Good morning, and thank you for joining our first R&D day. My name is David-Alexandre Gros, and I am the Chief Executive Officer of Eledon Pharmaceuticals. Kindly note that we will be making forward-looking statements today regarding Eledon's expected future performance or plans, and that these are intended to be subject to Safe Harbor protection. Please review both this slide as well as Eledon's risk factors in our publicly filed SEC documents. Eledon was formed in September 2020 through the acquisition by what was then Novus Therapeutics of Anelixis Therapeutics, a private immunology-focused biotech that was spun off from the ALS Therapy Development Institute. Our current lead asset tegoprubart was the rationale for this acquisition because we believed it represented a best-in-class immune modulating therapy that could have applicability across a wide range of indications. Since then, our strategy has been clear. We are building a company focused on patients for whom anti-CD40 ligand and related therapeutics may provide a life-extending treatment option. We have structured today's discussion to allow us to take a deep dive into tegoprubart, the CD40 ligand costimulatory pathway, the four indications we are currently pursuing, and the clinical trials which we are running. To do so, I am thankful to be joined today by a panel of external experts as well as Eledon's Chief Scientific and Chief Medical Officers. Our agenda for today is the following. Our President CSO, Steven Perrin, will kick things off to talk about tegoprubart in more details, and we will then go through the indications, starting with IgA nephropathy, with Dr. Jonathan Barratt from the University of Leicester. After which, we will move on to talk about ALS with Dr. Stanley Appel from Houston Methodist. We will then move to transplant, starting with kidney transplant with Dr. Flavio Vincenti from the University of California, San Francisco, and then with Dr. Peter Witkowski to talk about pancreatic islet cell transplant. Dr. Witkowski is from the University of Chicago. We'll then go back to Jeffrey Bornstein, our Chief Medical Officer, who will go through our clinical programs. Afterwards, we'll open up with a Q&A session. To ask questions, please enter them in the text box on your screen, and I will then direct them during the Q&A session to our presenters. With that, let me turn things over to Steven. Thank you, David-Alexandre. Today, my presentation is going to focus on an overview of the CD40 ligand pathway, and then I'll also cover an overview of the development of tegoprubart, our anti-CD40 ligand antibody. I'm the President and Chief Scientific Officer at Eledon Pharmaceuticals. CD40 ligand and CD40 were initially expressed on the cell surface of immune cells, with CD40 ligand being expressed on the cell surface of activated T cells after they receive antigen presentation. CD40 receptor, on the other hand, is constitutively expressed on the cell surface of B cells and antigen-presenting cells. Excuse me for one second. I'm gonna try to go backwards and see if the slide will just go back one. Okay. I don't know why it keeps advancing. I'm trying to hold it on one slide, and it won't stop advancing. Hold on. You go. CD40 ligand and its receptor, as I said, were expressed on the cell surface initially on immune cells, with the ligand being expressed on the cell surface of activated T cells after antigen presentation and the receptor being expressed on the cell surface of antigen-presenting cells such as B cells, macrophages, dendritic cells, and other antigen-presenting cells where it's constitutively expressed. It became apparent as antibodies were developed that block this receptor pathway pair, that the costimulatory receptor pathway is a critical downstream second event after MHC presents foreign antigens to the T cell receptor on T cells. When costimulatory signaling is activated, that's what induces the development of germinal centers and a pro-inflammatory signaling cascade that involves clonal expansion of the activated T cell, clonal expansion and maturation of the B cell, production and class switching of high-affinity IgG antibodies to that antigen, and subsequent expansion of that B cell population as well, along with the maturation and production of those IgGs and the development of long-lived memory and plasmablasts that will then subsequently make additional antibodies to that foreign antigen that was presented. In addition, as the antibodies were developed that block this receptor pathway pair and they were brought into rodent models of autoimmunity, it became very apparent that blocking this pathway had very significant effects on ameliorating multiple different autoimmune models, everything from animal models of multiple sclerosis, rheumatoid arthritis, psoriasis, lupus nephritis, and others, and that blocking this receptor pair could potently block disease progression in those types of models. Because the receptor pair is also involved in the activation of not only adaptive but innate immunity, antibodies were tested in the ability to prevent acute and long-term transplant rejection. To this day, monotherapy blockade of this particular costimulatory receptor pair in multiple species, including rodents, pigs, and non-human primates, is one of the most potent ways to block acute rejection as well as long-term transplant rejection. In some cases, after duration of treatment, you can stop treating, and by blocking this costimulatory receptor pair can actually induce long-term transplant tolerance. Because of the exciting data that was generated back in the 1980s and 1990s blocking this pathway, several companies were working on humanized versions of the antibodies that would block the activity of this receptor pair. Biogen and IDEC were two of the first companies to put fully humanized IgG1 antibodies into the clinic in fairly small phase I-B, phase II studies in lupus nephritis, as well as an autoimmune indication where autoantibodies eliminate intact platelets called idiopathic thrombocytopenic purpura. In those early studies, they again were able to show amelioration of clinical outcomes as well as biomarkers of disease, including an increase in platelet counts in ITP, as well as a reduction in autoantibodies in lupus nephritis. Unfortunately, unanticipated thromboembolisms cropped up in those studies, and the programs were put on hold. There was a period of time in the early 2000s where investigators across the globe really were trying to understand what occurred and what caused platelet activation and thromboembolisms in those studies. What was discovered is that those were full human IgG1 antibodies that had Fc effector function and CD40 ligands expressed on the cell surface of the platelet. When the antibody was binding, it was causing platelet activation and subsequent thromboembolisms. If you clip the Fc portion of the molecule off and worked it just with the Fab, or if you made a fusion protein that didn't have an Fc portion of the molecule, or if you crippled Fc effector function in a full antibody by making point mutations, you could mitigate the risk of platelet activation and thromboembolisms by targeting the ligand. Of course, as people were trying to understand those things in the 2000s, many companies went to develop blocking antibodies to the receptor in order to mitigate the risk of activating platelets. Fast-forward today, we now have a better understanding of why blocking the ligand versus the receptor has some differences. The reason why the ligand was targeted first is because in preclinical models, blocking the ligand was always more potent than blocking the receptor. We think that that has really three biological mechanisms or rationales, and one of them I've alluded to. They have very different expression profiles. The ligand's not constitutively expressed. It pops up into the cell surface of the T cell after antigen presentation when that foreign antigen presentation is robust, and it's transient in nature. It gets internalized fairly quickly. The receptor, on the other hand, is constitutively expressed on antigen-presenting cells, including B cells, macrophages, dendritic cells, and other specialized antigen-presenting cells in the body. One can envision that the biodistribution and activity and ability to block signaling is gonna be different between the ligand versus the receptor. In addition to that, people often focus on CD40 ligand only activating costimulatory signaling by binding to CD40, its receptor. In reality, CD40 ligand binds