Eledon Pharmaceuticals Inc Aktie

Good morning, ladies and gentlemen, and welcome to The American Transplant Congress Data Update Call. [Operator Instructions]. This call is being recorded on Monday, June 22, 2026. I would now like to turn the conference over to Paul Little, Chief Financial Officer. Please go ahead.

Good morning, everyone, and thank you for joining our BESTOW Long-term data update conference call. I'm joined on today's call by David-Alexander Gros, Chief Executive Officer, Steve Perrin, our President and Chief Scientific Officer; and Dave Hovland, our Chief Regulatory Officer.

Earlier today, Eledon issued a press release detailing the updated clinical results presented at the American Transplant Congress. You may access the release and this presentation under the Investors tab on our company's website at eladon.com.

I would like to remind everyone that statements made during the conference call relating to Eledon's expected future performance, future business plans, our future events or plans may include forward-looking statements as defined under the Private Securities Litigation Reform Act of 1995. All such forward-looking statements are intended to be subject to the safe harbor protection provided by the Reform Act. Actual outcomes and results could differ materially from these forecasts due to the impact of many factors beyond the control of Eledon. Eledon expressly disclaims any duty to provide updates to its forward-looking statements, whether as a result of new information, future events or otherwise. Participants are directed to the risk factors set forth in Eledon's reports filed with the U.S. Securities and Exchange Commission.

Now it's my pleasure to pass the call to our CEO, Dr. David-Alexander Gros. D.A?

Thank you, Paul, and thank you all for joining. Turning to Slide 3, we can see our program [indiscernible] truly becoming a drug in a pipeline asset. Let me start by pointing out a few areas of progress in our programs before we dive into the new data.

First, we have progressed our subcutaneous formulation of tegoprubart and have already completed a healthy volunteer study. We now expect to begin testing this formulation in transplant patients early next year. This formulation will allow us to present more options to patients and to physicians in terms of how they prefer to use Tego. Second, we have a new indication where we have begun clinical trials, and that is in kidney transplant tolerance induction. This is being run as an investigator-sponsored trial at the Massachusetts General Hospital here in Boston, and 2 patients have already been transplanted.

In terms of agenda for this call, I will start by reviewing the Long-term Kidney Transplant Data presented at ATC, starting with kidney function as measured by eGFR, followed by acute rejection and the different effects of rejection that seem to be seen on kidneys treated with tegoprubart or tacrolimus, followed by safety update and lastly, followed by patient reported outcomes. As you will see, this data now clearly demonstrates the emerging advantages of using tegoprubart for kidney transplantation, including one, higher kidney function, reaching statistical superiority at 18 months; two, no rejections in the tegoprubart arm after post-transplant versus ongoing rejections in the tacrolimus arm. Three, higher kidney function in patients that experienced or injection on Tego and remains on Tego versus patients that experienced the rejection on Tac or that were switched to Tac after Tego. Four, in terms of safety, we previously presented black and white safety differences between Tac and Tego in the first year post-transplant, and today, we'll discuss CNS, kidney and GI-related adverse events that continue to be seen more frequently in the Tac arm; and five, for the first time, we are going to show patient-reported outcomes at 52 weeks where we saw improvements favoring Tego on 2 different validated measures of symptom burden.

We'll wrap up a kidney transplant discussion by discussing regulatory feedback in our Phase III plans. Afterwards, we will cover exciting data from our Islet Cell Transplantation Program where 12 of 12 patients with high-risk Type 1 diabetes have been able to achieve normal blood glucose levels along with insulin independence. This data was first presented at ADA a few weeks ago and subsets were subsequently presented here at ATC yesterday in an oral presentation.

Turning to Slide 4. We are in the long-term extension phases for both our Phase II and our Phase Ib kidney transplant studies designed to examine the use of Tegoprubart as part of a calcineurin-free regimen. In both of these studies, patients received anti-thymocyte globulin also called ATG as induction therapy, followed by tego, mycophenolate and a corticosteroid taper for chronic maintenance therapy. The Phase II study also included a control arm with tacrolimus instead of tegoprubart alongside mycophenolate and steroids. Note that in the Phase II BESTOW study, patients had a choice at the end of the 52 weeks, whether to continue on tegoprubart in the long-term extension or switch to tacrolimus. 96% of patients chose to remain on Tego which is a very high percentage and one that shows how satisfied the patients were with their therapy.

Turning to Slide 5. We have been focusing on 2 efficacy end points. The first efficacy endpoint is the historical approvable endpoint in kidney transplantation as well as the endpoint that the FDA has guided us to use as our primary endpoint for our upcoming Phase III study. In the first year post-transplant acute rejection typically refers to T cell-mediated rejection, which is treated with steroids or ATG and despite being part of the endpoint, is only poorly correlated with long-term organ function and survival. The second efficacy endpoint is eGFR, while this is not an approvable endpoint, it was the primary endpoint that we used in our Phase II BESTOW study. That was because eGFR is the best single predictive variable in terms of kidney graft function and survival, as is true in other kidney conditions, the higher patients eGFR, in other words, the higher their kidney function, the longer they are likely to have that kidney function.

In transplantation, a higher eGFR has also been associated with lower rates of subsequent hospitalizations. The graph on this slide on the right is the latest published large natural history paper on post-transplant eGFR. The study included nearly 5,000 patients followed for 6 years. The red line are patients taking a C&I with a vast majority of those patients taking tacrolimus. This line decreases over time because the tacrolimus is eating away at the patient's kidney function as a result of the drug's direct toxicity, it's a nephrotoxin as well as the drug's indirect toxicity since tacrolimus causes both hypertension and diabetes.

Turning now to Slide 6. This slide is showing long-term eGFR between the Tac and Tego arms. The X axis is time as measured in months, and the Y-axis is kidney function, and in other words, eGFR. The numbers on the X axis are the numbers of patients at every time point. These numbers decline with time as a result of the staggered enrollment into the study. In other words, it's not that patients are dropping out of the study between months 18 and 24. It's just that most of the patients that made it to 18 months post-transplant have not yet made it to 24 months post transplant. Looking at the graph, one can see patients on tegoprubart, on average, have higher mean eGFRs at every time point post-transplant with the curves separating after 12 months, resulting in a statistically significant difference of over 12 mL per minute at 18 months. Also, there is a trend upwards for patients on Tego during the long-term extension versus a slight downward trend for tacrolimus.

Turning to Slide 7. In this Kaplan-Meier curve, we are looking at the probability of biopsy-proven acute rejection over time. The X-axis is measured in days. The numbers under the X-axis represents the number of patients still in the study that have not had an episode of BPAR at that time. You'll note that these numbers are correct. -- but they appear slightly different from the numbers in the prior slide since the prior slide numbers do not exclude patients after they have had a BPAR episode as long as they remain in the study. We are happy to report that there have been no cases of BPAR in the Tego arm after 6 months with the patients being the longest on therapy now nearly 1,000 days post transplant.

In the Tacrolimus arm, over 9% of patients have had a total of 7 cases of BPAR after 6 months, including 2 patients that experienced acute rejection after 1-year post-transplant. These two patients, where one patient that had a recurrent case of mixed T cell and antibody mediated rejection and a second patient that experienced their first acute rejection, which was antibody mediated. Of note, late acute active antibody-mediated rejection carries materially worse prognosis than acute T cell-mediated rejection in the first 6 months post transplant, since early treated T cell-mediated projection is largely reversible, while later antibody mediated rejection is a type of projection that can cause [indiscernible].

Looking at the graph, one sees an obvious question, which is how do these patients do after they experience a BPAR episode, what happens to their kidney function, was there a difference between how patients did on one therapy versus another? In other words, could kidneys recover differently depending on what type of immunosuppression is being used.

Turning to Slide 8. We can see what happens with Tego and Tac. Here, we are looking at eGFR over time, where the Y-axis is again eGFR and the X-axis is time measured in months. There are 3 lines here because when a patient on Tego in the trial had a BPAR event, the treating physician had the choice whether to keep the patients on Tego or to switch the patients to Tac. On this slide, the dark blue line are patients on Tego who remains on Tego after their BPAR episode. The light blue line are patients who were on Tego and were switched to Tac at the time of their BPAR and the orange line are patients who are on Tac to begin with and those remain on Tac after BPAR. As one can clearly see patients on Tego demonstrate higher eGFRs after every time point. Note also the upward eGFR curve over time for Tego, again suggesting that kidneys continue to recover function. As a result, the difference in eGFR between patients treated on Tego, remained on Tego after the rejection episode and those on Tac who experienced a rejection in the first year post-transplant, increased from 15 ml per minute at 12-months to about 25 ml per minute at 21 months.

Patients who were on Tego and were switched to Tac post rejection also had lower eGFRs at 12 months versus those who had a BPAR but remained on Tego.

Turning to Slide 9. We see the long-term data from the single-arm Phase Ib study and that this long-term data is very similar to what we just saw in the Phase II. This study was launched before the Phase II BESTOW study, so we have patients that are out further, including 2 patients that are already out to 3 years. First thing to note is that, again, there were no incidents of BPAR in this population after 6 months. In terms of eGFR, the middle tan line are patients that were on Tego and did not experience a rejection. The dark blue line on top are patients who experienced the rejection and remained on Tego and the light blue line on the bottom are patients who were switched to tacrolimus after they experienced a rejection, and once again, we can see the advantages of being on Tego and remaining on Tego versus switching to Tac.

Now let's watch our attention to safety, starting on Slide 10. Here, we are looking at the safety and tolerability data that we previously presented towards the end of last year regarding how patients were doing in the first year. This slide is a summary slide, and it includes all of the AEs that were frequent. In other words, have seen at least 5% of the time in 1 or both arms where one of the arms also demonstrated twice the risk or greater of having that AE versus the other arm. The teal color text referents AEs that we're seeing more than twice as often in the tacrolimus arm, and the black represents the 1 AE that was seen more often in the Tego arm. I'll start with [indiscernible] that was seen more often and remind everyone that this was dipstick proteinuria. It was not done in the central lab, this proteinuria started and ended at varying times. There was some slight -- there was some slight ties to this proteinuria, if patients had an immune source of their underlying kidney disease, but all of these proteinurias resolved by themselves without needing therapy and none of them appeared to impact kidney function.

In the time post year 1, we have not seen a single case of proteinuria in the long-term extension study. Now in terms of the TO, the side effects from Tac, many of these obviously continue over time so that patients that had tremors, patients that had developed hypertension or patients that became diabetics continue to have their symptoms into second year, right? If somebody developed diabetes, they were not cured of their diabetes as they enter their second year post-transplant. If we flip to the next slide to look at safety and tolerability in the second year, what we are listing here are the new AEs. So patients that had ongoing hypertension or ongoing diabetes that they had developed in the first year as the result of being on tacrolimus are not being counted again on the slide. Overall, as you'll see, in terms of number of events, it's relatively similar between Tac and Tego, maybe with a slight advantage towards Tego. Once one looks at the same analysis that we did in the first year, so frequent AEs were 1 arm at twice the risk, we saw some higher levels of PMV or BK reactivation in the Tego arm, that reactivation was measured in terms of DNA [indiscernible]. But I would note that all of this viremia was controlled typically either using an antiviral for CMV or by decreasing the dose of MMF. So we did not see any end-organ disease or syndrome in either arm.

However, on the tacrolimus arm, we saw twice as much Herpes Zoster as we did in Tego, and then we continue to see the CNS effects and the CNS signal very strongly, with multiple times the new reported incidents in the Tac arm versus Tego. We also saw more acute kidney injury about 3x more kidney injury in the Tac arm, which might be associated with the decreased kidney function that we reported earlier. And finally, a GI side effect, diarrhea became very clear at this time around. Tacrolimus' GI side effects are well known. Interestingly, in the first year, almost 1 in 3 or about 1 in 3 patients in the tacrolimus arm had developed diarrhea and in the second year 1 in 5 did.

