant like kidney or pancreas transplant. And then tegoprubart is given on day minus 1, 0, 1, 3 then weekly for a month and then every 3 weeks, the same way as it's given in the kidney trial. And these are the results in our first patient. So this was patients with a relatively high BMI and high insulin requirements of 80 units per day. And as you see, this is the hemoglobin A1c, which reflects glucose control. Normal glucose control is below 6. So this patient started with 8.4 and as you see, gradually decreased the A1c and also insulin requirements from 80 units to 16 units. And at this point, we performed a second transplant, provided more islets and then 2 weeks later, patient was able to completely stop insulin and remain insulin independent with optimal glucose control A1c of 6. Patient unfortunately decided to relocate to distant location and decide not to that this is too much challenge for him to come back every 3 weeks to ask for infusion and switch to tacrolimus, but still remains insulin independent. These are the results in second patient. And this patient, as you see, the same thing, improvement in blood glucose control. And after 1 month after only a single transplant patient stopped requiring insulin and became insulin independent. And actually, next week, we will celebrate 1 year of insulin with the patient. And every 3 weeks, we test the islet function -- every 3 months, we test the islet function by the mixed meal glucose tolerance test. And then it just shows you that the islet function remains stable, the same glucose control, the same C-peptide, which corresponds to the insulin secretion at 1 month, 6 months and 9 months. So again, stable islet function. And this is patient #3. Again, this is the patient with high BMI, very high insulin requirements prior to transplant, 90 units of insulin, very poor glucose control before the transplant. After first islet infusion, again, improvement in glucose control and then decreased insulin requirements from 90 to 20, 12 and then received a second transplant and patients a few weeks ago became insulin independent as well. And what's important has been tolerating tegoprubart therapy very well. And this is his current glucose control. This is the continuous glucose monitoring. As you see, very stable glucose control without any insulin -- any need for insulin support. So these are the -- this is again, mixed tolerance test, assessment of the islet function in all three patients together. What I'd like to point to you that each patient decreased insulin requirements by over 60 units in this particular study when we use tegoprubart. Historically, we know that islet transplant allows to lower insulin requirements by 40. So this tells us that this regimen, it's more effective and the islets are working much better, providing better glucose control. And this is just to show that, again, this is the C-peptide in mixed tolerance test, which corresponds to the insulin -- amount of the insulin secreted during the test and it just basically shows that there is a high C-peptide, high insulin secretion and very efficient islet function in our patients. So in summary, in all three subjects achieved stable islet graft function, improved glucose control and all three achieved insulin independence. There was -- there were no unexpected adverse events, no severe hypoglycemic episodes. What's important, no opportunistic infection, which we can see with other medication, no thromboembolic events, which we were worried based on the old studies. No signs of kidney toxicity of neurotoxicity, which we see in patients on tacrolimus and no problems with gastrointestinal system. There were no signs of rejection. No signs of de novo donor-specific antibody. And what's important, all labs will remain within normal limits or there were not clinically significant. So overall, patient has a great experience. They have no side effects. And importantly, for us, also, there is no need for any medication adjustment, which is necessary when we have patients on tacrolimus. There is a constant need of checking the labs, adjusting the dose, which is also challenging for the patients. We also look at the islet engraftment, again, based on the mixed meal tolerance test and C-peptide secretion, and we compare the results in our three patients, in green on tegoprubart to our historic controls. On the light blue, this is the islet engraftment in patients on tacrolimus And islet engraftment in our tegoprubart patient was two, threefold higher than in historic controls on tacrolimus, but also to our best ever patients with best results on tacrolimus in Reparixin study. And those three patients, they remain insulin-free over 10 years after the islet transplant and they have not as good engraftment as we observed in our tegoprubart patients, which give us hope that the islet function can remain stable for a long time. So what is the plan? We will -- we're planning to extend the tegoprubart therapy in our first patients in those patients for the second year, the same way as it's been offered into the kidney transplant patients. We already received funding from breakthrough T1D to extend the study for 6 more patients. Three patients -- in three patients, we already started the immunosuppression, and they were actively looking for the pancreas donor, and they are about to receive the islet transplant, hopefully, in July. Three more patients has been identified. What's also is very exciting that recently, we received funding from Breakthrough T1D, additional funding to test the same approach, the same therapy in type 1 diabetics who already has some kidney dysfunction. And we haven't been able to offer them any therapy because of tacrolimus toxicity. So this is really exciting, and we're looking forward.

Okay. Next one. Yes, Steve. Steve is Back. Thank you.

So Eledon is obviously very excited about the opportunity of islet cell transplant for treatment for patients with type 1 diabetes. We're excited not only by a long history of nonclinical data, but the data that -- microphone is not high enough. Sorry, I'm short compared to Dr. Witkowski. I mean really excited about the early clinical data that we're seeing that, again, translates blocking CD40 ligand from preclinical work that's been done over the last 30 years into the clinic. We're excited to continue to support Dr. Witkowski in his ongoing study that he just presented and enroll an additional up to nine patients in that study. As he mentioned, he recently got funding from BT1D to expand into a slightly different patient population with impaired kidney function, and we're going to excitedly provide tegoprubart for that study as well. As you may have seen today, we also have agreed to support supplying tegoprubart for an additional cohort in Sernova's ongoing clinical trial with their Pouch technology using cadaveric islet cells on their pouch as a potential treatment for patients with type 1 diabetes. And we intend to utilize some of this early data from Dr. Witkowski's study to approach the agency in 2026 on what a clinical development program could look like for tegoprubart in conjunction with islet cell transplant as a treatment for patients with type 1 diabetes. We strongly believe that the field has been working in islet cell transplant for quite a long time. And one of the biggest impediments to its adoption more globally is that the CNIs, as he showed you, are incredibly toxic to the transplanted islets. And that if we can substitute tegoprubart for CNIs, you're going to see better engraftment, better islet cell metabolic function and hopefully better outcomes. So Eledon is really, really excited about the opportunity to continue to utilize tegoprubart in conjunction with islet cell transplant for people with type 1 diabetes. And hopefully, over the next year or so, we'll be announcing some additional collaborations in the field. And I'll welcome Dr. Cleveland to the stage.