to multiple different integrins that cause costimulatory signaling in various cell types. As an example, it can block the activation of CD8-positive cytotoxic T cells mediated by CD11 signaling. When you block CD40 ligand, it blocks multiple different costimulatory pathways. The third one, which is probably the most biologically interesting that's unfolded in the last decade or so, is that because CD40 ligand is expressed on the cell surface of CD4-positive lymphocytes, when you block its signaling, not only do you block pro-inflammatory differentiation, you can actually repolarize those CD4-positive cells to become FOXP3-positive T-regs that secrete TGF-beta and IL-10 and can create a tolerogenic environment. This is very unique to the ligand. The only other costimulatory molecule that really has this ability is when you block CD28 signaling in the absence of inhibiting CTLA-4. When we went to go develop tegoprubart, a second-generation anti-CD40 ligand antibody, we focused on developing a humanized full IgG that lacked Fc effector function. We made this decision so that, the predictability and manufacturability we could leverage, because monoclonal antibody production is a fairly well characterized art at this point, and they typically have very good drug-like properties. We have seen that with the development of tegoprubart and the fact that the antibody has 2-2.5 times longer half-life than some of the other pegylated Fabs and fusion proteins that are in development that target the ligand. In addition to that, monoclonal antibodies tend to have a fairly low ADA activity, and we haven't seen very much ADA thus far in our clinical development processes compared to other types of biologics that target the ligand, such as fusion proteins. The differences between targeting the ligand and the receptor as far as, the ability to prevent transplant rejection, is actually quite, interesting. Dr. Vincenti has a very nice slide in his presentation that he'll be re-reviewing, subsequently, on how it blocks the ability to prevent, renal transplant, rejection in non-human primates. Tia, do you want to advance to the next slide? Thank you. As you can see in this slide, tegoprubart that blocks CD40 ligand, it formerly was called AT-1501. It's a second-generation humanized IgG1 antibody, and it lacks Fc effector function. You can see in the left-hand graph, we compare binding to CD40 ligand to a, previous developed antibody called 5C8 that had high affinity. There are 4 different clones of AT-1501 there that have very similar binding kinetics to 5C8. The big difference is the 2 right-hand panels. You can see that 5C8 when you look at interactions with Fcγ receptors, it binds to Fcγ twos in particular, which were the Fcγs that the Fc interacted with that activated platelets. As you can see, tegoprubart doesn't interact with any of the Fcγ receptors, particularly the Fcγ two class. It also doesn't interact and activate complement. Next slide, please. We went on to show that tegoprubart does bind CD40 ligand on the cell surface of platelets but doesn't activate them compared to 5C8, that historical anti-CD40 ligand antibody. These are FACS sorting experiments where you take the antibody, you pre-incubate it with immune complexes in the presence of human platelets in vitro. As you can see, and I'm sorry, these graphs are actually mislabeled a little bit. I apologize for that. As you can see in the graphs here in this slide on the right-hand side, there's a shift in the curve with the red FACS analysis showing that PAC-1 expression occurs in the presence of 5C8, and that's showing that there's activation of platelets by the expression of PAC-1 as opposed to in the presence of tegoprubart, which is actually the left-hand graph. You don't see that shift in the curve. 5C8 and tegoprubart both bind CD40 ligand on the cell surface of platelets, but 5C8 activates them, whereas tegoprubart does not. We went on to show and brought tegoprubart forward into very extensive non-human primate toxicity studies. Even with weekly dosing up to 200 mg per kg, we looked very carefully for platelet activation and did not see activation of platelets in those studies. Based on the good safety profile that we saw in primates, we moved on to phase I studies, which was a single ascending dose study primarily in healthy volunteers, but we did do a cohort of subjects with ALS just to see if the pharmacokinetics was different. As you can see, this was a twofold dose escalation design going from 0.5 up to 8 mg per kg. If you just look over to the right-hand side of the table in the placebo group that was aggregated, there's actually more adverse events in the entire aggregated tegoprubart group. Again, a very good safety profile that we saw in the phase I study. Based on these data, we started to collaborate with folks in the field to replicate some of the work that was done with the initial anti-CD40 ligand antibodies, and we started working with Norma Kenyon at University of Miami. Norma developed an islet cell transplant model in non-human primates back in the early nineties, where she either did pancreatectomy or she could ablate the beta cells in the pancreas of the animal so they could no longer make their own endogenous insulin. You can see in this experiment where we're looking at two single animals, the top panel is an animal that is on standard of care. This is an animal that after pancreatectomy or ablation of the beta cells, needed exogenous insulin to survive, which is the blue line. Norma then comes in and starts treatment. In standard of care, she's doing induction therapy with ATG and Enbrel. For maintenance therapy after transplant, she's treating these animals with a calcineurin inhibitor called tacrolimus. You can see after transplant day 0, by about day 30, the islets that she's transplanted can start to make their own insulin. She can wean the animals off exogenous insulin, which is the blue line. These animals can now stabilize their glucose levels, which are the black dots. You can see that this animal, we ended up having to euthanize due to acute rejection by day 84, and that's due to the nephrotoxicity that's often observed when you treat animals as well as people with this calcineurin inhibitor, tacrolimus. You can see in the bottom panel, this is again a single animal that was treated with monotherapy tegoprubart. You can see that much like the top panel, she ablated the beta cells and had to put the animal on exogenous insulin. She does the transplant, starts treatment with t egoprubart at day of transplant, and by day 30 can wean the animal off. You can see very nice, stable long-term glucose levels post-transplant, due to the insulin that's being produced by the islets. If you go to the next slide, I'll show some of the dynamics of C-peptide production or insulin production in these animals. You can see again on the top panel, which is standard of care, these animals are producing C-peptide levels, and they do respond to a meal challenge where there's increased glucose in circulation, which is the orange bar. You can see in that animal around day 42 a nice spike in response to meal. By day 84, the islets are getting pretty sick, and that's at the time that the animal has experienced a significant amount of toxicity and we had to euthanize. If you compare that to the bottom animal, which is the monotherapy tegoprubart animal, really nice long-term islet function, really stable response to meal stimulation and increased glucose levels in circulation. As you can see, that really nice dynamic function goes way past when we had to put the animal on exogenous insulin in the previous slide. That's because the animal was so healthy and was gaining so much weight. We hadn't transplanted enough islets to really keep the animal completely off exogenous insulin as it gained weight. This was really compelling data. We did a fair number of animals in this study, and later on today, Dr. Witkowski will talk about and present the aggregated data from Dr. Kenyon's experiments that we did with her. High level, the way we think about the pathophysiology of transplant rejection is that when the organ comes in from the donor to the recipient, there's a significant amount of antigens that get presented due to damage during the surgical procedure as well as just stress and immune components that are present from the cells. Again, as these antigens are recognized, you get that costimulatory activation with amplification and clonal expansion of T cells and B cells and formation of germinal