In terms of other AEs or other things to note, we had an equal amount of discontinuations in each arm. We did have a death in the tegoprubart arm. This was tied to a cardiovascular event, in a patient that had a history, including obviously, history of kidney disease, and this death was not attributed to drug, and we did not have graft loss in either arm. Importantly, we did not see a single case of PML or PTLD in either arm. We have now had about 200 humans exposed to Tego, and to date, we have not seen PML or PTLD, which could be from a competitive perspective, an important differentiating factor. So we are very encouraged by this ongoing difference in safety and tolerability, favoring Tego.

Moving to Slide 12. This is a slide that was not originally in the deck, and yesterday, during ATC, I sat on a panel where patients presented this slide and I asked her afterwards to be able to use the slide today and got her permission to do so. This is a young lady in her 20s who was describing what it's like to be 9 years post-transplant, including what the side effect burden of the tacrolimus that she is taking is like. And this is her slide. And here, you can see how these AEs that we've been discussing over the past 2 slides aren't just numbers on a page, but can have a tremendous effect on a person's quality of life. As you can know, just her title, the side effect of her taking tacrolimus infiltrate into everything that she does. In other words, they infiltrate into her whole life. I won't read everything, but even with her tremors, she was working in a dialysis clinic and she needed to be able to insert sharp needles into patients, and she noted how difficult that is, when one has tremor, including making -- creating levity by talking about as she would scare her -- the patients when they would see her with her tremor, but obviously, leading to a very difficult position for a young person trying to establish themselves in their field.

Similarly, she explained how debilitating her brain fog or headaches could be and how often she's getting headaches that can force her to stay at home. And finally, the diarrhea we just discussed, these GI issues for her lead her to rethink how it is that she eats and how it is that she travels, since she needs to take into consideration the Tac effects on her GI system, including not eating if she has to travel because of what might happen if she's been eating.

Switching to the next slide. We are excited today to present what we think are the first patient reported outcomes in a controlled study versus [indiscernible]. And here, you are seeing 2 different burden scales that were examined. The first one is the empty SOSD scale, and that is a scale that is looking at post-transplant symptoms occurrence and symptoms distress. That scale looks not only at how frequently side effects like tremors might occur, but also how severe the side effect is? And the second scale is the KDQOL scale, which is the kidney disease quality of life scale with that title being self-explanatory.

In both of those, tacrolimus showed a statistically inferior change from baseline over time versus Tego. So with the MTSOSD, patients on Tego were doing better over time. They improved in terms of their -- of how the patients reported that they were feeling as can be seen by the decreasing, by the decreasing numbers on Tego. In fact, patients on Tac are pretty much flat at the end of a slight uptick. So clinically meaningful differences here are considered to be about 10 points. So as you can see, between week 25 to 52, the patients in the Tego arm overall continued to prove and by week 52 there was not only a statistical difference between the 2 arms, but one that was also clinically meaningful.

For KDQOL, one notes that for some of these, there -- the numbers are very similar between the 2 arms, right? For kidney disease, burn of kidney disease or kidney disease effect on daily life and that makes sense, because these patients had a kidney transplant. And so we're looking at the positive effect of getting the kidney transplant. However, when it comes to overall quality of life in terms of the symptoms and the problems that the patients are facing, we see again a statistical and clinically meaningful difference between Tego and Tac favoring Tego. I will note that in the Tac arm under the mental component subset, the numbers get worse. So that over -- in other words, over 52 weeks, patients reported a downward trend on that scale for the mental component, which is, of course, consistent with the side effect profile of Tac that we were just discussing.

Moving on to Slide 14. We continue to be on track, as we've previously guided to begin launching our Phase III study towards the end of this year. The study will be a 52-week perspective, global multicenter, active controlled, randomized Phase III trial. The study will look very much like the Phase II study, but it will be significantly bigger. We plan to enroll approximately 600 patients in 2 arms that they'll be randomized to 1:1. The induction therapy will be the same, as will the maintenance therapy with 1 arm being on Tac and another one being on Tego. The primary endpoint will be the triple endpoint that I just mentioned, this efficacy failure endpoint, consisting of BPAR, graft loss and death, and of course, we will look at key secondary endpoints, including eGFR, so kidney function, which will measure at 12, 24 and 36 months, safety, including the diabetes, new onset diabetes, late graft function, all of the neurotoxicity of Tac, hypertension, including crises and diarrhea, and we will include patient-reported outcomes in this study as well.

We have discussed this with the U.S. FDA, and we have received clearance from the U.S. FDA to proceed with our Phase III study.

Moving on to Islet Cell Transplantation. The patient population that we're studying here is a high-risk patient population. As we know, there are 1.5 million to 2 million patients living with T1D living in the United States today, of these, about 12% experience what is called Recurrence Severe Hypoglycemic event. And a severe hypoglycemic event is defined as a patient blood sugar falling so low that they need third-party assistance in order to help rescue them and get their blood sugars back to normal. So the way recurrent severe hypoglycemia is defined is by at least 2 episodes requiring this third-party assistance within the past 12 months. And this is also how the FDA defines Recurrence Severe Hypoglycemic Episodes. These patients are some of the patients that have the highest risk of diabetes complications. And as you'll see, there is, ironically, many of these patients not only get very low blood sugars, but paradoxically, they keep their blood sugars very high as wll that they have high [indiscernible]. So in other words, over time, they not only have all the risks associated with getting very low blood sugars, they also have all of the complications associated with having high blood sugar.

The procedure itself can be seen on Slide 17. It is a noninvasive procedure in terms of the fact that it's done by interventional radiology. In our study, we are taking donor cells from deceased donors, so people that have donated their organs, the pancreas is removed. It is placed into a machine that purifies and isolates the islets. The islets are then put into an IV bag and infused by the interventional radiologists directly into the portal [indiscernible], they then flow into the liver where they ingraft and begin to make insulin.

Moving on to the next slide. We can see our Phase I/II study. This is an investigator-sponsored trial that is being done at the University of Chicago. It's a -- the design is an open-label, single-dose, 52-week study. It's the same dose that we're using in kidney transplantation, and we have now transplanted 12 patients. Here, induction therapy is the same using ATG. The chronic maintenance therapy is slightly different since we're not using corticosteroids because of the fact that these patients are diabetic. Now in terms of the end points, as we think about the future, and I'm happy to announce today that we have been ahead of schedule and so have already begun interacting with the agency, so the FDA about this program. And from these interactions, we anticipate that in a registrational path study, the primary endpoint would be a composite of 1 insulin independence, which the FDA is defining a 6 out of 12 months without the need for insulin with the patients maintaining an HbA1c below 7, while not using insulin; and two, the cleat absence of the severe hypoglycemic events that we just discussed.

On the next slide, Slide 19. We can see the demographics of the 12 patients in the study. There was more females than males. As you'll see, the patients are adults, 42 years old on average, and they have had diabetes for a long time, 29 years on average. So these aren't patients that are new to diabetes. These aren't patients that don't know how to manage their diabetes. All of these patients in order to get into the study needed to have optimized care for their diabetes. One of these patients, as an example, was a cardiologist. And albeit the cardiologists, she knows how to manage diabetes, and yet, this individual once had a severe Hypoglycemic event while driving its car and ended up having a car accident as a result. So it's not that these are patients that don't know how to manage their diabetes. These are patients that despite being able to get the best diabetes care for them. They continue to have these recurrent severe hypoglycemia events. You'll note that the baseline A1c is high at about an 8 on average as is the average baseline insulin that some patients are on. 7 of the patients required 1 transplant in order to get off insulin and 5 of the patients required 2 transplants in order to fully get off exogenous insulin.

In those 5 patients, 3 of them that was principally due to the body mass of those patients. So these were larger patients, as you can see, with about 30 BMI that required a high level of insulin. And so a transplant from one individual just wasn't large enough, wasn't sufficient to produce the insulin that they needed.

Moving on to the next slide. We see how the patients did few things to note. The first one is that every single patient was able to achieve insulin independence. Also, every single patient was able to achieve a nondiabetic HbA1c. And on average, the patients saw a 2.6% reduction in HbA1c versus their baseline, which is which is a very large improvement. Of note, 11 of the 12 patients achieved nondiabetic HbA1c within about 2-months after their transplant. But if you look at the lines, you'll see that in terms of the FDA endpoint, basically all 11 of these 12 patients achieved that endpoint of being below the 7 within about 4 weeks. So the effects that we're seeing here are not only dramatic, but they're very fast.

In terms of severe hypoglycemic events after transplant in all 12 of these patients, we have not seen a single case of a severe hypoglycemic event after transplant. These patients have all gone from getting them sometimes frequently and very frequently to no longer having to worry about them at all.

Moving on to Slide 21. We are now looking at the engraftment rate, the calculating engraftment rates post transplant. This is comparing the 12 patients on Tego to 6 historical patients that were chosen by the principal investigators as comps from the University of Chicago. And you can see that we are seeing a higher engraftment rate for patients that are on Tego versus patients that are on Tac. And intuitively, that makes sense. We know that Tac is toxic to the insulin-producing cells in the pancreas, as we just discussed a little while ago in terms of the kidney transplant study, patients that received the kidney transplant and we're on Tac 1 in 6 patients that did not have diabetes at the time of their transplant developed diabetes by the end of their first year as a result of this toxicity. And here, we're seeing the toxicity in terms of what it means with engraftment rates.

The Tego by not having -- we assume by not having the toxicity is allowing for greater 2001315032 and greater cellular function of the transplant itself.

Moving up to the next slide. We can -- we are now looking at the effect of tacrolimus over time on the kidneys of these transplanted patients. On the left-hand side of the slide, we can see the data from a study for the Lantidra product. Lantidra, are approved the deceased donor islet cells, and in their registrational study, they saw what is the left-hand side of the slide, which is decreasing kidney function over time. On the right, you can see for 9 of our patients where we -- that were examined by Dr. [ Witkowski ], their eGFR over time. And once again, we are not seeing a negative effect of Tego on kidney function. In fact, we're seeing signs of the opposite, the green line are patients that had lower eGFR, slightly lower kidney function at the time of their transplant, probably due to the ongoing diabetes that these patients have. And once their diabetes was able to be under control, although these are small lens, there does appear to be a trend where those kidneys are recovering function.

One, we have done on compassionate use patients where that was on tacrolimus after having had a -- an islet cell transplantation and that patients could no longer tolerate the tacrolimus because it was destroying their kidneys. And after that patient was switched from Tac to Tego, they quickly began recovering their kidney function as well. In terms of safety in the study, the safety continues to look very good. Similarly to the kidney transplant study. Here, all 12 patients were able to achieve the stable [indiscernible] functions and rapidly improve the [indiscernible] to live without severe hypoglycemic events. We did not see any signs of rejection or in de novo specific antibodies. Importantly, as opposed to what the investigator report seeing in his patients with C&I, as we discussed, we'd not see any kidney toxicity, but we have not seen any neurotoxicity, GI tox, hypertension or thromboembolic events on Tego. The Tego patients did experience some non-severe infections, but all of them could be controlled by lowering the dose of the [indiscernible].

[Audio Gap]. When taken together with our clinical progress in islet cell, [indiscernible] and now as we enter a tolerance induction, we as a team and Eledon as a company, continue to build momentum in the transplant space, pursuit of our mission of one transplant for life.

First question comes from Thomas Smith from Leerink Partners.

Hey guys, good morning. Congrats on these updated data. On the Phase III plans in renal transplant, it sounds like you have FDA feedback to proceed here. Could you talk [Audio Gap] little bit or other factor.

[Audio Gap] In fact, in our discussions at least as FDA was much more focused on eGFR as opposed to ibox.

That makes sense. And just one question, if I could, on the islet cell program, truly remarkable data there. Just wondering in the initial feedback that you've got from the agency and I guess, and think through some of the implications of this planned composite primary endpoint. Could you just talk about perhaps thresholds that the FDA is looking for that you might need to show on this composite endpoint that could potentially enable [indiscernible]?