All right. Well, admittedly, I'm a congenital heart surgeon. And that puts me in a really niche field for really the health care market in general. What I do serves a very small portion of patients, and I spend most of my time at the bedside, practicing reiterative medicine that's just doing the same thing over and over again and getting the same results. But every once in a while, technology comes along that offers promise to alter the way we do care, to transform the current care paradigms. And so I'm really excited and the work we've been doing with blocking anti-CD40 ligand in order to potentially offer the children we care for a different life and a longer life because we're not -- while we're talking about a small niche market, we're talking about 20, 30, 40, 50, 60 years into the future. And so it's really important that we think about their care differently. So my hope today is I can sort of just share our story with you for that ultimately to be a reflection of what can potentially happen with the remainder of the health care market and other organ systems. Dr. Adams went over this extensively. We have a problem in organ transplantation. There's a lot of patients who get listed for organ transplants. The same number of transplants happen every year. It's essentially stagnant. And the reality is the demand for organ transplantation just exceeds the supply. Within the microcosm of what I do from day to day, this is what that looks like. Every single year in the United States, we do anywhere from 400 to 500 pediatric heart transplants, and it hasn't changed in the last 10 years. The problem with that is we're adding patients at a rapid rate. We figured out medically how to keep them alive longer. We figured out how to kick the can down the road. And so the waitlist has increased by about 40% since 2011. So it's actually higher than 36.7% at this time because this graph is to 2022. But the problem is that's impacting really fragile children who are all under the year of five years of age, primarily because older children compete with adults for organs, and so they get those organs preferentially the way that organ allocation works at this point in time in the United States. But children who are less than five are receiving less and less transplants. And what that translates to is they're sitting on the waitlist for months at a time with a median waitlist time of around four months, but 36% of children less than one years of age will die before organ can be found. So this is what our ICUs look like. It's babies attached to machines that were originally designed for adults. They're filling up our units at a rapid rate because we are trying to figure out how to keep them alive long enough until a suitable heart can be found to try to sort of combat that 36% waitlist mortality. This is a detriment to families. This is a detriment to the children. These are profoundly important developmental years that these children are spending in the hospital, not going home and an incredible tax on our system that's being funded essentially by our government at this point in time as most of these children are state insured. So this is our vision. We got vision for this about five years ago to utilize currently available technology in the form of genetically engineered pig heart, place them into critically ill infants in lieu of machines so that the children could be discharged home on the waiting list until a suitable human allograft could be found, so that we could bridge them safely over to the time when a human heart could be found. Incidentally, children who are less than one year of age, when they receive a human heart have the best outcomes of any solid organ transplant within any single organ system or age group. What's going to enable this is two key pieces of technology. One that has been certainly popularized in media recently in the form of genetically modified pigs who like the 3 major carbohydrate antigens and have human transgenes added in to make them more immunologically compatible. And then what we're here to talk about today is co-stimulation blockade. These are really the tenets of what's going to make this technology successful. In order to sort this out and sort of prove concept on our way to the clinic, we needed an animal model because this didn't exist. So we went about creating this, subsequently taking genetically modified pig hearts out of infant pigs, pigs that were four weeks old, placing them into pediatric baboons and putting them on a really simple immunosuppression regimen, tegoprubart, rapamycin and a very low-dose corticosteroid. We would leave these hearts in for four months, which is the median waitlist time required to find a human allo transplant and subsequently take those hearts out in favor for a prospectively cross-matched heart from another healthy baboon that was size matched as well, place that in and switch over to a traditional immunosuppression regimen comprised of calcineurin inhibition, mycophenylate mofetil and a corticosteroid. It is a really busy slide, but these are the results from the 15 orthotopic cardiac xenotransplants that we've done. One thing that's worthwhile noting is this is a really difficult model to figure out in terms of doing cardiac transplant in a veterinary facility on 3 and 4 kilogram baboons. But things that are really important to highlight are the results. So one, we have an animal who's still alive today almost 700 days with a functioning orthotopic heart that's sustaining her. She's running around her case. She's developing normally and appropriately, hitting all her appropriate developmental milestones. We subsequently have many others who have lived beyond a 1-month period of time and greater than 50% of our cohort, which happens to be some of the best results within the xenotransplant literature. And four out of the five longest living animal survivors with an orthotopic heart are here on this list. And that's historically throughout all of time. These results are well explained by how well the hearts function on the immune expression regimen that they're on. They maintain normal diastolic function, normal systolic function. This is a video of a heart that we went back and took out at four months. It's in a regular rhythm. It's got normal systolic function. And then at the time of pathologic expectation and evaluation, the myocardium was completely normal. So no inflammatory infiltrates on that three-drug regimen that I mentioned previously. These results are explained by the immunology. So if you look at the development of anti-pig donor-specific antibodies in all of these animals over time, they just don't form them. So the y-axis on this graph on the left side at 1 represents pre-transplant anti-pig DSAs. And you can see that if you track each and every one of these animals that live beyond 30 days, none of them formed anti-pig DSAs of any clinical significance. Of importance to us, particularly as we're looking to go back and take out these pig hearts and replacement for a human allograft, being on tegoprubart during that period of time also precludes allosensitization. So xenografts are really, really immunogenic, really antigenic and typically necessitate a large amount of immunosuppression to preclude rejection. In addition, they incite a lot of inflammation within the animal, which you would expect to potentially sensitize them to same species. And in this case, these are pre-transplant sensitization levels in the gray bars, postoperative day 115 xenograft exposure sensitization levels in the pink bars. So this is animal prospectively crossmatched to 10 other animals that were appropriate size, and there's no difference in pre and post xenograft exposure, same species sensitization. You could argue that that's for a lot of other reasons, but we fortunately and incidentally did sort of a self-control to determine how impactful tegoprubart was in precluding the development of anti-pig DSAs. So this is an animal who underwent removal of the xenograft at 133 days post implantation with an exchange for an allograft. I left a small piece of pig tissue within that animal knowingly, not thinking that it would be any issue as we switched over to a calcineurin inhibitor. When we switched over to a calcineurin inhibitor at day 133, immediately our anti-Pig DSAs took off despite therapeutic calcineurin inhibition. So tegoprubart was absolutely necessary to preclude a reaction to the pig tissue and highlights how important it's going to be in the field of xenotransplantation as a whole. When that happened inside of a massive inflammatory response that subsequently resulted in actually rejection of the allograft just due to the inflammation that occurred and the result of increase in reactivity to the baboon graft at that time. Mechanistically, I'm not sure we entirely understand everything that goes on with tego within the system and particularly why it has the impact it does. But I think one really key thing to highlight for you is the difference between calcineurin inhibition and tegoprubart and its impact on T regulatory cell function and circulating immune modulating cells. T regulatory cells are super, super important for setting up a mill of immune accommodation, which is paramount in the necessity of long-term graft function. When you're on calcineurin inhibition, it reduces T cell function, reduces IL-2 production and you have much less regulatory T cells circulating within the system, almost none in some series. In our animals on tego, they recover their T regulatory cell function almost immediately after induction with immunosuppression with ATG immunosuppression. This is a flow cytometry from 14 days after xenograft implant and induction therapy, where you can see a highlighted impact of a massive amount of T regulatory cells that recovered during that time. This played out clinically important for us where we were able to document that dips in T regulatory cells that are circulating with these animals coincide with episodes of rejection and subsequently, the recovery enhanced by additional doses of tegoprubart resulted in stabilization of those episodes, recovery and ongoing life for those animals with -- maintained with orthotopic xenografts. So these are just the basic points that we learned. We know that tego appears to prevents xenosensitization, prevents allosensitization, allows for T regulatory cells to recover and function normally. The longest living orthotopic xenograft that's in history and in the world at this point in time in published literature is maintained on tego to this day on a weekly basis. And then anecdotally, development and growth are not hindered. We haven't had a single animal have an infection on tego. It's resulted in an alteration in their care or a need for antibiotics, which is incredibly encouraging to me as I pursue this application in pediatrics. There's a few things that are worthwhile mentioning, things that get me excited about tego as we move forward. And some of those we've begun to pursue in the lab. There's about 50,000 people in the United States every year who need a valve replacement, 300,000 worldwide. We don't have a suitable valve replacement within human beings. The ideal valve would be one that's organic, one that doesn't require blood thinners, it's resistant to infection and it grows with the recipient. Xenografts are actually poised to meet this need, but you need a medication that's going to be tolerable to immunosuppress them for a period of time until the valve becomes xenografted. The biggest limitation is people aren't going to tolerate being on calcineurin inhibitors for a prolonged period of time in exchange for a blood thinner. Our animal results demonstrate that you can maintain these valve, have them function normally and grow appropriately on once-weekly isolated single-drug immunosuppression with tegoprubart. That's an exchange that we'd be willing to make, I know, in the pediatric world in exchange for multiple reoperations, five, six, seven reoperations on a child throughout their life. Lastly, and what's clearly been highlighted in some of the kidney literature presented today is the potential for allo transplant immunosuppression, particularly in the heart world. And I'll speak primarily to pediatrics because that's what I deal with. When a child receives a heart when they're one and they go on calcineurin inhibition, you're starting the clock until they're going to represent with kidney failure and the need for renal transplant. That's just the sheer nature of calcineurin inhibition. We have two patients in our unit right now who are 4 and 10 years out from heart transplant who are on dialysis now listed for kidney transplant. The ability to end the nephrotoxicity of calcineurin inhibition within cardiac allo transplantation would be a massive step forward and obviously transformative for children and adults alike eventually. And then lastly, and then if you could get to a place where that immunosuppression regimen can be decreased in the setting of what is proposition with tego, you're looking at the ability to reduce the overall lifetime risk of cancer and then the impact of infections on those individuals. So with that said, I'll pass it back to Dr. Katz.