centers. That leads to pro-inflammatory cytokine induction, that results in eventually both T cell as well as antibody-mediated rejection. Can I have the next slide? Blocking CD40 ligand, as I've described, has the ability to prevent transplant rejection along this pathway by first blocking the costimulatory recognition and antigen presentation, so you'll inhibit germinal cell formation, which will inhibit pro-inflammatory amplification. It'll block that B-cell maturation and clonal expansion of B cells, and therefore has the ability to block both cellular as well as long-term antibody-mediated rejection. Can I have the next slide? Switching over to ALS. Looking at animal models of ALS back at the ALS Therapy Development Institute, we're one of the first groups to describe that there's an activation of immune signaling in the muscle, in the periphery of animal models of ALS, which is shown in the left-hand graph. That occurs right around symptom onset at day 70. When we went and histologically looked at macrophage activation in these animals, much to our surprise, the macrophages weren't recognizing and destroying atrophying muscle, as you can see in that low-resolution picture. The green labeled CD68 macrophages were actually accumulating just on the nerves that run through the muscle to innervate it to make the muscle contract. You don't see any at day 30, you start to see it at symptom onset around day 60, and by day 100, all of the nerves in the periphery are actually covered in macrophages because the immune system is recognizing denervation. Can you go to the next slide? If you block CD40 ligand signaling in this model, you can see in the left-hand box plots that you decrease macrophage accumulation in the nerves because you're blocking the immune system from recognizing denervated nerves that they think are damaged. What that ultimately leads to is the middle box plot. There's a significant amount of neuromuscular junction loss between day 70 and 85 at symptom onset, as you can see in the vehicle-treated animals. When you block the CD40 ligand, you bring that almost back to normal, which is why there's much better muscle function, less muscle atrophy, and the animals are ambulatory and live longer. Ultimately, that results in motor neuron survival, which is the right-hand box plot. Even though the antibody is too big to cross the blood-brain barrier, it's a peripheral effect. It blocks pro-inflammatory differentiation of T cells, macrophages, and they don't cross the blood-brain barrier. Can I have the next slide? The way that we think about the pathophysiology of ALS is that the genetics tells us it's an RNA processing protein misfolding disorder, and that you can compensate that for decades because symptoms don't show up until 30, 40, 50 years old. Ultimately, when those pathways break down and you get accumulation of misfolded proteins, that decreases axon transport activity, you get weakening of the neuromuscular junction and die back. That's recognized by the immune system in the periphery. You get activation of macrophages that cause demyelination and death of those nerves. Ultimately, those pro-inflammatory differentiated T cells, macrophages cross the blood-brain barrier, and they activate the resident immune cells, microglia, and astrocytes in the CNS, resulting in neuron damage and loss. Can I have the next slide? Once again, blocking CD40 ligand signaling, as I showed you in the preclinical studies, has the ability to block multiple components of this. It'll block that macrophage recognition of peripheral nerves so that the nerves are healthier. There's plasticity, so they can reinnervate their motor units and therefore slow down muscle atrophy, improve ambulatory function, and they'll stop the pro-inflammatory differentiation of T cells and macrophages and monocytes from crossing the blood-brain barrier. You see a reduction in neuroinflammation in the CNS and improved motor neuron survival. Can I have the next slide? Moving over to IgA nephropathy. As I mentioned, there's a long history of blocking glomerulosclerosis as well as other types of autoimmune nephritis in rodent models. On the far left-hand panel, you can see that when you treat lupus mice, this is a genetic model of lupus with an anti-CD40 ligand antibody, you completely cure the mice. They actually never get sick, as you can see in that Kaplan-Meier plot. If you look at individual animals, which is the middle graph, animals treated with an IgG have very high levels of proteinuria in their urine. When you block a CD40 ligand, you can see that you ameliorate that quite well. In the second model, which is an Adriamycin-induced model of glomerulosclerosis, what I'm trying to show here is that if you look at macrophage infiltration, you can actually block infiltration of pro-inflammatory macrophages and T cells into the kidney by blocking CD40 ligand signaling. Can I have the next slide? The pathophysiology of IgA nephropathy is pretty well described at this point. The ultimate cause is genetic mutations in the enzymes that are responsible for putting the right sugar residues and putting the right galactose residues on IgA, and it results in the creation of a form of IgA that's improperly galactosylated called Gd-IgA1, and it's recognized as being foreign by the immune system. Again, you have germinal center formation and activation of the immune system in secondary and tertiary lymphoid structures, and they end up making antibodies that basically target the improperly galactosylated IgA. It ends up forming immune complexes that end up in circulation and get deposited all over your body. Ultimately, those immune complexes end up getting deposited in the kidney, and initially, they will cause localized fibrosis and kidney damage that ends up showing up as proteinuria, and that's what the clinical presentation ends up being. It's chronic in nature, and what ends up happening is that that much like we saw in the rodent model, you get infiltration of pro-inflammatory T cells and macrophages that then subsequently cause a pro-inflammatory response within specialized cells within the kidney and subsequent causes progressive longer-term damage in kidney function. And again, Dr. Barratt will go into the pathophysiology and mechanisms in more detail. Can I have the next slide? When we think about blocking CD40 ligand signaling, again, it has the ability to ameliorate multiple components of the pathophysiology. It blocks class switching. You're gonna have less IgA produced because it stops antibody maturation at the IgM phase. You'll have less IgA around to actually improperly galactosylate. Even if there is Gd-IgA1 synthesized by activated B cells in the germinal centers, it'll actually block immune complex formation because it's gonna inhibit germinal center formation, it'll inhibit B cell maturation and antibody production, so it's gonna reduce immune complexes in circulation. Ultimately, for immune complexes that have already been deposited and where there's some localized damage, it's gonna block that pro-inflammatory differentiation of T cells, macrophages, and other cell types, so there'll be less immune cell infiltrate going into the kidney and causing subsequent damage. Blocking CD40 ligand has the opportunity to block multiple different aspects of the pathophysiology that's associated with IgA nephropathy. Thank you for your time today, and I'll pass it back to David-Alexandre. Thank you, Steven. With that, we will transition into IgA nephropathy. Dr. Jonathan Barratt. Yeah. Thanks very much. It's a pleasure to be here today. I'm going to take you through IgA nephropathy and why we think this is a very good disease to look at CD40 ligand antagonism. IgA nephropathy is the commonest form of glomerular disease globally. It is importantly a disease of young adults, so it's a disease where we're making the diagnosis often between the ages of 20 and 40 years. It's an asymptomatic disease by and large, that is identified through urine screening for blood and protein in the urine or following assessments for high blood pressure or an abnormal kidney function blood test. The important thing here is that it affects young adults. IgA nephropathy is classically a slowly progressive disease. In a 20-year-old, a slow progression means that actually they're running into problems when they're in their 40s, their late 30s. Still at a very young age. That's why this disease is so important to identify and treat early so that we can protect kidney function for the lifetime of these individuals. In