Sure. So preliminary guidance from the FDA aligns with precedent in regards to the approvals that have been granted to date, one in particular, that DA mentioned, the Lantidra approval, but also publicly available information regarding programs that have been given a go ahead for, to proceed towards a BLA. So the numbers that are shown in our slides align exactly with that prescedent and publicly available guidance from the agency.

So that's -- in other words, the endpoint we assume or we estimate that were all the FDA is going to want to see about 40 to 50 patients in the program. The FDA did not give us a specific number. If you're -- in terms of what's the percentage of patients that need to not have severe hypoglycemic events or that need to be able to be off insulin for at least 6 months or maintaining an HbA1c less than 7%, although obviously, we -- right now, our success rate of achieving that appears to be very high.

The path forward there is going to be twofold. I think in the near term, we are going to look to help establish manufacturing, if you will, of decease donor cells today, as you saw the deceased donor cells do need to be purified out. And so we will look to establish 1 or potentially 2 sources for these cells. Once we have done so, which should take about 18 months, we could then use the data from those cells to show comparability to the patients that we've already done with FDA, and subsequently to that, be able to quickly finish enrolling the 40 to 50 patients that we would need.

The next question comes from Pete Stavropoulos from Cantor Fitzgerald.

A couple for me. For the patient-reported outcomes that measures symptom burden, can you just help us understand what those outcomes mean for patient experience? And what is considered clinically meaningful?

Sure. So the patients reported outcomes look at how patients are feeling as well as in the MTSOSD includes specifically side -- the side effects that patients may be experiencing because of their medication -- in what is commonly considered clinically meaningful for the MTS OSD is 10 points. So a decrease of 10 points is considered meaningful for the patients. And in the KDQOL in any one of the groups, an improvement or a difference of 5 points is considered clinically meaningful. So we show that clinical and statistical difference in both with MTS OSD at week 52, so overall. And that includes, again, specifically drug-induced ads. And then for KDQOL, when comes to symptoms and problems, we show a benefit. And there, that's an increase in the number where we get the difference of a treatment difference of about 6 points.

Any color that you can provide like feedback-wise, from investigators who treated both patients with Tego as well as Tac in the study? Any feedback in terms of the AE profile, the patient experience for both actually kidney transplant as well as Islet cell.

Yes, sure. Great question, Pete. This is Steve Perrin. Yes, we have heard from a lot of our investigators that the AE profile of Tego is is better in their mind than what they typically see on Tac. As you know, Tac is an incredibly difficult drug to manage with daily dosing because of its very narrow therapeutic index, when they see problems where they have to change levels of Tac due to infections or leucopenia it's very challenging to monitor levels of Tac daily, and it's challenging for both the physician and the patient, whereas with Tego it's an every 3-week IV infusions. So biologics tend to be a little bit easier to manage in that regard. And as D.A reviewed in the presentation here, we're just seeing an overall better AE side effect profile than Tac both at 12 months as well as in the long-term data. And the similar story for islet cell transplant, we've seen fewer side effects, thus far, albeit in a smaller patient population than our kidney study. So so far, the data is look very encouraging.

I'll add that for patients now, one can see their experiences online. We've now had patients -- we live in a new world where people will post how it is that they're doing. And so patients have posted their experiences on Tego on all sorts of social media platforms. These are not condoned by Eledon. But obviously, in today's environment, it's the reality of running a clinical trial. And what's striking looking at these patients is how well they're feeling, and they talk about it. You can see them get an infusion of Tego and talking about how it doesn't interfere with their day and they feel great and they're able to work through the infusion. You can hear them talk about the absence of side effects and how much better their life is post-transplant.

Last question for me is for the islet cell, the data that what you just mentioned are sort of well-known among both, I guess, patients and investigators and many physicians. So ATC they're fully aware of the outcomes of the data to date. Just curious to hear the overall interest in the program and importantly, how patient interest in this program, either interest conveyed directly to you guys or through principal investigator.

There is a tremendous amount of interest in the diabetes program. I think -- and this can be seen, again, online just by the sheer volume of people talking about Tego and talking about the islet cell data. There was a post, as an example, on Facebook with one of the patients talking about how well she was doing. And that post we're seeing 2.5 million times within the first 24 hours after she posted it, and we're seeing overall the women who posted had said that -- or posted have been seen over [indiscernible]. When it comes to the study itself, today, we have received over 1,000 inquiries from patients asking to be a part of the study. So I think the data is -- has made it into the community, patients are aware and there is a tremendous amount of interest in what we are doing here. And it shows just how large this unmet need is.

Your next question comes from the line of Vamil Divan from Guggenheim.

Let me add my congrats also. And this looks really like a nice update here. So two questions if I could. So one, just going back to Slide 6 in presentation, we see a sort of meaningful drop off in the Taco arm on eGFR as we get to the 24-month mark. And I know the number of patients out there is smaller, but anything specific you can comment on sort of like why you're seeing such a sudden drop there in the Taco arm?

And the second question, which we've gotten from investors a lot too, is just your thoughts around -- and sorry, I missed this in the comments, been juggling a few different piece of the news this morning. But just around you're potentially looking at a switch study sort of opportunity where maybe patients still starting on Taco for the first 3 months or 6 months, and then switch over to tegoprubart after that to avoid the longer-term toxicity with Taco so. I'm not sure if you mentioned it this morning, but if there's any color you could add on potentially looking at that from a regulatory perspective?

Sure. Thank you, Vamil. So to answer your first question, regarding Slide 6 and for folks trying to follow along, this is the slide that's showing eGFR over time. The reason you're seeing a decrease in month 24 is probably tied to the low end so that the patients that are on Tac at that time are probably just doing a bit worse than the patients that have not made it out 24 months. So we would expect that, that number would have some reversion towards the mean, as is the remainder of the patients reach the 24 months -- reached the 24-month time point.

In terms of your question, number two, which is switch. And I think what you were asking is, why don't we use tacrolimus in combination with Tego in year 1. And the reason for that would be in order to reduce our -- the short-term rate of biopsy-proven acute rejection. So those rejections that we're seeing in the first 6-months. So the reason why we're not combining with Tac and we're running attack-free regimen is because the moment you start to use Tac, do you then get into all of the Tac side effects. So from a rejection perspective, as you saw today, the advantage in terms -- from a numerical perspective long term becomes negligible.

In terms of the impact of rejections over time, again, as we discussed earlier, patients on Tego are doing better than the patients on Tac. So if you experienced a rejection on Tego, the impact on the kidney does not appear to be the same as the impact on Tac. And we already know that experiencing rejection in the first 6 months even on Tac is not associated with long-term organ survival or function. So it's hard to see, if you will, the advantage of adding the Tac in order to try to slightly reduce some early rejection in the first 6 months. However, the downside is very clear. The downside is going to be all of the AEs that we're seeing, including the increased delayed graft function and the associated costs of longer inpatient dialysis, post-transplant as well as the whole suite of AEs that we observed in the first year. So if we give Tac for 6 months, we're going to have patients become diabetics, and those patients will remain diabetics for the rest of their lives. We're going to have patients begin to experience the brain fog, the tremors the headaches, the hypertension and some of that will continue even after the Tac is discontinued.

So from our perspective, doing a short-term combination would probably not lead to a good safety efficacy trade-off. Now a switch could be interesting longer term in terms of switching patients that are on already on tacrolimus and are experiencing these AEs and trying to switch them to Tego in order to relieve them some -- as much as possible of side effects. And as I mentioned, we've now done that using compassionate use for 1 patients that have had an islet cell transplantation. The feedback from the agency earlier had been that the agency wanted us to start with a de novo study before doing a switch study, but we recognize that switch is a very large market. There are probably 250,000, 270,000 Americans today taking tacrolimus. And so that could be a large opportunity if those patients started to switch to Tego. But that would be a new indication, and that would require another Phase III.

So from a life cycle management, that is something that we can consider to pursue over time, but that is something that we would start and we would need to start after we started our Phase III in de novo.

Your next question comes from Rami Katkhuda from LifeSci Capital.

Wanted to pass along my congrats on the update as well. I guess in the Phase III kidney transplant study, what non-inferiority margin has the FDA accepted for the composite endpoint? And then more broadly, how are you thinking about ATG induction doses? Is that going to be standardized across the board?

Thank you, Rami. So great question. The FDA has not given us a final non-inferiority margin, as you know, the last drug that was approved, which was [indiscernible] had 20% not inferiority margin in -- the FDA has told us that they considered the exact non-inferiority margin would be a review issue, since it would be due or tied to the ultimate advantage or lack thereof of being Tego versus Tac. So the reason that [indiscernible] was able to get a 20% margin was because [indiscernible] was showing significant advantages from a safety perspective, versus Tac.

In our discussions, we discussed an 18% non-inferiority margin with the agency and the agency did not tell us that was not an approvable margin, although we do not have spine plates as an example around that margin. So we are powering our study around that 18% non-inferiority margin and it allows us at the 600 patients or so to have a 90% power to reach non-inferiority if from an efficacy failure perspective, we were within 8%. That's a net 8% versus tacrolimus. So in other words, 12% versus 20%, or 15% versus 23%.

Got it. And then we found it particularly impressive that no BPAR events were observed with Tego after month 6. I guess, can you provide more color about the clinical importance of late rejection events? And could this become an important differentiator if reproduce ultimately in Phase III?

Great question, Rami. This is Steve. Yes, historically, the biggest issues with Tac post 12 months is not T-cell mediated rejection, which is fairly treatable with steroids or ATG. It's antibody media rejection, which is much more challenging and mixed rejections as well that tend to have poor prognosis. So post 12-months, we anticipate that we're going to continue to see those on the Tac and based on historical data. The nice thing about [indiscernible] blockade, and again, we have some lessons learned from [indiscernible] CD40 Ligand and preclinical models is superior to [indiscernible] activity here. The direct mechanism of action of blocking CD40 Ligand is to block germinal center formation and B-cell maturation, therefore, should have a direct impact on decreasing the incidence of antibody [indiscernible] rejection longer term after graft function. So we're hoping to see that not only in the long-term extension data, but also in the Phase III.

And here, it's D.A again, at ATC, we're presenting the data both in the poster as well as an oral session and at poster physician after physician commented on the fact that we were not seeing acute rejection after 6 months. So people definitely found it striking.

Your next question comes from Robert LeBoyer from NOBLE Capital Markets.

Congratulations on both sets of data that you presented today. My question has to do with the ibox measure. And you mentioned that the FDA won't require it in your trial. I was expecting to hear something from the agency as to its acceptability as an endpoint or some kind of comments or decisions or opinions on ibox as a measure. Have there been any communications or signals or anything expected from the agency on that?

So the FDA -- and thank you for the question, Robert. It's D.A. The FDA had initially guided or was supposed to provide an answer I believe it was about 60 days ago and has not yet done so. So in other words, the FDA is behind there from -- and we don't obviously have perfect insight into what is going on at the agency and how the agency is talking to the consortium that is advocating for ibox. But from our perspective, we now have an agreed upon endpoint with the FDA. Ibox, if you recall, for us, was an upside where -- because it would have been an additional endpoint that if we hit would allow us to get an extended claim on our label in terms of superiority. So right now, it does not -- based on our discussions, appear that, that will be the case at least for our study. But if the agency changes its mind and approves that endpoint, we could always -- it's something that we might be able to to add in the future to or -- to our study as needed. Let me turn it over to Steve.

Robert, great question. I mean, there was a session here yesterday at ATC that was hosted by TTS. The tone in the room was a little bit disappointed that they haven't received that feedback at 60 days. They have petitioned the FDA with some letters to try to formally push decision forward. But the FDA, at this point, according to the session yesterday that TTS hosted the FDA has not gotten back to them with feedback yet.