Yes, this area of xenotransplantation is actually very fascinating. I want just to share a little bit of some clinical work that we were doing in the last year or 2 years with collaborator with eGenesis, the pig editing company and with Harvard Medical School. So the first patient about a year ago, received the first ever person kidney into a patient. He was doing well for four months. He visited the clinic at about four months. He was fine in the morning, went home and died at night probably from cardiac -- massive cardiac event with a functional xenograft. Second patient was done just celebrating this week, six months of survival at home, functioning, no dialysis with a kidney. I was involved in eGenesis and in Xeno for a while. It was a dream that we ran about two years ago that this will maybe happen one day. Here it is. Not only that, he throw the first pitch of Red Sox's game just a few weeks ago. So a functional patient with a peak kidney now crossing the six months' time point. We expect to continue -- and these three patients -- I mean, these two patients were on tegoprubart as part of their massive immunosuppression therapy they're getting. So this tegoprubart play a major role as you, I'm sure, learn from Dr. Cleveland presentation. We expect to continue to support activity in kidney, and there is now movement with the agency to really approve NDA -- I mean, INDs for Phase I studies. They're going to happen with kidney transplantation from pigs, xenotransplantation. There is also seems like our path much clearer to go to registration and to go to approval of kidney xenotransplantation. As you heard from Dr. Cleveland, we're hoping with the continuation of the preclinical work to move into human pediatric xenotransplantation sometime in the next year, 1.5 years. So all this is really exciting and promising. I think we are at the beginning of a new period in organ transplantation using xenotransplantation. And the opportunities here is the sky is the limit.