various natural history studies, it's been shown that end-stage kidney disease will develop in around 30%-40% of patients over 20 years. This is when these 20-year-olds are in their 40s. This is significant. It's still as patients are still at a young age, and it's estimated up to half of all patients with IgA nephropathy will develop end-stage kidney disease in their lifetime. Now, if you develop end-stage kidney disease, the treatment of choice is a kidney transplant, rather than dialysis. The unfortunate situation that we have is that if you're lucky enough to have a kidney transplant and you've got IgA nephropathy, the worry is that this disease will recur. It will recur and it causes significant increased likelihood of you losing that kidney transplant due to recurrent disease. The important thing here is that with each successive kidney transplant, you become sensitized to HLA antigens, and you eventually will get to the point where you're almost untransplantable, and that can occur after your first or second transplant. These patients with IgA nephropathy who are transplanted at a young age are likely still to be at a young age in terms of perhaps in their fifties or sixties, where they could reach the point of being untransplantable because of allosensitization due to loss of graft from recurrent disease. In fact, this is one of the situations that I'm called about the most, is how do we handle recurrent disease in IgA nephropathy. I think that's why it's so exciting when we think about the IgA nephropathy program we have that I'm gonna talk about, but also the transplantation program that you'll hear about in a little while. Steven has touched on the pathophysiology, but essentially this is a disease of circulating immune complexes. These immune complexes form due to the presence in the bloodstream of an abnormal form of IgA, this so-called Gd-IgA1, which carries abnormal sugars at the IgA1 hinge region. It's believed that this form of IgA is present in excessive amounts in patients, and this triggers the development of IgA-specific autoantibodies, which are IgA and IgG. Together these form these immune complexes which deposit within the mesangium of the kidney and where they can trigger inflammation and scarring. The way that we know that glomeruli are inflamed is because we can detect blood and protein in the urine. The more blood, the more protein in the urine, the worse the degree of inflammation. Proteinuria is a good biomarker of the extent of glomerular inflammation. It's more than that. We know that the higher the amount of proteinuria, the worse the outcome. That's not just as a reflection of glomerular disease, but the fact that proteinuria is toxic to the rest of the nephron. As albumin and the associated proteins are passing down the tubule, those proteins are interacting with proximal tubule, distal tubule epithelial cells, activating those cells and driving tubulointerstitial inflammation and scarring. When we think about proteinuria, we think about this as a biomarker of how much inflammation is going on within the glomerulus, but also what burden that is having on the remaining parts of the nephron in terms of driving pathological changes in the tubular epithelial cells. Of course, as you lose nephrons, the other nephrons have to work harder. We know that as you have a reduced number of nephrons, those remaining nephrons that are working harder are more prone to damage. They're more prone to scarring, which will accelerate the amount of proteinuria that we see and accelerate the rate of decline of kidney function. This is really typified here in terms of some data from IgA nephropathy from the Toronto Glomerulonephritis Registry. What you can see very clearly is the amount of proteinuria that patients are excreting in a day is very closely linked to the long-term survival of kidney function. The more proteinuria you have, the more likely you are for your kidneys to fail. We've known this for many, many decades, and it's really the centerpiece of what we do when we are assessing our patients in clinic to risk stratify them and to focus our treatment, because we know also that if we're able to reduce proteinuria, we can protect against the loss of kidney function. This is some work that I presented at the ERA-EDTA Congress last year, where we looked at the data that was the basis for the FDA's agreement that an early change in proteinuria is a reasonably likely surrogate for future kidney function protection, and in fact, is an approvable endpoint. That we've used the data that decision was based on, and we modeled the impact of a 30% reduction in proteinuria at 9 months and what this would mean for long-term kidney survival. What you can see here is this, you're able to achieve a 30% reduction in proteinuria at 9 months with a new intervention, that you will delay the time to dialysis on average by over a decade. That's clearly significant and very important for our patients. Of course, our patients are only in their twenties. This means we're delaying things perhaps into their forties or fifties when they still got a lot of life still to live. There is plenty more scope to be able to increase proteinuria above and beyond 30% or to combine therapies with different modes of action to generate a greater proteinuria reduction. We know there is a linear relationship between the magnitude of proteinuria reduction and the long-term kidney survival. I think this is very clear to us, and we've known this for a long time, but more importantly, the regulators now understand this, that an early reduction in proteinuria is a valid marker of a drug's effect on the long-term kidney outcomes that are important both to us and to patients. How do we manage patients at the moment? Well, the central way we manage IgA nephropathy is with goal-directed supportive care. That means controlling blood pressure, altering lifestyle, and minimizing proteinuria as much as we can with drugs that block the renin-angiotensin system, so ACE inhibitors and ARBs. We know that the evidence base for that approach is the strongest by far. We have limited information, and it's contentious as to the efficacy of corticosteroids in IgA nephropathy. What is absolutely not in doubt is the toxicity associated with corticosteroid regimens. In fact, that's the reason I don't use corticosteroids to treat IgA nephropathy, because I can guarantee my patients they will have toxic effects. I am less certain about whether it's going to do them any benefit. In Japan, they remove the tonsils. It's really not practiced anywhere else in the world, but they have a strong belief that tonsillectomy works in that particular population. For international guidelines, it's not recommended. In my practice, of all the patients that I see with IgA nephropathy, I can get the proteinuria down to below a gram in about 40% of patients with supportive care alone. What that means is that the majority of the patients that I see, so 60% or so, will still remain at high risk of progression despite the best supportive care I can give. These are patients I want another treatment for because above one gram of proteinuria, these patients remain at high risk of progression. We have our first drug approved for the treatment of IgA nephropathy, and that's Tarpeyo, and this is a drug that specifically targets the mucosal immune system to suppress the production of pathogenic IgA. It results in around a 30% reduction in proteinuria, so still a lot more proteinuria reduction we need in our patients to get them to avoid dialysis for the rest of their life, but it's a start. What I think more importantly is this has actually proven that the FDA have lived up to their word and that, indeed, they will approve a drug based on a proteinuria surrogate. This is the first drug ever to be approved in nephrology based on an early change in proteinuria as a reasonably likely surrogate for long-term kidney functioning effect. This is what really is critical in a slowly progressive kidney disease, is that we're able to have a reliable early surrogate to trust drug efficacy. This really is pivotal and a real sea change in the view that regulators have about how we approach diseases such as IgA nephropathy. If we look at this graph here, this is a meta-analysis of proteinuria changes over time. What you can see here is that in placebo-treated arms, really there's very little change, spontaneous change in proteinuria, as you would expect. I would discount most of the drugs here because actually, our CT evidence suggests