Okay, yes. I think the FDA is supposed to, but not yet done so. I think that sums it up quite well. But the second question I had was on the islet cell program and you touched on the manufacturing and the standardization of the islet cells themselves. I was wondering about the actual administration and you mentioned that a radiologist would be administering the cells by IV through the portal vein? And I was wondering how standard of a practice that is and whether there's any additional training or any additional risk of variation or whether this is something that's [indiscernible] practice and routine for the specialty or whether this is something that is unique to the trial?

Robert, this is Steve Perrin. So a great question. I think you've asked two, one, about manufacturing and our path forward there and the second one about how routine the surgical procedure is. This procedure goes back decades and the insertion of cells into the portal vein is a very routine procedure. It's done not only in the United States, which is a little bit less common here just because historically, islet cells haven't been approved by the FDA as an organ, but as a drug product. But globally, as an example, thousands of these transplants are done in Europe. It's been improved in Canada for a very long time as well as Australia, Japan and other countries. So this is a very routine surgical procedure that we don't anticipate issues with training or anything like that, you should be able to roll out fairly seamlessly.

As far as your first question, I think Eledon's strategy there is very similar to what you've seen us do with [indiscernible] transplantation. We've collaborated and worked with any Xeno transplant company, including United Therapeutics as well as [ E-Genesis ]. Preclinically, we have global collaborations all over the world in nonhuman primates using other types of genetic pig organs as well. And we're agnostic to supply Tego to protect those organs because we think it's superior to CNIs in that regard. And it's clearly become one of the the best ways to prevent [indiscernible] transplant rejection. Our strategy, in islet cell is very similar. We're going to support and obviously listen to the guidance from the agency historically that you need a robust manufacturing process and whether that's a collaboration partnership with Latidra, which is already an approved product that we could jump into, a larger Phase II/III design much more quickly than in parallel, setting up our own manufacturability.

We're agnostic to other [indiscernible] coming down the line as well, be it embryonic stem cells or induced pluripotent stem cells as well if a cell-based company has a robust technology to differentiate cells into pancreatic islet cells and they need immuno-protection, we're happy to partner with them and provide tegoprubart for that. And if you've seen we've done that with both [indiscernible] as well as [indiscernible]. So our strategy in Xeno and islet cell is very, very similar in that regard.

There are no further questions. I'll turn the call back over to Dr. David-Alexander Gros.

Thank you, operator, and thanks, everyone, for joining today. Appreciate everyone's time and interest and we'll end the call.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.

All right. Thanks, everyone, for joining us here on the Second Annual Guggenheim Healthcare Innovation Conference. I'm Vamil Divan, one of the biopharma analysts here at Guggenheim and joining us in this room next, we have the Eledon Pharmaceutical team. We did have one victim to some of the travel issues who is not able to join us, and that's the CEO DA Gros, but we do have Steve Perrin, President and CSO of the company.

So we'll run through the story. And obviously, a lot of activity in the Eledon story over the last little bit here. Maybe before we dive to last week's data at ASN and kind of takeaways from that, just sort of for people less familiar with the story, give an overview on sort of how Eledon came together, the path to where you are now. And then we'll talk about last week and steps forward.

Sure. Vamil, thank you for inviting you Eledon to present today. So Eledon Pharmaceuticals is developing tegoprubart, an anti-CD40 ligand antibody focusing on transplant as a primary indications. There's a couple of reasons that. A lot of it's historical, and that blocking CD40 ligand has been one of the most potent ways to prevent transplant rejection in multiple species over time, including mice rats, nonhuman primates. And our goal is to replace tacrolimus or CNIs as is the cornerstone immunosuppressant transplant rejection. And we want to do that regardless of the type of transplant, be it heart, kidney, liver, cells where the organ came from, including both allograft as well as xenograft transplant.

Great. So maybe just to frame that, the opportunity, let's talk about tacrolimus, obviously been on the market for quite some time, a lot of challenges. Maybe you can talk through sort of the issues that tacrolimus poses to doctors and patients and how you're hoping to advance the care of these patients beyond that?

Sure. So tacrolimus was approved about 30 years ago in a non-inferiority study against the standard of care at that time cyclosporine, and it showed a better safety profile than cyclosporine did at the time. But tacrolimus, although it's a pretty good drug at preventing transplant rejection in the first 12 months, it has both immediate and long-term toxicities that make it very challenging from a health care perspective and doctors as well as for patients, including cardiovascular tox with increased hypertension. It has nephrotoxicity. So it's actually toxic and hurts the actual organ in the context of kidney transplant that you're trying to protect.

Patients that have gotten other types of either organ or cellular-based transplants, such as cardiac and liver transplant, eventually see the same type of nephrotoxicity that one sees in a kidney transplant population. So nephrotoxicity is a significant side effect and a problem. There's also metabolic toxicities. It's toxic to the beta cells in our pancreas. And so about 20% to 30% of patients on tac end up getting new onset diabetes, which requires patient care for life and it's quite debilitating. And then finally, there's also a whole host of neurological toxicities that are associated with tacrolimus including brain fog and tremors, which are quite debilitating to patients, leading to compliance issues and longer-term risk of graft rejection post 1-year transplant.

Okay. Great. So you've had a couple big data readouts recently, the Phase Ib additional data from that back in August and then obviously, the Phase II. Last week maybe we walk through the program that you've developed here for tegoprubart and some of these data releases and we'll go from there?

Sure. So with our focus on transplant, our lead indications has been kidney transplant, driven by the fact that kidney transplant is the biggest market, the most number of transports that are done for kidney about 25,000 per year in the U.S. and about 25,000 in Europe. So that has been our main focus. We historically have been running several different parallel clinical trials in transplant, an open-label Phase I study that was initially mostly ex U.S. to understand how to integrate, tegoprubart into a CNI-free regimen with the rest of polypharmacy that's required to prevent transplant rejection.

And then we launched a Phase II trial called BESTOW, about 2 years ago that was going to try to basically look and see if we could compete against tacrolimus in a superiority design, and if you want, I could go through the trial design in more detail if you want?

Yes, I think it would be helpful to frame that -- the design and then let's talk about some of the results?

Sure. So standard of care immunosuppression for the prevention of transplant rejection requires 2 different phases. There is a phase of induction therapy, if you will, around the time of transplant that usually is a high dose of methylprednisolone combined with ATG for T-cell depletion and T-cell control. Often, there's also prednisone that started around the time of transplant and then tapered down to a lower dose usually over the first month. And then standard of care has a tacrolimus dose it's industry a little higher. And then over time, they try to get to a lower trough level. The goal of the BESTOW study was to basically keep as much of the immunosuppression the same between the 2 arms as we could by replaced tacrolimus with tegoprubart as the cornerstone immunosuppressant to prevent rejection.

The BESTOW study was a much bigger study than our Phase I study that I just described. It was a more global study. It enrolled about 120 patients total, randomized 60 per arm rolled in the U.S., Europe, Canada, Australia and Brazil. The primary endpoint, it was powered as a superiority design to examine kidney function that comparing a tac on to the tego arm, and it was powered to detect a 9-point difference between the 2 arms. And then for secondary endpoints, we collected things for the standard non-inferiority endpoint that's historically been used for approval of drugs in kidney transplant, including patient and graft survival, biopsy-proven rejection and then additional secondary endpoints around potential new surrogate endpoints, such as iBox as well as all of the serious side effects that I just mentioned for tacrolimus.

Okay. Great. So you presented the Phase II last Thursday. It feels like it's been a while since it came out but -- it's not less than a week. So you can talk through the results and then just sort of the feedback you received from the community at ASN?

Sure. So yes, we released our data last week at Kidney Week. Really exciting data from my perspective. I've been working on this drug for over 10 years, and I've been working on CD40 ligand for over 30 years. So it's been kind of a long road getting tegoprubart to this first great readout in a fairly large Phase II study. And the data exceeded all of our expectations for the most part, right? We have consistently seen some of the best kidney function that one has ever seen in the clinical trial with mean eGFRs in the high 90s, often in the low 70s in some of our cohorts in the Phase I, and we saw that again in the BESTOW study. The surprise that we got there was the tac arm performed significantly better than what we would have estimated historically. And we powered our study based on historical data, where most of the time, if you talk to doctors treating patients with tac or if you look at historical trials such as the iscalimab study, mean eGFRs on tac tend to be in the 50s -- mid- to low 50s.

So we're surprised when tac came in at amino 66. So we missed the [ premier ] by 3 points. With that said, longitudinally, if you look at any time point in our study. And if you look at any subgroup, we pretty much beat tac across the line. In some of the subgroup analyses, we actually beat tac by as much as 10 points, including living donors. Patients that received poor quality kidneys as measured by KDPI. And if you start combining some of those parameters, the delta is actually got bigger and bigger. And if you actually stratify as a continuous variable across kidney quality with KDPI and living donor, it actually reached statistical significance in the study. Amazingly, we also hit a couple of other things that was quite exciting that you might not have expected how profound it was, but we actually hit the non-inferiority endpoint. The study was not powered to hit the the regulatory approved endpoint for transplant in 12 months, which is non-inferiority on patient survival graft survival in acute rejection, but we actually hit it even though the study wasn't powered to do so.

And then the real big, big win was when you compare the safety profile for the 2 arms. I mean all of the toxicities that I described for tac actually showed up in a 12-month study. We saw an incredibly large delta in nuance of diabetes between the tac and tego arms. We saw hypertension imbalances with higher in the tac compared to the tego arm. We saw delayed graft function was a big component that we saw that patients post-kidney transplant is often sometimes takes your kidneys a while to start functioning and producing urine and you have to be on dialysis from that time frame. There is a significant delta on the duration in numbers of people that had delayed graft function on the tac arm compared to the tego arm. And the neurological outcomes were also quite profound where there was an incredible amount of tremors in the CNI arm compared to the tego arm.

Okay. I know you've only had this data for like 3 weeks now. So I'm just -- I think you're still going through the details. Is there anything in this population or the way the patient is managed, that could explain why the tac arm did better than what we've seen historically?

To your point, we're a couple of weeks into the data. But yes, we've had some clues and some of it is just the nature of clinical trials, right? Unlike real-world data where patients aren't managed as carefully in the context of a clinical trial setting, patients go into the clinic as often as they want. And we obviously paid for and manage this study, and we wanted doctors to give patients the best possible care that they could, but it was incredible to us how frequent visits often were in the tac arm compared to real world. And because they've been using this drug for 30 years, they have a very good understanding of how to manage and control the trough levels of tac exquisitely as long as they're seeing their patients often enough, which they did in our study. So that probably contributed to why there was very, very good kidney function on the tac arm compared to what you might see in real-world data.

Okay. So then maybe thinking about the data you have now, I think your next steps would be kind of analyzing it's more than getting in front of the FDA. So maybe you can just talk about what are the next steps? What should we expect to hear from the company next?

Yes. So clearly, the team is now transitioning post BESTOW to, next up, which is to design and launch and execute a Phase III study in kidney transplant. We've had some earlier dialogues with the agency to get some clarity about what that might look like, including that a single Phase III study would be sufficient. They've been guiding us for a long time that the endpoint we're at 12 months would be the non-inferiority endpoint that we've utilized for a long, long time in kidney transplant. And then as I mentioned, there is a new surrogate endpoint that the FDA is currently reviewing. It's called iBox. It was approved in Europe about a year ago as a secondary endpoint. But the consortia that's been promoting the utilization and approval of iBox is trying to guide it a little bit differently here in the U.S. where they're advocating for a subset of the iBox components, which I could describe to you, if you'd like, called abbreviated iBox, could be utilized as a co-primary end point alongside the composite endpoint for approval, which expands the label, if you will.

I mean, it's kind of like taking -- we call it, 2 bites of the apple. You don't have to hit your iBox as an endpoint to to hit your non-inferiority for approval. But if you do, I can give you some better details on your label post approval.