So before we go into Q&A, I'll begin to wrap up thinking about the commercial opportunity here. We sometimes forget how large a market transplant is already from a commercial perspective. So if we go back historically, transplant was one of the first blockbuster markets. When cyclosporine was approved back in the early '80s, that became a $1 billion-plus drug globally. And then it was replaced by tacrolimus, which too became a blockbuster. And in fact, what's interesting with tacrolimus is that despite the fact that it's now a 30-year-old drug, branded tacrolimus, so Astellas still reports revenues of its branded tacrolimus of about $1.4 billion. So this is a market that is multibillion dollars in size and where we've had blockbuster -- now multiple blockbuster drugs going back over 30, 40 years. And here, we have an opportunity for -- as Bill discussed earlier, for the first time in decades to have a drug that can show superiority. So most of the drugs have been approved since then. And for example, when tacrolimus took over from cyclosporine, the initial approvals were around noninferiority. But hopefully, now using prognostic endpoints, we'd be able to show superiority with tego. I'm going to focus on the U.S. I'm also going to focus on kidney transplant because that is the largest indication. Now our vision for tegoprubart is to be used across all transplant types. So all solid organs, cells and regardless of the source of the transplant. So whether it's stem cell-derived cells, so man-made cells, whether it's Xeno or a deceased or living donor. And the reason to focus on kidney first is that is where most of the transplants are occurring. Today in the U.S., kidney transplantation represents about 60% of the transplants done. Now if we think about what prior drugs have achieved, so what cyclosporine achieved and what tacrolimus achieved. And we ask ourselves, well, could tego be an even bigger drug, and we believe that it could. And the reason for that is that both the supply side of the equation as well as the demand side of the equation support it. So from the demand side of the equation, as we've discussed earlier in -- earlier today, there continues to be even specifically for kidneys, an increasing need for transplanted kidneys. And that's because patients are living longer, there's more end-stage renal disease from hypertension. There's more end-stage renal disease from diabetes. And so all of that is helping to drive an increased demand versus what we have seen in the past. From the supply side, we are seeing a lot more organs transplanted today. So here, and this was briefly showed by Dr. Adams earlier, what you're looking at is the total number of transplants performed in the United States going back 25 years. And so that's the dark blue line on top. And those organs come from two sources today: living donors, so typically family members that donate their organs to somebody they know or disease donors, which is what we typically have in mind. Someone passes and donates their organs to another individual. Now if you go back 25 years, you'll notice the number of living donors hasn't really changed. We are doing the same number of living transplants. So the change is -- and the increase in the supply is coming from the deceased donors. And that's the result of multiple things, including new technologies and the fact that we're now able to take hearts that used to be considered too risky to be transplanted, but transplant them and have those patients do well. So we're -- if we go back to what cyclosporine and tacrolimus have been able to achieve, we believe there's going to be increased demand as well as increased supply, which should help the market. Furthermore, this increased supply should also provide a tailwind in terms of the potential market size. And the reason goes back to these higher-risk organs. So one of the things that's occurring is as we're getting more comfortable as a field using higher-risk organs and using higher-risk kidneys, these kidneys because they're higher risk, may do better with a drug that is not nephrotoxic and physicians may want to use a drug that is not nephrotoxic on these higher-risk kidneys. And that, too, should help grow the market for tego. Moving to how transplanted kidneys and especially how immunosuppression for transplanted kidneys is paid for. This is a different way than is typically seen in other parts of health care. So as we probably all know, dialysis today is covered by the government. The federal government guarantees that anyone in the United States that needs dialysis should be able to get access to it. And similarly, that's true with immunosuppression as well. So there is -- under federal law today, pretty much anyone in the United States that's received a kidney transplant in the U.S. is eligible for Medicare to pay for their immunosuppression if they don't have another source of insurance. So about -- as you can see here, 1/3 of patients have private insurance, but there's about 50% of patients that are using Medicare to pay for their immunosuppression. And that coverage lasts for life, and it's regardless of the age of the patients as well as the patient's ability to pay. So as long as someone doesn't have their own insurance, then they can apply to have Medicare cover their immunosuppressants. And we think this too will help to help ensure that patients can have access to novel medicine like ours. From a call point, this is a very concentrated market. And when I first started talking today, I mentioned that this was one of the things that made it attractive for us as a smaller biotech. It made it attractive for us because we could do clinical trials here. But as we move hopefully into the future into being commercial, then it will also make it attractive because we can build the commercial infrastructure that's necessary to sell a drug here. So in the United States, there are about 220, 230 transplant centers that do kidney transplants, but 20% of those centers do half of the kidney transplants in the country. If we look at the top 80% of kidney transplants done in the U.S., the number only goes up to about 102. So you don't need a large sales force to call on 102 institutions, and that's something that a smaller company like ours can tackle. Interestingly and also importantly, these are -- because the market is so concentrated, we already know the centers. So the 40 centers, 45 centers today where we are conducting tegoprubart kidney research, right, our clinical work in the U.S. are pretty much the top centers that you see here. Today, we've spoken about kidney transplant. We've spoken about islet cell transplant. We've spoken about xenotransplant. We've spoken about a little bit liver transplant, where we'll be presenting data. Dr. Adams will be presenting data in August on some of the nonhuman primate work with tego. We've spoken about heart transplant, but there are opportunities beyond these areas as well. There's, of course, other types of transplants, so whether it's intestine, lung, et cetera, but there is a large market for therapeutic adjacencies. Perhaps the largest market is switch. All of the discussions we've had have been on de novo, so new patients that are going on immunosuppression. But there are 400,000 Americans today, if we focus on the U.S. that are living with a transplanted organ. Most of those patients are on TA. And those patients might have an opportunity to switch from their current immunosuppression to tegoprubart in the future, and that would represent a market of -- an immediate market of hundreds of thousands of patients. Other potential markets include antibody-mediated rejection, graft versus host disease and desensitization. So those are patients that have -- already have antibodies that make it harder for them to take a -- to receive a graft. And perhaps one of the most exciting areas as we think about long term, and this has been a little bit of a holy grail in transplant is tolerance induction. So imagining a world where patients would be able to get transplanted, get put on immunosuppression for a certain amount of time, but then be able to get off immunosuppression and no longer need immunosuppression and still have their organ protected. Now it might sound like a little bit of science-fiction. But if we go back to five years ago, if we had this discussion and we had talked about someone going home with a pig kidney and being six months out and throwing out a baseball at a Red Sox game, that too might have sounded far-fetched. And yet the field has advanced, and this is where we are today. So when it comes to tolerance induction, I'm happy to announce today that we are starting a tolerance induction IST at MGH, and that is now up on clinicaltrials.gov as we start enrolling into the trial, we'll get back together and provide more details on that trial. But just in terms of time, we thought it best not to dive into tolerance today. So to wrap up, our goal is to become the new cornerstone immunosuppression with the ultimate goal of permitting patients that receive an organ transplant to be able to keep that transplant for life. We think one of the reasons why we may be able to do so is because of the -- while calcineurin inhibitors have unlocked modern transplant medicine, there is still an opportunity to outperform how they're doing in terms of protecting organs, particularly for the long term as well as improving patients' quality of life by removing some of the side effects typically seen with those drugs. We're currently running BESTOW, and we look forward to that data later on in this year, and this is the first head-to-head trial of our drug of tegoprubart where we're looking to show superiority versus tac. In order to look at that superiority, the endpoint we're using is eGFR. As we discussed, eGFR is the best single predictor of long-term graft function and iBox can improve the power of that prediction. So we will, of course, report eGFR as well as talk about the iBox, iBox scores moving forward. If we can get to organs that can function longer, then that might allow us to help reduce the wait list for transplanted kidneys really in thee ways. One way will be because the longer a transplanted kidney works, that individual will not need another transplant, potentially may not need another transplant ever, which would free up another kidney. For other organ types, for example, we talked about heart and impact there. If patients aren't losing their -- those patients aren't losing their kidneys after getting another organ transplant, then that too could free up kidneys that could go to other individuals. And finally, of course, xenotransplantation could -- is maybe one of the best ways to completely solve the organ shortage overall. From a market perspective, as we've discussed, this is a proven blockbuster market, and we believe that the opportunity is likely larger today. And finally, in terms of catalysts, -- we have a very exciting rest of the year. I think we've had an exciting first half, but the second half is poised to be even more exciting. We'll have data that we'll present at the World Transplant Congress in August, and so that will be our Phase Ib update. At WTC, we'll also present data from the nonhuman primate liver transplant work. Moving into November, we look forward to presenting the Phase II data. Outside of kidney transplantation, we expect to continue to enroll, as Dr. Witkowski mentioned, patients in the ICT study. In ICT, we're also excited with the new Sernova collaboration, and we expect to enroll in their study as well this year. Going now beyond allo transplantation, we expect to continue to enroll xenotransplant patients and to have more news on that front, so more patients enrolled. And finally, as I mentioned, we're kicking off the MGH immune tolerance induction, excuse me, study, and we expect to be able to enroll our first subject in that study this year as well. So an extremely busy 6 months upcoming for Eledon. As we go into next year and really into the first half of next year, with all of that information, we expect to begin to engage the agency on our Phase III for kidney transplantation as well as on what could be a path forward in islet cell transplantation. Hopefully, we'd be able to begin to enroll in the trial with -- for patients with impaired kidney function, and we will look to a path in humans for liver transplant, so liver transplant IND early next year as well. So with that, I will ask my -- the presenters to come up, and I am happy to open up the floor to questions.