that they really don't work. You can see the impact of a renin blockers here, in the green lines, and then you can see the impact of corticosteroids. While corticosteroids do reduce proteinuria, for me, the risk-to-benefit profile and the toxicity associated with steroids is too significant for me to justify using these in my patients. If you're interested in this at all, I suggest you go onto the National Kidney Foundation website, where the FDA and the NKF ran a program talking to patients with IgA nephropathy about the unmet needs that they have. You'll see in there, patients describing what it's like being on steroids and why they'd rather live with IgA nephropathy than actually ever have to have steroids again if you've got no experience of what the effect is of having to take corticosteroids in significant doses. Where might tegoprubart sit in terms of the pathogenesis? Well, I think it's clear from what Steven has said that this drug and blocking co-stimulatory activation has multiple opportunities to impact on the generation of both the pathogenic form of IgA, the production of antibodies against IgA, and then fundamentally the formation of circulating immune complexes. Actually this gives us an opportunity to turn off the pathogenic IgA immune complexes at the very top of the cascade and therefore stop their deposition in the kidneys and stop the downstream activation. What we know is that if we can turn off the production of pathogenic IgA or stop the kidney being exposed to that IgA, the kidney is capable of remodeling and being able to recover to some extent. The best example of that is there are situations where kidneys that are full of IgA nephropathy have been transplanted into patients who did not have end-stage kidney disease but did not have IgA nephropathy. Then those kidneys have been biopsied 2, 4, 6 months later. What you see is that there was lots of IgA stuck in that kidney before it was transplanted in. Over time, that IgA disappears, inflammation resides, and the kidney remodels. There is an opportunity if we're able to turn off the tap, if we're able to turn off the production of this pathogenic IgA, these autoantibodies, that we will be able to stop the kidneys being inundated with these immune complexes and give them an opportunity to recover and remodel. That really is the goal of any therapy in IgA nephropathy. Steven has already mentioned this study, which is an animal model of glomerular disease. He's already shown you some data from this. What's important here is that an anti-CD40 ligand approach is capable of not only blocking the pathological changes that we see both within the glomerulus but also importantly within the tubulointerstitium, but it translates through to protection of kidney function. You can see here improvements in serum creatinine. You can see improvements in proteinuria. The two key things that I'm looking at when I'm assessing the effect of a drug in my patient population. In summary, I think our understanding of the pathophysiology of IgA nephropathy has increased incredibly over the last decade, and there are multiple sites within that pathogenic cascade where CD40 ligand antagonism is likely to be beneficial in my patients in terms of turning off the production of pathogenic IgA, turning off the production of circulating immune complexes, and therefore protecting the kidney against that immune complex deposition and associated inflammation. At the moment, our current standard of care is, delivers some element of, kidney function protection, but by no means is perfect. We have plenty of scope to improve what we are doing at the moment, even with the addition of our first approved therapy, Tarpeyo. I think the important thing here is, as Steven has mentioned, that this drug is well-tolerated in individuals, and that's gonna be really key in terms of thinking about its use in IgA nephropathy. Most importantly, there's clear biological plausibility about why this approach is relevant to IgA nephropathy and why I think this approach is gonna offer us an absolutely new way of thinking about how we can modulate the immune system in this disease. We are desperately in need of new therapies for this disease because we don't want 20-year-old patients ending up on dialysis in their forties. It's absolutely soul-destroying for them, and having to talk and work with them as they go through that transition is incredibly disheartening. If we have therapies that are capable of stopping that, this is going to be groundbreaking really for my patients. I'm gonna stop there and hand back to the next part of the presentation. Great. Thank you, Dr. Barratt. We will now transition to ALS. Dr. Appel. David-Alexandre Gros, thank you so much. It's a great opportunity for me to join the group. Can we go back to the first slide again? The introduction. Don't need to see my name, but what I do wanna do is one of the great difficulties in the field of ALS is I've called this amyotrophic lateral sclerosis. This is not a single disease going just down one pathway. Unfortunately, there's great heterogeneity in site of onset, length of disease, age of onset. Our youngest patient that was not familial, that is with a family history, was age 18, and our oldest patient first symptom age 88. So even though the mean is about 56-60, there's a huge heterogeneity. It's important that we understand this to begin with because it gets in the way of most of the trials as we try and do a placebo-controlled double-blind trial. Next slide, please. If we look, the incidence, that is new cases a year, is about 5,000. The prevalence is somewhere between 4-6 per 100,000. People say it's a very rare disease. In our hands, it's not that rare. The actual lifetime risk is something like one in 400. That compares to MS, which is one in 300. The bottom line is this is a disease that is cropping up more and more as we begin to recognize it earlier. 5%-10% of the cases are genetic. The most common cause that's inherited is C9orf72. Although the etiology, as stated here, has not been completely elucidated, we do know some 30-40 mutations that are tightly linked to ALS. I also want you to recognize that in neurodegenerative diseases, neuroinflammation and mutations targeted to the immune system, i.e., myeloid cells, macrophages, microglia, T cells, et cetera, are telling us that for absolute certainty, neuroinflammation is a driving force. Disease onset and rate of progression is heterogeneous, as I said. Next slide, please. Now, what happens is that we've been going over and over, unfortunately, with a great unmet need in ALS. Radicava is approved and has a definite benefit, primarily with an elegant study that came out of England by Professor Al-Chalabi, showing that it helps with respiration, slowing things down as respiratory function becomes compromised. Edaravone, which is to target free radical as a scavenger, was approved in Japan and the U.S., not approved in Europe. One of the major problems with Edaravone, hopefully will be overcome with the oral version, is the fact that it's IV. Now, what is clear is that ALS really. We're there in a new age of thinking about ALS as approaches of focusing. One of the interesting things is that for 20 years, I have been saying that neuroinflammation is important. I was told I was way outside the box, and I said, "Guys, look at the box. It's empty." Now everyone is targeting neuroinflammation. With respect to ALS, neuroinflammation doesn't initiate disease, except in those mutations that target the immune system, but neuroinflammation propagates disease, and that's a very important point. Unfortunately, with respect to how we monitor disease and disease progression, we have a scoring system called ALSFRS, which is a questionnaire and is not linear, number one. Number two, is difficult because of the fact that patients may change with respect to how they're answering these questions. Anyway, it's the best we have. However, as noted here, biomarkers are critically important because biomarkers are a way to determine whether in fact your specific therapy is hitting target. Let's go to the next slide, please. Everyone is always worried about will their molecule get into the CNS? Because in the CNS, we've got the cell bodies. In point of fact, ALS starts in the periphery. It starts at the neuromuscular junction. In the beautiful slide that, Dr. Perrin showed us, he showed us evidence of inflammation at the neuromuscular junction that is outside the blood-brain barrier. Any therapy given has an opportunity to influence