Okay. Maybe one question here, just obviously, from a market reaction to the data on Thursday was pretty negative. What do you think is the disconnect in terms of what -- like what, based on your conversation with investors before and after relative to your expectations and kind of -- it sounds like pretty positive feedback from the kidney community what do you think the investors are missing?

So the -- so obviously, we have a lot of different constituents. The doctors and nephrologists at the meeting have been incredibly excited about our data to the point that the inbounds from them have been pretty incredible. There's also a great pod-cast that was conducted post ASN, if you haven't listened to it, that really summarizes a lot of components of the meeting, but because we we're a late-breaking abstract. Starting at about a minute 12 out of that 1-hour pod-cast, 3 different KOLs talk about our data and how remarkable it actually is from a safety perspective in particular. And how exciting that could be for them and for patients. It's definitely worth listening to.

But safety alone is something that people have really, really focused on the -- people I think have been incredibly surprised at how good our safety was at 12 months compared to tac. And people know that those toxicities that I've described associated with tac are cumulative. You're going to see them accumulate year after year after year, and we've seen that in other studies. So I think that, that was one of the most exciting pieces. What I think the investment community missed a little bit is -- they have -- they thought that we had beat tac in the superiority component of our study. And that really was just the primary endpoint in a Phase II study that we could have had safety be the primary end point. We kind of shot for the fences on that outcome. And if tac didn't over-perform and behave more like historic, we probably would have hit it. But I think what the investors didn't do is go past the tagline that we missed our primary endpoint. We hit the non-inferiority endpoint, and we really hit a grand slam home run on all of the safety pieces.

Okay. Okay. Great. So let's -- looking beyond that a little bit, that as we think about the opportunity moving into Phase III, can you just talk about sort of the commercial dynamics here that you have to think about of the company. I think the other thing that, as we've talked to people about the Eledon story over the last year, the last launch in kidney transplant was belatacept, which didn't do quite as well as people were expecting. So your thoughts on belatacept, sort of maybe why it didn't sort of become the blockbuster people thought it might be? And then how would tegoprubart be a different outcome?

Sure. So I mean, one thing with -- -- so bela is a good drug, right? If you look at the bela data that's been published in the literature, the 12, 3-year, 7-year data for bela looked quite striking. It was approved 15 years ago. At that time, one of the disconnects I think, was that people didn't understand that eGFR was the best long-term predictor of graft function. At that time, there was a conception that biopsy-proven rejection rates was actually the best predictor. And we now know that there's a lot of data to suggest that actually BPAR rates don't have anything to do with predicting long-term [ graft ] function. And that's one of the reasons why it's not a component of iBox. When bela launched, their goal was to launch on safety for one thing. And second of all, the study because of the timing on when BMS launched that study, they actually were not comparing themselves to the approved standard of care, which was tacrolimus. They actually went against cyclosporine, which tac had beaten in that non-inferiority study.

So I think those complicated the launch a little bit. And then I think the third piece was on the safety side that had a couple of minor hiccups, if you will. It has a black box in liver transplant because when they went into their liver transplant studies, they saw some deaths and it also had a higher incidence of PTLD. And we still see that today. It's not real common, but it's something that happens. And that's scares people, which is probably why bela only has about an 8% of de novo kidney transplant market share.

Okay, let's go beyond kidney. As you mentioned, the goal would be for all transplant potentially. So you do have the islet cell program going on with the University of Chicago. Maybe you can talk about islet cell and then other opportunities you have beyond de novo kidney?

Yes. So our second focus has been both islet cell and xenotransplant. In islet cell we have an ongoing study as an IST, as you mentioned with Dr. Rakowski at University of Chicago. He's been fairly outspoken about the data as has the diabetes community. He got 5 of the 6 patients off exogenous insulin very quickly after their islet cell transplant. It's a pretty minimal immunosuppressive regimen compared to what we see in kidney transplant because protecting cells doesn't require quite as much immunosuppression and tego is really the foundation and cornerstone of that. Historically, islet cell transplant has not been well adopted in the patient community because no one wants to go and get an islet cell transplant and basically swap out their diabetes for the toxicities associated with tac. And so we think that this is an amazing opportunity.

Our goal here is to facilitate Dr. Rakowski and supply drug, so we can get 9 patients enrolled. Once we have about a year of data on those 9 patients, we intend to go to the agency and start to discuss what a Phase I/II/III strategy for approval of tego in the prevention of islet cell transplant rejection would look like. There is some guidance out there that what they've guided to Vertex as well as to cell trans. So Vertex has their terminally differentiated islet cell that are -- I think they completed enrollment of their Phase III recently. And then cell trans got approval about 2 years ago for cadaveric islets. They got approved on about 22 patients of data and Vertex's guidance has been 48. So we think we'll be somewhere in that frame, but we want to take that 9 patients worth of data, which we're quite hopefully be quite excited about and go and get some guidance from the agency on what a registrational type study might look like in islet cell transplant.

Okay. And the latest around xeno?

So xeno transplant, as people know, has made exciting progress in the last couple of years. If recently, unfortunately, we had a minor setback with the person that probably had the longest kidney transplant, which was an eGenesis kidney that was on tegoprubart in several other immunosuppressive medications made it out about 10 months post transplant. If you would ask me 1.5 years to 2 years ago that we would have somebody go out that far on a xeno-kidney transplant, it probably would have last and they actually did quite well. We still have a third patient that National has done that still has a viable kidney and it's doing well. And what's happening now, I think in the community with the approval of United Therapeutics IND path towards approval that's being run primarily right now out of NYU. And eGenesis also has approval for their path forward in kidney transplant xenotransplant. I think we're going to see the clinical trial protocols really start to add some better constraints about what we're doing with patients as far as what type of patients we can enroll how healthy they are.

The compassionate use patients were patients that were pretty sick. I'm hoping that as we start launching the clinical studies next year, rather than the passionate use studies, we'll see some good progress on how to utilize xeno kidneys in the context of tegoprubart and the other immunosuppressive drugs to prevent rejection.

Okay. Great. So maybe a last couple of questions I have. One is sort of the competitive landscape. We get this question a lot too, because there are other companies with CD40s, CD40 ligands. What are you seeing out there competitively in terms of -- it seems like a lot of the CD40 and other indications. But just what are you seeing in the transplant space from competitors?

So right now, we're the only company that's in transplant for the prevention of de novo rejection with a sponsored study for blocking CD40 ligand. Obviously, the other competing molecules from Sanofi, Biogen, Amgen are focusing on the larger autoimmune indications, if you will, with Sanofi focusing on MS, Biogen Idec -- Biogen UCB rather just reported positive Phase III data about a year ago in lupus and Amgen's reported positive Phase II data in Sjögren's syndrome in RA. I think the exciting thing about this target with the competitors and with our drug is after 30 years of people wondering if CD40 ligand was a validated target and if the check box there is yes.

It's clearly working in multiple indications. With our primary focus on kidney transplant and we're the only ones in transplant, I think we have a great opportunity to really make an impact and transform immunosuppression for transplant medicine in the next few years.

Okay. Great. So maybe last minute or 2 here, capital position? I know you're sort of in the middle of this raise now this week. Can you just share whatever you can in terms of your current position? What's your runway? And then tied that, what are the next catalysts we should look for within that runway to investors to be aware of?

Sure. So as of September, I think we've reported that we have about $90 million in cash. As you mentioned, we're in the process of closing a raise this week, which we're hoping would extend that cash runway out to Q1 2027. So that gives us a little bit more runway compared to what we would have had just with the $90 million in cash for September. What we're guiding for, for next year for catalyst would be clear regulatory guidance on all 3 of our indications. So have an end of Phase II meeting with the agency about what a Phase III trial would look like in kidney transplant. So that we can execute and launch that study by the end of next year. to get clearer guidance beyond what an islet cell registrational study would look like so that we can transition our investigator-initiated study with Dr. Rakowski into more of a multi-center islet cell transplant study, if you will, heading towards what might be a registrational study.

And then finally, eGenesis announced that they got FDA approval on what an IND would look like for kidney xeno transplantation with 33 patients of data. Tego is the cornerstone of that immunosuppressive regimen. So we need to go to the agency and basically articulate what the approval plan would be for tegoprubart as part of kidney transplant rejection.

Okay. Sounds great. I'd agree with you on the xenotransplant comments, like the progress we've seen there is pretty remarkable over the last couple of years and interesting that eGenesis has chosen tegoprubart to be there, the backbone there. So thanks so much again for attending the conference. We'll see how things progress here over the next little bit, we'll watching closely.

Thank you. Appreciate it.

Good morning, ladies and gentlemen, and welcome to the Eledon Pharmaceuticals Phase II BESTOW Results Conference Call. [Operator Instructions] This call is being recorded on Friday, November 7, 2025.

And I would now like to turn the conference over to Dr. David-Alexander Gros. Thank you. Please go ahead.

Thank you, operator, and good morning, everyone, and thank you for joining us on our call to review Eledon's Phase II BESTOW data that we presented last night. I'm -- this is David-Alexander Gros, I'm the CEO of Eledon, and I'm joined here today by my team with Steve Perrin, our President and Chief Scientific Officer; Paul Little, our Chief Financial Officer; Elie Katz, our Chief Medical Officer; Dave Hovland, our Chief Regulatory Officer. And we're also happy to be joined today by Dr. Andrew Adams, who presented the data last night at ASN. He is Professor and Chief of the Transplantation Division at the University of Minnesota.

Moving on to the forward-looking statement slide. We will be making forward-looking statements, so please review this slide carefully. Moving to Slide 3. We are developing tegoprubart principally around transplantation. We believe that tegoprubart can become the cornerstone maintenance chronic immunosuppressive medicine across all transplant types. So, across all solid organs, cellular types of transplants, as well as regardless of the source of organs. So whether organs are coming from diseased donors as is most typical living donors or as we advance the technology, even xenotransplantation.

Today, we'll be covering the data from our latest kidney transplant study. We presented data over the summer from a Phase Ib study as well and the patients from both this study as well as the Phase Ib study can opt to continue in a long-term extension study that will allow us to have data that we can report out in the future. Other than kidney transplantation, we also have trials ongoing in islet cell transplantation and are poised to start a study in kidney tolerance. And aside from that, we have -- we are continuing to do work in the xenotransplantation space.

Before we go and review our data, maybe we'll take a step back to talk about immunosuppression overall and the unmet need in transplantation. And for that, I will turn the microphone over to Andrew.

Yes. Thank you, David. I think for transplantation, the success that we've seen over the last few decades has really been mirrored with new development of drugs to prevent rejection. And while those drugs do a great job at that, the control of the immune system is really the foremost piece that we need to think about. And so, when a patient comes in for a transplant, unless they have an identical twin, they're going to see it as a foreign piece of tissue or organ. And the immune response will try and reject that organ. And so, we divide immunosuppression up into 2 phases. The induction phase is the initial phase when they get the transplant. And it's given at that time.

Usually, nowadays, it's Thymoglobulin, which is a polyclonal prep to reduce the number of immune cells that can attack the organ. And then secondarily, they're placed on chronic immunosuppression, which they have to take for their life. Any time they stop that immunosuppression, their organ will be at risk for rejection, and that will be taken for years. So, the unmet need in kidney transplantation really surrounds the drugs that we're using to prevent rejection of the organ, keep it healthy. And tacrolimus is a calcineurin inhibitor, a small molecule that's been around for a few decades now.

And while it does a great job at preventing acute rejection, it has some limitations. And so right now, it's the primary immunosuppressant for kidney transplant recipients. It's the standard of care. But as we see patients take that medicine over their lifetime, we understand that the limitations that it brings with it, including prolonging the life of the kidney is only in a limited phase. So, we expect diseased donor transplants only to last 8 to 10 years, living donor transplants a little longer than that. And many of those are related to the effects of the drug. It's toxicities that patients have to endure, including kidney injury, neurotoxicity like tremors, headaches, other things like increased risk of hypertension, nuance of diabetes, which increased their cardiovascular risk for their lifetime.