So thank you, firstly, for a lot of really good detail. You guys kind of touched on this, but when it comes to Phase II data readout this year from BESTOW, what should we be expecting? Maybe you can just walk back through what would -- what delta would achieve significance and sort of what you've talked about in terms of powering things.

Sure. So the question was around powering of the Phase II BESTOW. So the primary endpoint on eGFR where the study is 80% powered to detect a 9-point delta in eGFR between the two arms, so between tego and tac. And that would be a clinically meaningful difference.

Thank you for hosting this event.

And if you don't mind stating your name just this way, for the transcript.

Yes. Pete Stavropoulos, Cantor Fitzgerald. For one of the co-stimulatory blockers approved, belatacept, there was a high level of biopsy-proven acute rejection versus cyclosporine, although long-term outcomes of graft survival favored belatacept. For the KOLs, how concerned are you about acute rejections? At what Banff grade are you really becoming concerned? How manageable are they? And are all acute rejections managed the same way? And then for the company, taking into account the mechanism of action of tego, that's -- it's also a co-stimulatory blocker. What are your expectations for acute rejection rates from the Phase Ib and Phase II.

Sure. Andrew, let me turn the first part of the question over to you.

Yes. No, I think it's a great question. We learned a lot from that benefit trial with belatacept, the first trial in kidney transplant patients with a co-stimulation blockade reagent. Acute cellular rejection in the '70s, '80s, even into the '90s was a challenge to kind of deal with in that first year. So with the advent of CNIs, that kind of changed the acute rejection rates. Belatacept and tego are part of that class of co-stimulation blockade reagents. We typically have seen in the benefit trials, as you mentioned, a higher rate of rejection. What was interesting there, though, is that those rejections can be treated usually with T cell depleting therapy, which is used commonly in kidney and other organ transplant recipients now. The difference between patients treated with a co-stimulation blockade agent like belatacept versus tacrolimus was the long-term effects because of that rejection. So typically, acute cellular rejection was treated in those patients, and they didn't really pay a penalty in the long-term effects with regards to kidney function, filtration rate and then more importantly, de novo antibody production. So it's really the development of antibody in the midst of a cellular rejection that portends a poor outcome long term. And the unique properties of co-stimulation blocker reagents like tego are that they prevent antibody from forming to begin with. And so the grades of rejection are treated differently, some with steroids initially and some with T cell depleting agents. But I think the more important point is that's generally easily reversible with T cell depleting agents and the effects long term are more related to the intrinsic properties of CNIs, whether they're profibrotic, causing scar tissue to develop after rejection or antibodies, which also can cause long-term loss of function versus co-stimulation blockade reagents that don't have that effect. And so in the end, I think people that are on reagents like tego benefit long term with their function versus being on CNIs where we see that decline in function over time, even in the midst of rejection.