things outside the blood-brain barrier. In our own work, acute-phase protein and the gut microbiome are perfect bits of evidence that the peripheral compartment enjoys or rather deals with the inflammation that is systemic. ALS is a systemic disease, and in studies that we've done with acute-phase protein, things like lipopolysaccharide-binding protein is elevated. That's made by the liver. CRP is elevated. That's made by the liver. Evidence of systemic involvement. What may be driving this, I wanna show in a study that we did a good number of years ago, in which we have the mitochondria from a patient with ALS that is loaded with calcium, which means the mitochondria is not functioning normally. It's spitting out lipid peroxides, which is getting everyone in trouble systemically. However, within the CNS, there's a CNS compartment of inflammation, neuroinflammation, where the cell body is interacting with macrophages that come in from the periphery, with microglia that are there. The microglia are signaling the astrocyte. The astrocyte is signaling the neuron. And all of these are participating in a CNS inflammatory process leading to neurodegeneration. The next slide, please. If you look at the next slide, this is from a study we did a number of years ago, by one of my colleagues from Hungary, Dr. Laszlo Siklos. And this is a control nerve biopsy, muscle biopsy that gives the neuromuscular junction. Mitochondria look relatively healthy here. It was only in ALS, not in neuropathy, that we had these alterations. Here's an ALS with dramatic increase in calcium in the presynaptic terminal. The next slide, please. Shows you in a neuropathy, you don't have the changes, but you do in ALS. This is, at least in our hands, where maybe three-quarters of the ALS patient's disease starts at the neuromuscular junction following injury within the motor neuron that becomes self-propagating. The next slide, please. Here, we have an idea of how we're dealing with the immune system, and in our own work, regulatory T cells that we're doing with license to Coya Therapeutics, regulatory T cells suppress neuroinflammation. The next slide, please. What happens here is that the regulatory T cells are neuroprotective, and they block activated TH1, and in blocking, you have an anti-inflammatory milieu. The next slide, please. However, what happens is that T cells become activated because they're no longer blocked by regulatory T cells. The macrophages become activated, and they will go into the CNS, but they're activated systemically, and they're activated at the neuromuscular junction, as Dr. Perrin showed, and this in turn causes a downregulation of the T cells which are no longer suppressive. Next slide, please. If you look now, we did a study. How did we get to regulatory T cells? Well, what we did is we crossed a Rag2 knockout mouse and a CD4 knockout mouse with the mutant SOD mouse, and we expected the mice to die later. That is, removing a toxic T cell. The mice died earlier. We then transplanted the mice, and when we transplanted them, we were able to prolong the mouse by approximately almost double survival. Next slide, please. We went to ALS in man, and what we cartoon, you've got activated M1s that are altering Tregs, causing the Tregs to become dysfunctional and blocking this, and this is a self-propagating neuroinflammatory cascade. Next slide, please. Just to show you, if we look at the ALS suppressive function, the FOXP3 is the transcription factor hallmark of T regulatory cells. As ALS points increase in length, you've got a decrease in cells, and this shows you that the suppressive function of the Tregs from ALS patients is dramatically altered compared to controls. The red are the rapidly moving ALS patients, and the green is the suppressive function over different concentrations of Tregs. Next slide, please. Just to give you an idea that the Treg, i.e., inflammatory cascade, is influenced by the burden. If you've got patients moving very, very rapidly, it turns out that their suppressive function, if you monitor them, will be less and less. Also, the burden of disease is key. The burden of disease is also key here. That is, if you've got a greater burden of disease, you have lesser suppressive function. Next slide, please. Here are serum biomarkers that have been illustrated and done by others. We would confirm this as well, and when we do, we would say that there is no question that inflammatory biomarkers like MCP1, IL-17, TNF, IL-6, IL-1 beta are elevated. We have data that has just been published that says, in fact, these inflammatory biomarkers are not just elevated, but they, in fact, are extremely important perhaps in monitoring the success of any therapy. We suspect that these will be very applicable in. The next slide, please. If you look at where Eledon is, and we're excited with what has been accomplished. As Steven Perrin was saying, here are antigen presenting cells. Here is the CD40 ligand, and the bottom line here is that if you block this, then in point of fact, you're going to prevent these cells from participating and therefore down-regulate the neuroinflammatory cascade. That's the critical event that we're talking about. Next slide, please. In summary, neuroinflammation is increasingly recognized as an important mediator of disease progression in ALS, and is characterized by peripheral monocyte activation, alterations in the immune system systemically, involvement of the gut microbiome and the liver, as well as CNS activated microglia and astroglia. There's a pro-inflammatory polarization with increased expression of TNF alpha, MCP-1, IL-1, interleukin-6, interleukin-17. In ALS, there's a loss of Treg specific function correlating with disease outcomes. In fact, in studies we published, it also is predictive of survival. If you've got poor function, you have fewer patients surviving for a longer period of time, and they account for the variability and heterogeneity of disease. Now, neurofilament light chain is a measure of a structural change in the cytoskeleton of the motor neuron, and it is elevated in ALS, and it is something that is being studied also correlating with disease progression. Very importantly, if we have ways to interfere, and the CD40 ligand therapy of Eledon is a way to interfere with the co-stimulatory interaction, it will suppress neuroinflammatory responses. Reductions in pro-inflammatory cytokines, pro-inflammatory chemokines, NfL levels in the circulation, so you don't need to go to the CSF. You can measure this in the blood, as well as changes in the slope change of ALSFRS may individually correlate with ultimate clinical benefit, and in fact, is of course the target of the therapy and an exciting process going forward. I thank you for your attention. Thank you, Dr. Appel. We'll now move to kidney transplantation with Dr. Vincenti. Thank you. I'll give you a brief overview of the unmet needs in transplantation inhibitors. Cyclosporine in 1983, followed by especially tacrolimus in the 1990s, totally revolutionized the field of immunosuppression and transplantation. The calcineurin inhibitors decreased dramatically the acute rejection rate in the first year after transplant and provided much better outcomes. In fact, transplantation became the treatment of choice for patients with end-stage kidney disease because successful transplantation gives a survival benefits in addition to, of course, improvement in the quality of life. However, while the calcineurin inhibitors provided excellent one-year patient and graft survival, we have found out that over the long term, they may be less effective at suppressing the immune response, especially the humoral response, antibody-mediated rejection. They're associated with a number of toxicities, and most importantly, nephrotoxicities. Many of these toxicities may contribute to the fact that after, depending on whether the patient receive a deceased kidney or a living donor kidneys, these kidneys have a limited lifespan. About 5,000 patients on the wait list that die every year while waiting for a kidney transplant because of the shortage of organs. In fact, every year, about 5,000 patients who lost their kidneys are added to the list, again, aggravating this shortage. Now, costimulation blockers have demonstrated efficacy in the prevention of allograft rejection, both in non-human primates and in clinical trials. Belatacept was the first costimulation blocker agent to be approved by the FDA in 2011. Belatacept showed that it could suppress rejection and improve kidney