And then lastly, it's really a complex drug to use. There's a therapeutic index that's very narrow with calcineurin inhibitor. Unlike a daily drug that you might take an aspirin or another medicine for high blood pressure or high cholesterol, tacrolimus is very complex. The dose changes often, especially in the early transplant period. There are multiple capsules that are needed to take twice a day. And so it's really a high pill burden and that leads to problems with adherence and complexity of care. So it really makes the case that we need a new medicine to help reduce toxicity and prolong the life of the kidney transplant.

Thank you. Moving on to the BESTOW study itself. The BESTOW trial was the first study comparing head-to-head tacrolimus, so the current standard of care to a CD40 ligand antibody. The study was designed around standard of care. So essentially, we had 2 arms, one on standard of care, including including rabbit ATG as an induction immunosuppression and a second arm where we removed the tacrolimus and replaced it with tegoprubart. So, a calcineurin-free arm.

Moving on to Slide 8. The endpoint of the study was superiority as measured by eGFR or kidney function. The reason why we used that as an endpoint was that eGFR as a single variable is the best single factor to help predict how long a transplanted kidney is likely to function. Historically, eGFRs have been in the low to mid-50s range. And as you can see on this slide, over time, the side effects of calcineurin inhibitors that Andrew mentioned, so the direct nephrotoxicity as well as the indirect nephrotoxicity from hyperglycemia and hypertension can eat away that kidney function and so cause the eGFRs to decrease.

As one of our secondary endpoints, we also looked at what is the actual approvable endpoint today from the U.S. FDA's perspective. And that is a different endpoint. It does not use eGFR. It's a composite endpoint looking at biopsy-proven acute rejection, graft loss and death. And the approvable endpoint has been noninferiority based on that composite.

Moving on to the conclusion slide. Overall, we are very happy with the way tegoprubart performed. Tego did everything that we could have hoped that tego would do. If we start with approvable endpoint, so the composite endpoint that I mentioned, despite the fact that the study was not powered to demonstrate noninferiority between tego and tac, we were able to demonstrate noninferiority between the 2 drugs looking at that composite endpoint.

From the eGFR perspective, so from the graft function perspective, tego again delivered strongly. The graft function that we saw on tegoprubart, which was around 69, so in the high 60s range is very consistent with levels that we've shown in the past, and we believe is the highest that's been demonstrated in a clinical trial to date.

In terms of safety, the safety that tegoprubart demonstrated was excellent and showed significant reductions versus some of the typical side effects that one sees on patients with tacrolimus, including those that Andrew mentioned, such as the new onset diabetes, the tremors, the brain fog headaches, hypertension and delayed graft function.

In terms of the endpoint looking at separating eGFRs between tego and tacrolimus, we showed numerical superiority of tego versus tac, but not statistical superiority since tacrolimus ended the year with a mean eGFR of approximately 66 mls, principally driven by one subgroup, as you'll see.

Looking at all of these endpoints together, we believe these results support advancing tegoprubart into a Phase III and considering the efficacy that was demonstrated as well as the safety, we believe that this can position tegoprubart as the next-generation cornerstone of kidney transplant maintenance immunosuppression.

Moving on to participant flow. There were 127 patients enrolled in the BESTOW study. The goal was to enroll at least 120. The patients were enrolled pretty much 50-50 between tego and tacrolimus. We had slightly more study discontinuations on the tacrolimus arm, and we had slightly more treatment discontinuations on the tego arm, principally driven by patients that had experienced a rejection and switched on to tacrolimus. But overall, the completion rates were similar between both.

If we now look at the donor and recipient characteristics, overall, these resemble what we would have expected in a kidney transplant clinical study and both groups were quite similar. I will point out that numerically, the biggest difference in donor or recipient characteristics can be seen in the deceased donor group, in the deceased donor organs tended to be in the tac arm, organs that had KDPI scores of less than 35%. So, these are considered the highest quality organs that can be transplanted, and there were about 20% more patients in the tac arm. So, 57% of the patients in the tac arm that received a deceased donor received one of these organs versus only about 37% of the patients in the tego arm. And we'll look later on what impact this may have had on study outcomes.

With regards to additional immunosuppression, which is a topic that we've covered in the past, we were targeting for patients to receive an ATG dose of 4.5 milligrams per kilogram. And on average, physicians came pretty close to that with a 4.3. There were still some patients that got some low ATG doses in the 3 or just under the 3 range, as well as some patients who got some higher doses. If you look at this page, you'll notice there was one patient that got a very high dose of ATG, but that appears to not have been intentional.

The other difference in terms of induction immunosuppression is around the corticosteroid use. We did note a lower average dose of corticosteroids that were used for the patients on tego and physicians tended to wean patients down on corticosteroids faster in the tego arm than the tac arm. So, they wean patients down on tego in 23 days versus about 31, 32 days on tac.

What this tells us is that there are still -- there may still be room to optimize induction immunosuppression as we move into Phase III, which could help improve some of the early rejection that we saw.

Moving on now to the efficacy endpoint. As you can see on Slide 13, the mean eGFR for patients that completed treatment at 52 weeks was 69 on tego versus 66 on tacrolimus. Importantly, tegoprubart was numerically superior at every measured time point in the study. Although as I discussed, it was this numerical difference, the 2 -- and you can see this in the 2 curves overlapping here was not statistically significant.

Moving on to the next slide. If we look at our prespecified subgroup analyses, we see once again that in almost all of the subgroups, and these are the principal subgroups where that can lead to different outcomes in kidney transplantation. There was a numerical advantage for using tegoprubart. The one subgroup where that advantage was not seen was in the diseased donor subgroup. And as you can see on the slide, particularly in this subset of patients that received the highest quality kidneys. So, let's take a deeper dive into this.

Moving on to Slide 15. If we look at the mean eGFRs for living donors, we see a very nice separation of the curves of about 10 points of eGFR. So, tegoprubart being at 72 versus tacrolimus at 62. And then if you look on the right-hand side of the slide, you'll notice that for the diseased donors, the curves overlap with tacrolimus actually doing better in the deceased donor arm than it did in the living donor arm. And this is surprising since typically living donors are the best organs and do as well, if not better, than diseased donors.

Now taking a further dive into the deceased donor arm, we noticed separating out the kidneys between high-quality kidneys, which are those with a KDPI less than 35 and medium to lower quality kidneys, which are those with a KDPI of over 35. As an aside, to help remember that in KDPI in this index that's used to score the kidneys, 1 is the best and 100 is the worst. So, it's good to be #1 when one is using KDPI. On the arm with KDPI over 35, tego has a nice spread, again, all -- nearly all the time points versus tac, but the curves come together in this subset of KDPIs less than 35.

Now what is surprising here, as you'll notice, is just how high the tacrolimus came in at an 80. So, we're seeing a 30% improvement in kidney function between this subset of patients and the living donors that we just reviewed. Now importantly, even in the subset, tegoprubart did exceptionally well with a 78 average eGFR, but the curves -- this is the area where the curves overlap.

Now if we remove that subgroup of patients, so those patients with the best kidneys, then the curves separate nicely once again. There's about a 10-point delta at 12 months between the 2 arms, and this becomes statistically significant. We expect that -- we expect that ibox will be approved by the FDA as a potential endpoint moving forward. And this would be an additional endpoint on top of the current approvable endpoint of non-inferiority and so potential bonus, if you will.

And here, in this study, we saw an excellent ibox, the lower is the better on the patients with tego at a negative 3.9., although since the primary driver of ibox is eGFR, there was no difference between the tego arm and the tacrolimus arm in terms of ibox. But you can see just how much or how well tacrolimus performed here if you compare it to the historical trials of calcineurin inhibitors in the past, which -- where C&Is have typically performed in the negative 3 range using ibox.

Moving on now to biopsy-proven acute rejection. We saw numerically more rejections on tegoprubart than tacrolimus. The acute rejection rate on tego was about 20.6%, which is similar to what we've reported in the past, and that compared to tacrolimus at 14.1%. If you look to the right to the Kaplan-Meier curve, importantly, you'll notice that patients on tegoprubart did not experience a rejection event after the -- after month 6. So, all of them were early.

We did see later rejections on tacrolimus as well as multiple incidences of rejections that were found on protocol biopsy, which suggests that there might have been an underdiagnosis of rejection on patients on the tacrolimus arm who might have been treated empirically and so not biopsied within the first 12 months.

If we look at how the patients on tegoprubart did, overall, patients did very well. Patients that experienced a rejection and remained on drug finished the year with an eGFR in the 70s. They finished the year with an eGFR of 73, and this compared favorably to patients that discontinued tego to move on to tac who, while their final kidney function was acceptable was inferior to what was demonstrated for the patients that remain on tegoprubart. The patients that switched to tac ended the year with an eGFR of approximately 50.

Moving on to the next slide to look at the composite endpoint. The composite efficacy failure endpoint on the tego arm was 22.2% versus 17.2% on the tacrolimus arm. And this is a difference that is within the non-inferior range, so the non-inferiority range between the 2 drugs. Also, this failure rate is in the same range that has been seen with historical drugs that have been approved in the past for rejection.

Of note, at the end of the treatment, 1 patient on tego and 2 patients on tac demonstrated donor-specific antibodies. So, similar between the 2 arms.

Moving now to safety, and this is really where we see tego shine. If we look at the overall treatment-emergent adverse events, the percentage of patients that where an adverse event was observed was similar between the 2 arms as was the maximum severity of those adverse events that were seen. Both arms saw a death and both arms saw one case of graft loss.

Now if we look at all of the AEs that were observed at least 5% of the time in one of those arms and we pull out any AEs where one arm demonstrated 2x or more the incidence of that adverse event, we added it to this slide. So, this is where one sees the biggest differences in the common AEs that we're seeing. And after this, we'll dive into the full safety tables. But before doing so, we can begin to get a picture on where the biggest differences were seen here.

On this slide, green is used to demarcate where tegoprubart demonstrated better safety than tac. I'll start by talking about where tego was inferior, and that was proteinuria. We saw, as you can see, more proteinuria on the tego arm than the tac arm. Of note, this proteinuria was typically diagnosed in the physicians' offices, so dipstick proteinuria, if you will. For most of these patients, the proteinuria was transient. It started at different periods of time and then went back down to baseline. The 2 patients where that was not the case that had persistent proteinuria were patients that experienced a recurrence of the underlying autoimmune disease that led to them losing their kidneys in the first place. So, there was one case of FSGS and one case of membranous nephropathy.

Looking at the rest of the AEs, where we saw a big difference between the 2 arms for infections, we saw many more cases of bacteremia, 7x tego versus tac, and that translated into 2.5x the cases of sepsis we're seeing on tacrolimus. Now sepsis is important because for hospitals and the system, it can be very expensive since typically a case of sepsis after transplant requires an ICU admission. And also sepsis is one of the leading causes of death in the first year post transplant.

If we look on the metabolic side, and this is when we talk to physicians, probably the #1 complaint that we hear from physicians about tac. Tac is known to be beta cell toxic, so it causes hyperglycemia as well as new onset diabetes, and we saw a dramatic difference in the number of patients that developed diabetes on tac versus tego. So overall, there were 7x as many patients on tac that developed diabetes. But if one pulls out those patients that already had diabetes, since diabetes is one of the most common reasons why patients need a kidney transplant in the first place. So, one looks at just the pool that wasn't a diabetic at the time of the transplant, it's about 1 patient in 6 on tacrolimus that develop diabetes. And this compares to less than 1 patient in 40 that developed diabetes on tego.