And from the -- to your question about rejection from our perspective and how we look at it, I think the primary endpoint is eGFR. And so it's kidney function. So we are very focused on being able to show a differentiation between tego and tac. And that's what is going to give us the confidence that over the long term, we'd be able to show better organ survival versus tac. In terms of the other -- or the other AEs that we look at, and I think there's a number. It could include infections, it could include, of course, rejection. There are some of the traditional AEs that are associated with CNIs. So the tremor, the brain fog, the hypertension, the new onset diabetes after transplant and the like. And we'll look at -- it's going to be important to look at not only the efficacy component, so the eGFR delta, but also the totality of how the drugs are comparing. So looking at the full panoply of side effects that could be occurring. Since some of them might be short term and might not have a long-term impact on the kidney, as Andrew just mentioned, for example, rejection, but there are some of the side effects that might occur that could severely impact patients for the rest of their life. For example, if someone gets post-transplant new onset diabetes, they now have diabetes for the rest of their days.

So for Eledon, how often does the DSMB meet? And is the DSMB the same for the Phase Ib and Phase II? Or do they see both data sets? And then sort of tied into the question, you recently disclosed that you're enrolling patients into the Phase Ib, receiving 10 milligrams per kilogram, half the original dose that the Phase Ib started off with and the Phase II is using. What drove that decision to test a lower dose?

Sure. Eli, do you want to talk about the DSMB?

The DSMB is one DSMB for both the Phase Ib and the Phase II BESTOW study. They see data from the BESTOW study every month to make sure that some criteria that we have in the study related to safety are not being made as far as stopping the study or modify the study. So far, in all the meeting up to this point, we got the conclusion that the study can go on without any modification. They review also on a regular basis, on a quarterly basis, all the data from the Phase Ib and the Phase II, the BESTOW study. So this is the -- what we have from the DMC. They have a very renowned infectious disease person on the DMC. We have nephrologists who is the Chair of the DMC, and we have a statistician and another internal medicine person. What was the other part of this?

So this is part of what gives us confidence in terms of how the trial is going. So obviously, the DSMB is able to look at the data. And here, there is some overlap between safety and efficacy since if you don't have enough efficacy that would be safety, there would be a safety component. And we're now at a point where half or more of the patients are out over a year in the Phase II BESTOW study. And so -- and all of the patients are out nine months or so. So a lot of the time period where rough patches may be seen in the first 12 months are behind, and we've been able to get through those well if we consider that the DSMB has allowed us to keep on going. Similarly, as Eli mentioned, we're seeing high enrollment rates into the long-term extension. We're at about 90% enrollment, which suggests that the patients, although we don't know how well those patients are doing, but it suggests that overall, those patients are doing well enough that they and their physicians are excited to keep going. And I think you asked the second part, which was around the 10 and 20 in the Phase Ib. So there's some historical factors to consider here. So maybe even taking a step back, the reason why we're doing a Phase Ib is obviously to have data to announce to the field, to have data to discuss with investors, but it's for the company because this is how we learn to use tegoprubart. When we started, the FDA had given us the feedback that we had to use maximal dose tego, which was the 20 milligram per kilogram with maximal dose ATG. So that's where we started. As we generated data and began to show safety and efficacy with that dose, we were able to get more flexibility. So we were able to get, first, the flexibility to look at different doses of ATG -- and then we were also able to get flexibility from the agency to begin to look at a lower dose of tego. And so that's why we're now able to look at 10 mgs, 10 mgs per kg.

Robert LeBoyer, NOBLE Capital Markets. In your discussion of iBox, you mentioned the European agencies might be ahead of the U.S. in accepting it as a clinical tool. And then in the prospects for Phase III, would you include it as an endpoint in the Phase III? And how would the timing of the European and the FDA acceptance of it as a tool affect the timing of the Phase III initiation?

So, Bill, maybe I'll turn it over to you for the question of the difference between the U.S. and -- was that the first part of the question...

Yes, that's right.

U.S. and EU regulatory perspectives on iBox, and then we can talk about how we'll use it in our trials.

From the European perspective, their process for qualification is much quicker. So we're able to do that in under a year, which is why we went there first. But because they don't have a reasonably likely surrogate endpoint to using what they call conditional marketing authorization, we weren't able to use it as a primary endpoint or co-primary and would only get it qualified as a secondary endpoint. So I think it opens the door that you would want to, from my perspective, include iBox at a minimum as a secondary endpoint in any kidney transplant trial that you would perform. I think the key is if qualification comes through from the FDA, which we're hoping is targeted for April of 2026, that would open the door to consider using it as a co-primary endpoint for a U.S. trial.

And then from -- you asked about what that means for timing for the company. So from our perspective, the timing is good because today, the reason we're using in BESTOW eGFR is that was the feedback the agency gave us when we first started to talk about doing the trial that became BESTOW back in 2021. Now next year, we'll be able to take the data from BESTOW. We're going to -- and from the Phase Ib. We'll have, of course, the eGFR data. We'll also be capturing the iBox data, and we will be able to have discussions with the agency on Phase III design using the data and with the benefit of the agency giving feedback on their perspective with iBox. So regardless of what the agency decides and what the agency asks for, whether it's the traditional endpoint, whether it's iBox, whether it's eGFR, based on the data that we're already capturing, we'll have the data in hand to appropriately design a Phase III study.

Vamil Divan from Guggenheim. So maybe just a lot of excitement heading into the data here. A couple of questions more on the commercial side. So belatacept was asked about before. And we get the question from investors a lot that product didn't live up to expectations commercially. So maybe from the thought leaders, any thoughts on sort of why belatacept did not get adopted the way Bristol thought when they launched about a decade ago and then to the company, just learnings you have from that launch, what you're going to do differently to have -- to more of an impact. And then you mentioned at the end, DA, about the switch opportunity. I'm just curious to get more from the KOL side. Is that something where you need a formal program to show the data in a switch population? Or could this initial data be enough to start getting some use in a switch opportunity as well? Or do you think maybe this might be something where you need to do in investigator-initiated trial? Or just how you think about that opportunity?