function, preserve glomerular filtration rate. However, since its approval, it has had limited use by the transplant community for a number of reasons, primarily concern about efficacy in the first year. In terms of acute rejection, in the current regimen utilized, belatacept is not as effective as the calcineurin inhibitors. Of course, potential increased risk of PTLD. Targeting the CD40 ligand may be a mechanistically more desirable approach than blocking CD80, CD86 with the fusion receptor belatacept. Now, what is the path for regulatory pathway to get a novel drug or novel biologic or a costimulatory inhibitor approved? The important thing is, one, to demonstrate non-inferiority in terms of acute rejection versus tacrolimus. Now, with the current therapies, the regimen incorporating tacrolimus and anti-proliferative result in an acute rejection rate in single digits. As long as there isn't inferiority in terms of the occurrence of acute rejection, that's quite desirable. However, regimen that eliminate calcineurin inhibitors will have superiority in terms of safety at one year, and may have long-term small superiority in terms of repressing donor-specific antibodies, antibody-mediated rejection, and better preservation of kidney function in terms of glomerular filtration rate. This next slide shows you the side effects associated with the calcineurin inhibitors. Let's just look at the tacrolimus side effects since this is the most common CNI. Very high incidence of new onset diabetes. This is called NODAT, and that's an important issue and problem. Renal impairment, nephrotoxicity. Most patients who are on tacrolimus will have some degree of diminution of their glomerular filtration rate, especially over time. Neurotoxicity is important both in terms of tremor, and a number of patients have problem with cognitive functions with tacrolimus. Alopecia and hypertension. A number of cardiovascular risk factor increase with the calcineurin inhibitors. Now, this is an interesting study that was published by Australian investigators in the New England Journal of Medicine many years ago, whereby they took patients who had had a kidney transplant, biopsied them, every 3 months the first year and then yearly for 10 years, and assessed the incidence, the occurrence of rejection, borderline rejection, clinical rejection, as well as calcineurin nephrotoxicity. As you can see in the red bars, over the period of 10 years, a greater percentage of patients demonstrated in the kidneys, in the renal allograft, the presence of nephrotoxicity, whether it was vascular changes or fibrosis. This study basically summarized the fact that, after several years, almost all patients who are treated with the calcineurin inhibitors will have some injury to their allograft. In terms of outcome, this is also a very interesting study published in, initially in 2011, showing the long-term graft failure rates, both in deceased donor and living donors. These are the two figures on the left side. In yellow, this occurs between in 1989 to 2009. This is important because this is the period when we introduced our most effective regimen, tacrolimus and then mycophenolate mofetil. What it shows in yellow is the attrition rate the first year. As you can see, as we go along the years with the introduction of the novel agents, the one-year attrition rate decreased dramatically. However, the attrition rate 1-3 years, 3-5, and 5-10 has remained stable over or unchanged over all these years. Suggesting that most of the improvement that we see long term occur, in fact, the first year. Beyond the first year, we have not made much improvement in the attrition rate. Again, on the figure on the right shows the survival differences between deceased donors and living donors. Living donors recipients of living donors' kidneys always do better. However, again, year by year, there is an attrition of graft and increasing and a decreasing graft survival. Again, as I said, up 5,000 patients every year who lose their kidneys are added to the wait list. Increasing the shortage of organs. What has been the experience with costimulatory blockers? Belatacept's experience showed that a novel biologic targeting the costimulation pathway can be developed through clinical trials in kidney transplantation and can obtain regulatory approval of the drug. However, belatacept has some issues with it, and that's the reason why it hasn't been used as extensively as we were hoping. One is because efficacy at one year is not as good as the calcineurin inhibitors. Although long-term, as we published in 2016 in the New England Journal of Medicine, it does provide a long-term benefit in terms of patient outcome, survival and graft function. However, there is an increased risk of PTLD. This is post-transplant lymphoproliferative disease. The issue with the belatacept, while it's a small increase, when these occur, they occur more frequently in the brain compared to the rare occurrence of PTLD in the brain in patients treated with tacrolimus. There is a black box for liver transplant. It's not clear why, but the liver transplant clinical trial that was terminated, patients treated with belatacept did not do well. It was never clear what was the reason for that. Of course, quite different from what we saw in kidney transplant patients. The current clinical development would require a steroid concomitant therapy, which is tapered very quickly to maybe 5 milligrams a day. The anti-proliferative agents have been used, but whether long-term they are needed is not clear. What is quite clear that with all biologic, and especially biologic that target costimulatory receptor or ligands, that these patients, in order to have a lower rejection rate, require induction therapy with depleting agents, and the current depleting agent is Thymoglobulin. In the phase III trials of belatacept, we utilized the anti-IL-2 receptor antibody basiliximab or Simulect, and these agents are not good enough to sustain the early response to costimulation blockade. Now, in terms of tacrolimus based regimen, the choice of induction agent is not as critical, but it's much more important in biologic therapy that eliminates calcineurin inhibitors. This is a interesting study in terms of the effect of antibodies to CD40 ligand in non-human primates. This is a study with the first antibody from Biogen 5C8. Dr. Kirk treated non-human primates in monotherapy and showed that they had prolonged and excellent graft function. When these kidneys were biopsied, Figure A and B on the right side, they were normal looking. In contrast, if you look at section C, the kidney of non-human primates that were untreated, had a lot of mononuclear cell infiltration and vascular damage. Now, the big issue, of course, has been which is the better target, the CD40 receptor or the CD40 ligands. This slide shows the aggregate data from antibodies that have been used in non-human primates blocking the CD40 receptor versus the CD40 ligand. I think it's quite clear from. You know, some of these studies of course have limited number of animals in them. However, the aggregate is pretty clear that when we use antibodies to target the CD40 ligand, the outcome of the graft is superior to those experiments where antibodies to the CD40 receptor was utilized. Now, I think part of the reason is shown in this slide, and these are studies by Adams and his associate. On the left side shows that if you use antibodies to the CD40 receptor, you block the CD40 receptor. If you use antibodies that block or neutralize the CD40 ligand, you of course also disrupt the interaction of CD40 ligand with the CD40 receptor. But also at the same time, you disrupt the interaction of CD40 ligands with a number of integrins, most importantly possibly is CD11B. CD11B with CD18 are a receptor that transduces signals that activate the T cells. By blocking only the CD40 receptor, there may be other mechanism whereby T cell can get activated and result in rejection. In the middle panel, this is a study again by the same group, xenograft pig kidneys in non-human primates, and the primates were treated with three regimen. One regimen utilized anti-CD40 receptor antibodies. The second, an anti-CD40 antibody with an anti-CD11B. The group with the dual antibodies did better than the group just receiving anti-CD40 antibodies. Those who were treated with anti-CD40 ligand had the best outcome. Possibly not only because we're blocking CD11B as well as the CD40 receptor interaction, but other maybe, possibly other integrins. CD40 ligand targeting