We noted that there was an increased hyperkalemia that was seen on tac that can be seen with weak worse graft function sometimes and can also be associated with cardiac arrhythmias. In terms of neurological side effects, and this is the -- when we talk to patients, the #1 complaints that patients tell us about with tac, the tremors were very pronounced in the tac arm with 1 in 4 patients on tac reporting tremors, as well as 1 in 6 patients on tac reporting muscle spasms.

Now if we put these AEs in context with the eGFRs that we reported, the eGFRs show that these were some of the best treated patients ever, considering how well they were doing. And yet despite what appears to have been as optimal care as a patient could receive, the AE profile continued to demonstrate the typical AEs that are seen with tacrolimus. I'll come back to the cardiovascular and blood AEs on a later slide.

Moving on to opportunistic infections. We saw overall similar amounts of viral infections between the 2 arms. If we look at end organ viral disease, so where the virus infect is found in the transplanted kidney. We found more CMV disease numerically in the tac arm, as well as more BK nephropathy in the tac arm, although those are purely numerical and overall, the numbers are obviously quite similar. And you can see the difference in terms of sepsis and bacteremia on the slide, which we just discussed. Otherwise, in terms of fungal infections, the number was similar between the 2 arms.

Moving on to the renal AEs. What stood out here was delayed graft function. So delayed graft function is what happens when a patient receives a transplanted kidney, but the kidney does not start to function immediately. And so these patients need to go back on dialysis. And this can obviously from a patient's perspective, adds a psychological weight. And then from the system and the hospital's perspective can add significant costs, especially since some hospitals can keep patients as inpatients while they do the dialysis in order to see if the kidney begins to start.

So, what we observed with regards to the late graft function was that we saw more higher incidence of delayed graft function for the patients on tacrolimus, where 1 in 4 experienced DGF. And when patients experienced delayed graft function on tacrolimus, that delayed graft function lasted for longer than it did when patients were on tego. So, patients that had DGF on tego needed about 4.5 days of dialysis versus over 6 days of dialysis for the patients on tac.

If we look at the deceased donor arm, which is where delayed graft function is seen, that translated to an estimated difference of 115 days extra on dialysis for every 100 diseased donor patients that would be transplanted. So, if we extrapolate out these numbers, one would assume that one would see many more TGFs and associated dialysis for the tacrolimus arm.

In terms of the metabolic arm, we discussed the high blood sugars, the diabetes and the hyperkalemia. We did see more hypophosphatemia, so low phosphate on the tego arm, but that did not appear to be clinically significant.

Moving on to CNS. We mentioned the tremors and the muscle spasms, which are the #1 complaints we hear from patients. The #2 complaints that we hear is around the brain fog, headaches and dizziness. And with those complaints, we saw about twice the incidence on tacrolimus as we saw on tego.

If we move on to the cardiovascular side effects, hypertension is a well-known side effect of tacrolimus, and we observed more hypertension in the tac arm. Importantly, this translated into 5x as many patients experiencing a hypertensive crisis on the tacrolimus arm versus the tego arm. And finally, we did note that 5% of the patients in the tacrolimus arm experienced heart failure, while no patients experienced heart failure in the tego arm.

Moving now to differences in blood. We noted more leukopenia in the tego arm, as well as more lymphopenia in the tacrolimus arm. The leukopenia tended to be seen early on. So, during the polypharmacy phase, while the patients were also on induction therapy. And in terms of the impact on infections, we covered that on an earlier slide. There were numerically some more non-melanoma skin cancers on tego, although the numbers were similar and within the range that would be expected and not much difference in terms of GI.

So, to conclude, looking at all of the data that we just covered, we are very excited about the prospects of tegoprubart, where we believe we have a drug that could be approved if we're able to replicate in a Phase III, what we observed in this Phase II. Importantly, we were able to demonstrate noninferiority between the 2 drugs, which is the current approvable endpoint.

From a graft function perspective, the graft function that was observed on tego was excellent in the high 60s in a future trial. Although tacrolimus did very well here, there could be reversion back to the mean and to where those arms used to be. And we'll also obviously take deep dives into our data to understand if there are changes that we need to make in a Phase III design in order to make sure that patients are equally distributed between the 2 arms.

From a safety perspective, tegoprubart did better than what most of us would have expected and is demonstrating a very favorable profile versus tacrolimus. In terms of our current financial profile and what to expect moving forward, we ended September with about $93.4 million in cash, and this is sufficient to fund our operations for another year, so into late 2026.

We're going to have a lot of milestones coming up over the next 12 months in terms of tegoprubart in kidney transplantation, we will now take this data and go see the FDA to talk about path to approval in Phase III design. We expect to do so in the first quarter or first half of next year. As I mentioned earlier, all the patients in our Phase Ib and our Phase II studies have the option to enroll in a long-term extension study. About 90% of patients elect to do so. And so next year, we look forward to presenting data from that long-term study.

We expect that with time, the direct and indirect nephrotoxicity of tacrolimus should impact patients' kidneys so that over time, we would see more separation of the curves versus what was seen at the 12-month endpoint. And assuming that we get support from the agency in the start of the year, that would give us the opportunity to launch a Phase III study in late 2026.

Aside from kidney, we're running other programs, particularly in islet cell transplantation. We currently have 6 patients enrolled in the study. We expect to report out data on the first 6 patients by year-end. We also expect to enroll another 3 patients or 9 patients in total into the study by year-end, which would allow us to have to report out in the first half of next year on those 9 patients. And once we have 9 patients of data, we believe that will be sufficient for us to go talk to the agencies or to the FDA about what could be a path to approval for tegoprubart in islet cell transplantation.

Next, we are getting ready to launch another Phase II islet cell transplant study. This would be another investigator-sponsored trial, but in multiple sites. And this one would focus on patients that have high-risk diabetes that also have kidney dysfunction. And so because of their kidney dysfunctions, these patients are -- wouldn't normally get an islet cell transplant or pancreas transplant since once wouldn't want to give them tacrolimus since the tacrolimus could end up destroying their kidneys. We expect that once we have a chance to talk to the FDA about islet cell transplant and have a path to market, we could be in a position to launch a Phase III study in islet cell transplant.

And with that, I will turn over the call to the operator to take questions. Operator, please open the line.

[Operator Instructions] And your first question comes from the line of Thomas Smith from Leerink Partners.

First, with respect to the eGFR primary endpoint and the tacrolimus outperformance, appreciate all of the subgroup analyses that you presented. But maybe a question for the company and for Dr. Adams. Is there any rationale for why tac would have outperformed in that diseased donor subgroup? Any sort of mechanistic rationale or anything else notable about the patients that were included in that subgroup that could explain that?

Yes. Thanks. I think part of it, DA went over with regards to that subgroup having what we think of as really good kidneys. And so, some of the effects that we see on tac don't always occur in the early period, and it can be seen later. So -- and I think the distribution even within that, it's a lump of less than 35 was even uneven within that group. So, I think it's a continuous kind of measure of donor variables that would impact the survival of the kidney long term. So, when you have a really good kidney and you have something that impacts kidney function, you may not see that early on, you'd see it later. I think based on all the data that we know about C&Is is long term, we'll see the effects of that as it goes on, more prominent on kidneys that are of a lesser quality to begin with and more prominent later in kidneys that are better functioning.

Got it. That's helpful. And then just a question on the path forward from here. Can you talk about how you're going to approach the FDA and what you intend to propose to the agency here with respect to the Phase III design? Are you currently thinking that you'll follow the established pathway with the non-inferiority on composite efficacy failure? Or are you still thinking that there could be a path to a superiority claim over tac on ibox or some other endpoint?

Sure. It's DA, and thanks for the questions, Tom. In terms of path forward and discussions with the FDA, it's not any different from what we've been discussing in the past. So, the current approvable endpoint is the non-inferiority composite endpoint. What is in front of the FDA today with regards to ibox is the potential for a expanded label for an additional label claim of long-term or expected long-term superiority in terms of organ survival, so 5-year superiority. But that claim is an additional claim to the base claim that is based on the non-inferiority endpoint.

So, our plan is to approach the agency the same way we were going to do so. We're going to propose the traditional endpoint, which the FDA continues to make clear is the primary endpoint. And there is no downside to -- if the FDA agrees to including that second superiority endpoint. Since if one hits it, it's a bonus, if you will, right? You get the bonus extra claim on your label. But if you don't get that extra claim, you still -- the drug is still approved. And obviously, here, with the performance that we're seeing in terms of the very good organ function as well as just the superiority profile that is becoming more and more evident with tego, we think that commercially, that will be very viable.

Understood. That's helpful. And if I could just sneak in one last question here for Dr. Adams. So, I was just wondering if you could talk about your view on sort of the totality of the efficacy and safety data here. Like what do you view as the most compelling benefit shown for tego in the study? And how do you think this drug would be incorporated into your renal transplant service, call it, 5 to 10 years from now, assuming this profile is replicated in Phase III?

That's a great question. The transplant community has been waiting for a better drug for 30 years. And while we use tacrolimus, we see its limitations day in and day out with patients and then the long-term effects of it. And so having the option to have a drug like tego that provides superior or really good kidney function in the short term and in the long term by preventing the immune response, preventing donor-specific antibody, we know that from its mechanism of action. The expectation is these kidneys will last longer over time.

But secondarily, it's the patients that we see day in and day out that experience the various side effects that we see on tac that, in some cases, can be quite serious. The neurologic effects it's not just we see tremor and the brain fog. But in other cases, we see serious effects like seizure, the diabetes that comes in. All of those we know are going to contribute not just to the effects on the kidney, but overall effects on health. And so having the opportunity to use a drug that has a much more favorable safety profile like tego, I think, is a great opportunity and something that we would incorporate in our practice.

You can see that difference when you compare apples-to-apples like in the living donor transplants, where you know the kidney function difference there exists. But expanding to diseased donors, the number of older donors of donors with more comorbidities, so in the higher KDPI group where tego performed better is only increasing in the U.S. So those are more of the kidneys that we're using in the disease, more DCD donors. Those are all things that contribute to KDPI. And so I think there'll be more of an opportunity to use in that population as well.

And your next question comes from the line of Pete Stavropoulos from Cantor Fitzgerald.

First one is for Dr. Adams. You just sort of did touch on it, but if you can go a little bit deeper. From a clinical standpoint, how meaningful is the differentiated safety and adverse event profile observed with tegoprubart and particularly the reductions in new onset diabetes, hyperglycemia, tremor and hypertension for long-term efficacy, patient management and drug adherence.

Thanks. You hit on a few good points there. I'll start with the diabetes and hyperglycemia. We see patients that come in, again, not having had diabetes before. The first episode that they have is I saw a patient the other day in the ER with a blood sugar in the 600s. This is not an uncommon event that we see in patients treated with tacrolimus. And so, it does have a clinical impact, not just on kind of their health status, where they're admitted to the hospital. Now they've got a new diagnosis of diabetes and all that comes with that, including the health complications. So having a drug that has a significantly less propensity to cause that really will, I think, help patients in the long run, not just with their overall health and the health of the kidney as we know, diabetes causes damage long term to the kidney as well.

So having a drug that has that profile is something that will be desirable to use in place of tacrolimus, if that's an option in the future.

And a reduction in the delayed graft function, it looks notable, the difference between tego and tacrolimus. How clinically meaningful is that difference in your experience? And does fewer days on dialysis early post-transplant translate to a better long-term graft outcomes or hospital resource savings?

Yes. Absolutely. Patients that experienced delayed graft function ended up -- on average, end up staying in the hospital longer. They're on having to get sessions of dialysis that hopefully they wouldn't otherwise have to get when a kidney is functioning well. I think part of it is also thinking about where if we're using kidneys that are more prone to have that, again, increasing number and percentage of DCD transplants, older donors, longer cold ischemia times, all increase your risk for DGF. And so that's -- if you look over the last 5 years, those are only increasing in our practice.

And so in the future, having a medication instead of like tego that can decrease the rate of DGF is going to help in that practice reduce cost but also improve kind of the function of the kidney and the patient's overall kind of recovery after transplant.