So the first question -- thank you, Vamil, was around bela and how well bela has done. So what we think -- when we look at bela, we think we can do a much better job commercially than what has been achieved with bela. But to understand what occurred one has to go back to where bela was in those early days post launch. So one of the things -- and I don't know why Bristol chose to develop bela in that way at that time. But one of the things that bela did was it ran its studies versus cyclosporine in a time where tacrolimus was becoming the new standard of care. So when bela launched, what they launched with was an ability to say, look, we are noninferior to cyclosporine, we're noninferior to the older cornerstone standard of care that's already now been surpassed by the new standard, which was tacrolimus. What we're looking and our vision is to launch with something very different where we'd be able to say we have superiority versus the current standard of care. At the time, what Bristol was hoping to do was to show improvements in terms of safety. But unfortunately, at the time, what they had seen in their trials were some rare cases of PML. And that PML brought -- put a negative perspective, if you will, in the marketplace since sometimes physicians could feel like they were trading off the risk of PML for all of the other risks that came around -- that came along with the CNIs. That said, today, bela is actually, even without being promoted, is doing pretty well. There was data that was presented at ATC last year that showed that it was probably getting about 7%, 8% market share. And that's really with minimal or no -- I don't believe there are any reps today that are commercializing bela. So we are learning from bela. I think we're learning to design our trials that we're not going to run into the issues that they had. And as a result, we think we'll be able to do much better. And then the switch study, so for switch, we would need to run trials on switch. So stay tuned. We'll come back and talk about switch.

Sara Mediros from Cantor Fitzgerald. There was an investigator-sponsored trial using dual co-stimulation blockade as the sole immunosuppression maintenance therapy in kidney transplant. So that was the dazodalibep, which was the nonantibody fusion protein that acts as an antagonist of CD40L along with bela. So when you look at that data, is there anything that gives you conviction that a CD40 antibody inhibitor like tego will show better efficacy on its own? Sorry, that was a long question.

Thank you for the question. So the nice part with that question is we have the person responsible for that study. So, Eli, let me turn it over to you. In his previous life.

So this study we conducted at Viela Bio, the two investigators were Dr. Vincenti and Dr. Allan Kirk. The idea was the first time to put two co-stimulator blockers together and to see what happened. It was 20-patient study, one year outcome. I think what we learned is that it was safe. They didn't have any major safety issues. I think the patient felt very well compared to patients on casino inhibition. I think we have the reduction rate was about 25%. However, we have a difference between the first few patients and the net because we increased -- we realized what happened with rejection rate, and we increased the time of globulin induction and rejection rate went down. So we learned, as we know, we need induction at least for the beginning. So we are very pleased with the result overall. I think it's proved that co-stimulation blockers in general is a good mechanism to control rejection without all the sequela side effects of calcineurin inhibition. We were hoping at that time to continue to large Phase II and Phase III studies, but different things happened and didn't materialize.

I think you're trying to say the company was acquired.

Yes.

Rami Katkhuda, LifeSci Capital. I guess in BESTOW, are there any caps on the utilization of living versus disease donor kidneys? And should we expect a difference in efficacy? Have you seen anything in the Phase Ib, et cetera?

Do you want me to answer this?

So FDA require us on the BESTOW study to initiate with only diseased donor out of concern of safety because it was the first time using tegoprubart in large population of kidney transplantation. So it took some time when the BESTOW study was moving on until they require 10 patients and a review of the safety board and then to open it up for living donation. So there was a time issue. So all the first patients we enrolled were diseased donor. And then in July last year, we start to enroll living donation. So by virtue of this discrepant, we have less probably living donation compared to diseased donor in the study. Your question about is this going to affect results? We know that living donation usually doing better than deceased donor. However, we stratified and the statistical analysis will take this into consideration. So I don't foresee a major overall difference between the two groups overall at the results, but the results remain to be seen.

Got it. And then we talked about iBox potentially being used as a co-primary endpoint in kidney transplantation studies in the future. I guess, has there been discussions with the FDA on what would happen if you hit one of the endpoints, but not the other in each regard?

Bill?

Specifically in our proposal, our full qualification package that's under review now, we laid out the scenario to the FDA indicating that if you performed a co-primary -- if you use a co-primary endpoint with efficacy failure and your results demonstrated non-inferiority on efficacy failure, but failure to achieve superiority on iBox, then you would continue to the traditional approval pathway and you wouldn't go through an accelerated approval. So that's what we have proposed and discussed with them thus far.

Brandon Carney, B. Riley Securities. Just when considering the comparison with tac, have there been any adjustments to the dosing...

Do you mind start talking more into the microphone.

Sorry. When just when considering the comparison with tac, have there been any adjustments to dosing on tac through the years since it was approved? And what the current standard of care is like for that? And how does that affect compliance?

Andrew?

Sure. No, I think I would say, typically, tacrolimus is dosed based on time, so to levels. So early on, levels are higher because the rates of acute rejection or the risk of acute rejection is higher. So typically, those levels are 8 to 12 depending on the center, they may adjust that down to 6 to 12 months to something in between kind of 6 to 8, 7 to 10 range and then lower long term. The problem with that is -- and the reason people do that, of course, is because of the intrinsic effects on kidney function. So higher levels, more impact on kidney function, more side effects. So in an effort to minimize those effects on kidney function and other side effects, they've reduced the dose over time to try and see like what can we get away with to have the balance be in the right place. And unfortunately, what we see with drug minimization over time is the development of de novo antibody. And so typically, those long-term effects are, well, you may get away with lower levels of attack in the long run, you may see some minimization of side effects. but you see the development of de novo antibody, which then portends poor outcomes long term. So the development of transplant glomerulopathy failure of the graft long term. So to answer your question, yes, there is -- there are ways to kind of adjust doses of tac over time, and that's typically done. But unfortunately, the effects of that are now the immunologic effects that come up and damage the kidney long term versus a co-stimulation blockade reagent that you may be able to maintain long term and still have the benefit of no side effects or traditional side effects and prevention of de novo antibody, which then leads to longer and better function long term.

This is Albert from Craig-Hallum. I was wondering if you can speak a little more on this. You said a 9-point delta between the two arms and BESTOW would be a clinically meaningful difference I wonder if you can give us some more color on how this would translate to some expected differences in long-term survival, maybe similar to how it was explained for iBox. And then maybe a follow-up.