And one last question. We've seen patients who stayed on tego through acute rejection, maintain strong kidney function, whereas those switch attack declined substantially. How do you interpret that? And what are possible drivers of this difference? And this was also seen in the Phase Ib.

I'll turn that question over to Eli. So, Eli differences in...

Yes. So, this is a very important point. When you start a study like Phase II with investigational drug like tegoprubart, the first instinct of physician when rejection happen is to switch to tacrolimus. We talk through the study, we talk to investigator and told them that it's really important to learn how to treat rejection on tegoprubart without stopping tegoprubart. And what we learned is that if you treat the rejection in a standard way, like usually being treated either with steroid pulse or sometime thymo globulin and you maintain the patient on tegoprubart, you avoid, again, all the negative impacts of nephrotoxicity and others that tacrolimus has, especially in vulnerable kidneys like kidney that sustain rejection.

So, what you see here is that when patients switch to tacrolimus and usually, they are being switched at this study because of this uncertainty about continuing investigational drug when patients develop rejection because the physicians are very used to use tacrolimus and trust tacrolimus.

So, the switch was not really for any specific medical reason, or not because the rejection was more severe than others, but more kind of type of behavior of the investigator. So, this difference at the end of 1 year is pretty clear. And I think what we learned that if rejection happens on tegoprubart, treat it and keep the patient on and the patient will do very well, the kidney will do very well.

Those who will sustain rejection and on top of the rejection, you add insult to injury by giving them tacrolimus, not surprisingly, end up the first year with 50 ml per minute eGFR.

And your next question comes from the line of Rami Katkhuda from LifeSci Capital.

Two quick ones for me. You may have touched on this already, but were rejections with tego observed more frequently in patients receiving lower than recommended doses of ATG similar to the Phase Ib study? And then maybe another one for Dr. Adams. I guess, how do you view the higher rate and severity of rejections with tego just given the totality of eGFR and safety data that's been observed to date?

Rami, thanks for joining the call and for the questions. I'll take the first question. Here, we did not see a difference in terms of rejections from lower rates of ATG. Although as you saw, the most patients and typically the patients were getting the target dose of about 4.5 mgs per kg. But we have observed -- if you take our Phase Ib data, as you know, we have observed that when patients get lower doses of ATG, rejection can occur more frequently with tego. And in terms of what the differences numerically mean, I'll turn that over to you, Andrew.

Oh, sure. No, I think you bring up a great point and something I think the community is been challenged with is historically, before the time of tacrolimus, rejection was -- acute rejection was really something that was focused on. And so almost hyper focused. And so now when we see a slightly higher rate of rejection, the real question is what is the penalty for that?

And as Elie pointed out, when you stay on tegoprubart and maintain renal function, excellent renal function in that case, the long-term prospects or prediction for survival of that kidney are excellent. And so I think the class of medications like tegoprubart is in the co-stimulation blockade, there is a different flavor, but the long-term consequences of that are better than you see in tac, where you see a penalty when patients are on tac and have rejection, their kidney function declines, as Elie kind of pointed out, kind of 2 hits where you have a drug that doesn't impact kidney function and you can treat rejection and maintain good kidney function overall, that's a much better predictor of how that kidney will do long term, which is what the community now is focused on, not 1-year survival, but 5-, 10-, 15-, 20-year survival. And without a new class of medicines to help support those kidneys long term, we won't see those benefits.

I'll add one point to what Andrew just said, which is that acute rejection in the first year is a very poor predictor of long-term of long-term kidney graft function or survival, which is why if you look at the ibox algorithm, rejection is not a part of that calculation. That calculation is principally driven by kidney function, by eGFR. And the reason why rejection is not included is because it just doesn't predict how well those kidneys are going to do long term or how long they're going to survive.

Makes sense. And I guess maybe more broadly, what key changes could you potentially make in a Phase III study based on the results?

So for potential changes in the Phase III study to improve outcomes, I will turn that question over to Steve.

Yes. Great question, Rami. I mean, obviously, we're 2 weeks post data here. So, looking at our data carefully. But some of the trends that you saw in the presentation that DA highlighted, there's certainly room to shore up the immunosuppressive regimen. There was a significant amount of variability on how methylpred was administered around the time of transplant as far as total dose and when it was administered, how the steroid taper worked over 30 days was very variable.

So, we can protocolize some of these things to try to improve consistency. As you might recall, we saw all of the rejections in the tego arm in the first 6 months and then none thereafter, and that could be due to variabilities in immunosuppression as an example. And then, of course, we need to dive in and figure out how you might stratify patients in the Phase III study.

And your next question comes from the line of Vamil Divan from Guggenheim Securities.

So, maybe just building off that last question, I'm also thinking about the Phase III here. And one, I'm curious on thoughts on the longer-term trial because obviously, as you've discussed, the tacro side effects and toxicity I think that would sort of allow for more separation for tego over time. So kind of driving it as a 2 or 3-year trial to really show that superiority in the primary endpoint of the trial as opposed to just sort of longer-term follow-up. Just curious on your thoughts there. And then tied to that also, I know it's still early in your planning, but you mentioned you have about a year's worth of cash on hand right now. Just your thoughts on how much this Phase III program will likely cost. And then I don't know if Paul or anyone want to comment on just sort of your thoughts around your capital position and having proper financing to run the trial.

Okay. So, Vamil, thank you very much for joining and for the questions. So you had 2 questions. The first one was around longer-term endpoints. And the second question was around finance, and I'll turn that one over to Paul. But in terms of the endpoint, we don't foresee changing the duration of the trial, again, the primary approvable endpoint today is noninferiority at 12 months. So that is what -- that will be the core endpoint that we'll use.

In terms of whether we see separation of the curves at 18 months and could those patients be followed by 18 months, we could add that as a secondary endpoint in terms of the ibox endpoint, that would be a discussion to have with the agency about 12 versus 18 months. But for the core endpoint, we expect to keep that at 12 months and not delay our time to approval.

And in terms of the cash needs, I'll turn that over to Paul.

Hey, Vamil, yes, at this time, we have 1 year of cash left, which is we expected at this time. And we're not providing any guidance at this point on what that Phase III is going to cost. It's still a little early in the process.

But you can look at how much money we've been spending. This study was about 130-patient study, so 60 plus in each arm. We would expect the Phase III to be in the 200 to 300 patients per arm size.

And your next question comes from the line of Robert LeBoyer from NOBLE Capital Markets.

Thank you for the presentation and the comprehensive answers that you've been giving. I'm looking at Slide 16, the one that mentions the KDPI scores and the differences between patients who were above 35 and those that were below. And I'm wondering if this was a new finding or whether this was something that was known before the trial that just came out in the trial.

Thank you for the question, Robert. In terms of the KDPI finding, this was not an expected finding. So, this is something that we noticed during our post-hoc analysis of the data. Elie?

Yes, remember also, this is, as we mentioned, this is the first ever study that put tego or CD40 ligand against tacrolimus. So, this information wasn't tested before. This type of concept was not tested before because this is the first study that tried to look at differences. And when we try to understand kind of what we saw, it became apparent that this KDPI and the quality of the disease donor kidney is important factor that affect the function and affect eGFR. So, we're actually learning is that the only 2 weeks after data, and we still need to dive into that in more details, but it seems like that the KDPI is something we need to take in account in disease donor moving forward.

Okay. And is this something that you would consider as an entry criteria for the next studies to secure a superiority and claims of a larger difference between the 2 groups in patients over 35 to get a label for usage in those patients? Or is it too early to say design of the Phase III.

Yes. Sorry, yes. One thing for sure to say is that we're going to take it in account when we design the study as far as stratification and how to balance this patient in a more equal way between the groups. Because as Dr. Adam says, right now, we see imbalance between the distribution of KDPI, even in the less than 35 group, there is imbalance in distribution, so-called in favor of tacrolimus. So, we need to find a way when we design the Phase III study to enroll patient in a way that this imbalance is going to be corrected. This definitely we need to do.

Other measures, of course, as I said, we are still looking at the data to try to understand it in a more deep way. And if other thing needs to be done in order to take this in account, we definitely will do that.

But in terms of the label, Robert, this is DA again, we -- the goal would be to have as many patients in the label as possible. So, this is not a reason to exclude patients. Again, we -- these patients did exquisitely well on tego. The KDPI group, less than 35 finished the year with a 78 eGFR on tego. So, there's no underperformance here from a tego perspective. Tego did great. But what was surprising was how well tacrolimus also did in this arm. And obviously, this is what led to our ultimately not hitting the statistical difference between the 2 arms. And no reason to exclude these patients. They're benefiting.

And your next question comes from the line of Albert Lowe from Craig-Hallum.

I had a few questions about safety. Can you tell us a little bit more about what grades of that proteinuria were observed? And can you also tell us more about what some of the AEs that led to treatment discontinuation?

Sure. So, in terms of the proteinuria, aside from the 2 subjects that I mentioned that had a recurrence of their underlying disease, so that had significant proteinuria, but that was associated with FSGS membranous nephropathy, the other patients typically had very low-grade proteinurias and those proteinurias returned back to baseline. So that was the first question. Did you -- sorry, did you -- was there another question?

Yes. What were some of the AEs that led to discontinuation of the study drug?

Sure. The most common AE that led to discontinuation was those rejections that you saw. So, where those patients experienced a rejection and were switched from tego to tac.

And your next question comes from the line of Yi Chen from H.C. Wainwright.

Based on the data presented today, would you consider for the Phase III trial enroll patients into prespecified groups and which could potentially increase your probability of approval?

So, as I mentioned a minute ago, I think that's definitely something we need to take into account and think about how to stratify what are those factors that you stratify by. And as you know, stratification is related to what factor can impact the endpoint. And this phase, we know now that this KDPI is really important factor that affects outcome related to eGFR. So we definitely will take it into account when we design a study and try to provide the right randomization scheme with the right certification to ensure equal distribution of this patient between the group. I think that's the basic thing we need to do. If the other measure we need to do, I think we'll take it. But right now, this is the obvious one to do.

And could you also tell us how long do you plan to follow up the patients in a Phase III trial setting? And also, what is the average life span of a kidney transplant patients with takeoff?

It's DA again, and thank you for those questions. So, I will let Andrew answer your second question in a second. To answer your first question in terms of the duration of a Phase III study, we expect that endpoint will be 12 months. Now for those patients, we would expect to continue to follow them in a long-term extension study as well. So, it's going to be important for us and for the field to see how tego does versus tac over many, many years. So, we offer a long-term extension to all the patients in our study that way -- on both arms. That way, we can continue to follow them and see how they evolve over time. And in terms of how well kidneys typically do, I'll turn that back over to.

Yes. So, your question was about the kidney transplant survival or the patient survival?

The average lives -- I mean, the patient survival after kidney transplant?

I mean that's a great question. So, the -- I would say that it can be impacted. When we look at how long a kidney transplant survives, it's attributable to either -- does the kidney fail or does the patient die from other conditions, including the kidney failure. And I'd say those things that contribute to deaths of kidney patients primarily are cardiovascular disease, infection. And I think when you consider the safety profile that tego showed in the Phase II trial with lower rates of problems that contribute to cardiovascular disease like diabetes, like hypertension, heart failure, other things.

And we know from other trials, even long-term profile of cholesterol lipids, other modifiable things that you can do for cardiovascular risk that puts patients at higher risk for death over time in traditional immunosuppression with tac. And so, I would expect one of the benefits long term is longer patient survival, and that's borne out in previous trials with non-C&I containing regimen.

There are no further questions at this time. I'll now hand the call back to Dr. David-Alexandre Gros for any closing remarks.

Thank you very much, operator, and thank you to everyone on the call for joining us early in the morning to discuss our VESTO study results. Have a great day.

And this concludes today's call. Thank you for participating. You may all disconnect.