Sure. Maybe, Bill, I'll ask you to comment on that. What is the 9, 10-point delta in terms of eGFR in terms of, of an iBox delta?

Sure. I'll reference a couple of different data points. One, one of the papers that I showed was looking specifically at the MCID for eGFR that's been published, and it's by Mayne and Jesse Schold. And they indicate that a 10 ml per minute eGFR difference changes the hazard rate of 1.47 for graft loss. So we know it's a 1.5x increased risk of graft loss at a delta of 10 mls per minute based on their data. Looking at the iBox data, it's almost by -- it's completely by coincidence. I didn't even know what the sample size was based on for the BESTOW. That 0.4 that I showed at the MCID, if you assume everything in the iBox is the same except for the eGFR, that translates into a 9 ml per minute, 8-point something, but roughly 9 ml per minute difference in eGFR, assuming no difference in proteinuria DSA or biopsy. So what I showed for the 0.4 is actually directly translatable to the 9 mL per minute and the long term and the effects of improving 5-year graft survival by 4% to 5%.

And then to quantify a slightly different way, if you look at the 50% of the population that has -- the transplant -- kidney transplant population that has an eGFR lower than a 50 increasing their eGFR by 9 to 10 points. So shifting the curve to the right would decrease the risk of graft loss over 10 years somewhere between 25% to 60%. So for -- and the next obvious question is, well, why don't you just give tego to those patients? And the answer is before the transplant, you don't know who's going to be at the higher end of the curve or the lower end of the curve. But it would be very meaningful to be able to shift that curve.

All right. Perfect. I was also wondering, you spoke on many opportunities beyond kidney transplant. Which one is perhaps the most exciting or which one makes the most sense to focus on near term as kidney advances?

So I think we've spoken about a number of them already today. So the whole xenotransplantation is incredibly exciting. The potential in islet cell transplant, which, as Piotr mentioned, could be a functional -- could help bring functional cures for type 1 diabetes is very exciting. And then the next largest market would be liver transplant. But all of these areas have deep needs and for the patients that would benefit from tego, I think there's a great amount of benefit throughout.

Yi Chen from H.C. Wainwright. Do you think IV...

Would you mind just making sure you talk a little bit louder into the microphone, sorry, otherwise, it's hard for us to hear you.

Do you think IV infusion is potentially a hurdle for market adoption? And how big the superiority margin needs to be to persuade the patient to take the IV drug over an oral capsule?

So we don't believe that the fact that this is going to be an IV drug is a large impediment to adoption. I mean if you look at patients that have end-stage renal disease, remember, it's not like these patients are often already on dialysis. And so for a patient that might be coming from dialysis and every 3-week IV is not a -- it would be a very different experience than someone who might not be on any medicines that needs to go on medicines. And then the trade-off is not oral versus IV with everything else being equal, right? The trade-off is IV, but you don't have all -- potentially, you don't have all of the other side effect issues, the hypertension, the brain fog, the tremors, et cetera, and you have a better chance to keep your organ for longer versus taking an oral medicine. And finally, when we talk to patients, it goes both ways. We do hear some patients that would prefer to have an oral component, but there are also patients that are happy to have an IV and to be in touch and to be seen by the medical system and hence, in their mind, followed more frequently. That said, when we've discussed it publicly, we're working on a subcutaneous version of tegoprubart for life cycle management. So as we think about the long term here, our vision is to have both the IV solution as well as the subcutaneous solution so that patients and their physicians can choose which option fits them best.

I think something you have to remember is that compliance issue. We see in transplant patients sometime that they are not compliance well with the oral medications. When you need to come every three weeks and get the infusion, you sure the patient is getting the drug. So this issue of compliance is much less significant when you have this type of management. Of course, if you're moving to subcutaneous, it's going to be even better. But there's some advantage from the patient and physician perspective to maintain compliance. This is sometimes big issue in transplant.

If I can also add, I'm using belatacept IV on my islet patient, and I found the way as a home infusion. It's very convenient for the patient. The schedule one-hour infusion at home, nurse comes, it's given. And they prefer that rather than remembering about the pills every day, twice a day and adjusting. So having home infusion as option is tremendous benefit for the patient, and they like it. They love it.

Samantha Schaeffer, Cantor Fitzgerald. So a question for Dr. Witkowski on islet cell transplant. There's a clear efficacy difference for CNIs and those outcomes are great. My question is more on the patient experience that you just touched on. So how do these patients feel in terms of being on tego over CNIs injections versus endogenously produced insulin post-transplant? And how do these outcomes affect quality of life?

Right. So I can tell you, it's amazing. It's a huge difference. So -- and those actually now two patients on tegoprubart because one patient left. I just see them every three weeks. We hug. And we just confirm that everything is great. They have no side effects. But more importantly, there is no need for any adjustment. While patients on tacrolimus, they can constant complaints about tremors, headaches, and I have to check the lapse often and adjust the dose. Please go up, please go down. Oh, did you forget? And it's -- I mean, it's a constant fight. -- where here, it's like day and night. Patients are happy, and I am happy and my team is happy to not have to chase the patient and make sure they're doing fine.

Brandon Carney, B. Riley Securities. Just on -- we've talked about the potential for tego in new transplants. But I'm just wondering if there's any opportunity for patients that have already had the transplants and are on tac now. Is there any potential to penetrate into that market?

Sure. So I think when we talk about switch, that is the market that we have in mind. So those are about 400,000 Americans today and a slightly lower amount of patients in Europe that are in a different immunosuppressant. And as these patients progress, particularly the ones that are on CNIs as they begin to get the side effects or they begin to have kidney involvement, we think there could be a market in allowing them to switch off their current immunosuppression and to go on tego. But that would require different studies. So it is something that we would look to do in the future. It's a big area for us. And stay tuned as we begin to think about different ways to begin to tap the switch market. Okay. Well, if there are no more questions, then I will wrap up our R&D Day. Thank you very much to all of our speakers. Thank you to my colleagues, and thank you very much to you all for joining us, both live and on the web. Have a great day.