will provide better inhibition for T cell activation. In summary, CNIs since their introduction in 1983, cyclosporine first and tacrolimus in the 1990s, have improved dramatically the field of immunosuppression in terms of kidney transplantation, reducing rejection, as well as expanded the whole field of solid organ transplantation. However, CNI beneficial as they are, have appreciable toxicities. To improve long-term outcome and as importantly, to preserve renal function, I think, the unmet need is to have a CNI-free immunosuppressive agents. The costimulation blockade, I think is the most desirable way to achieve that. In particular, blockade of the CD40 ligand pathway offers promise to again, suppress the immune system, both T cells and B cells. Hopefully, avoid some of the issues and toxicities that have been associated with the first generation costimulatory blockers such as belatacept that target the ligand CD80 and CD86. I'll stop here, and thank you for your attention. Thank you very much, Dr. Vincenti. I will now transition to islet cell transplant. I'll turn it over to you, Dr. Witkowski. Thank you very much for the opportunity to present potential benefits of anti-CD40 ligand blockade in patients with type 1 diabetes. Next slide. Among 1.3 million patients with type 1 diabetes in the United States, there are around 70,000 of those who struggle every day with poor blood glucose control despite their best efforts in using modern technology, insulin pumps and CGMs, continuous glucose monitoring devices. Those patients have so-called brittle form of type 1 diabetes, and they live in a constant fear of sudden death, seizure or reversible brain damage due to severe hypoglycemic episodes, meaning critically low blood sugar. Therefore, there is unmet need for more effective therapy like islet transplantation that can improve blood glucose control, protect patients from severe hypoglycemic episodes better than CGMs and insulin pumps. Next slide. Islets transplantation has been developed for over 20 years and allows some patients to become fully insulin-free. We call them insulin independent. However, clinical effectiveness of islets transplantation is still compromised by the limited islets quality and quantity supply, as well as by the toxicity of the currently used immunosuppression. Specifically, as we heard, calcineurin inhibitors, which are commonly used to protect transplants from rejection, can cause nephrotoxicity, neurotoxicity, as well as even toxicity towards transplanted islets. Significant improvement can be provided in the future by utilization of high quality and quantity of islets manufactured from the stem cells, also by replacing calcineurin inhibitors with less toxic and even more efficient immunomodulatory agents like tegoprubart, which is the first therapeutic with open IND for islets cell transplantation in the United States. Next slide. This is how islets transplantation is performed. Human pancreas is removed surgically from deceased donor abdomen in the same way as it is for whole pancreas organ transplantation. The pancreas is transported to the special laboratory where islets isolation take place. Islets are retrieved from the human pancreas. Islets are like micro organs, and they contain cells producing insulin. Islets are then suspended in a special solution and then infused into the patient's liver through a small catheter placed under local anesthesia by interventional radiologist. There is no surgery required. After the infusion, islets grow into the liver, and this is where they stay, produce insulin, and provide blood glucose control. Next slide. These figures present improvement in outcomes of an islet transplantation over the last several years in terms of the insulin independence. On the left in the left figure, and protection from severe hypoglycemic episodes on the right. Next slide. In the U.S., multi-center clinical trials have been sponsored by NIH, and they prove safety and effectiveness of islet transplantation procedure. In the long term, over 50% of patients remain insulin-independent for longer than 5 years in the most experienced transplant centers, and over 90% of patients is still well protected from severe hypoglycemic episodes. Next slide. tegoprubart has demonstrated the proof of concept in a non-human primate model of islet transplantation performed by Dr. Norma Kenyon from University of Miami. As you can see, animals in the tegoprubart group, the blue bars, had improved rejection-free survival on the left figure, as well as improved overall islet graft survival on the right, compared to the animals receiving tacrolimus as maintenance immunosuppression in the controls, the gray bars. Next slide. Yeah. Animals treated with the islet transplantation and tegoprubart also allowed for better metabolic control compared to animals receiving tacrolimus. They produce more insulin, as demonstrated by higher C-peptide and lower blood glucose levels, as presented in the figures on the left. Animals treated with tegoprubart were healthier and gained more weight as a result of better blood glucose control, as presented in the figure on the right. The next slide. In summary, despite modern technology, there is still many patients living with brittle form of type 1 diabetes who continue to experience life-threatening severe hypoglycemic episodes, and they are at risk of other serious complications. Islet transplantation offers a potential solution allowing for better blood glucose control while decreasing or even eliminating need for exogenous insulin supplementation. The current barriers to broader application of islet transplantation include the need for more robust sources of islets for transplantation, as well as the need for less toxic and more effective immunosuppression. Based on the animal work to date, tegoprubart has the potential to become backbone of immunosuppression for future and more effective clinical islet transplantation. Thank you. Thank you. We'll now transition to go over our indications and ongoing clinical development plan. Let me transfer it over to you, Jeffrey. Thank you, David-Alexandre. Hello, everybody. I'm Jeffrey Bornstein, Eledon's Chief Medical Officer, and it's my pleasure today to walk you through our development program. We have 4 active programs for tegoprubart, with studies in ALS, kidney transplant, islet cell transplant, and IgA nephropathy. In the ALS phase II trial, all patient visits are now complete, and we remain on track to provide top-line data in this quarter. Our kidney transplant trial now has active sites in Canada and the U.K. In parallel, we are working towards opening additional sites, including potentially in a third country. Islet cell transplant has 1 active site in Canada, and we remain on track to open a U.S. site toward the middle of the year. Finally, in IgAN, we now have open sites in Australia, New Zealand, Malaysia, and anticipate launching additional sites in several European countries in the coming months. We and our sites are working hard to find and enroll first patients in the kidney transplant, islet cell transplant, and IgAN studies. We expect that our continued opening of additional sites for each of the programs will help accelerate patient recruitment and enrollment. Our goal remains to report the data that we have available in these trials at the end of the year. I'll now move on to the individual trial designs. Next slide, please. Thank you. I'll start with our ALS phase II trial since it's the closest to data. This is a multiple ascending dose trial that evaluated 1 milligram per kilogram, 2 milligrams per kilogram, 4 milligrams per kilogram, and 8 milligrams per kilogram of tegoprubart administered via IV infusion every other week for 12 weeks. The lower 2 doses... The lower two dose cohorts had 9 patients per each, and the higher two had 18. The data monitoring committee met before the dose could be escalated and met one final time when at least 33% of patients in the highest dose cohort had completed. The study is designed to assess the safety and pharmacokinetics of tegoprubart across the various doses. This is the first ALS trial of an immune modulatory drug specifically targeting pro-inflammatory signaling associated with ALS. There are three important biomarker assessments associated with the study. The first biomarker assessment is for target engagement. As Steven mentioned previously, mechanistically, tegoprubart blocks CD40 ligand signaling, which should interfere with antigen presentation and inhibit B-cell maturation and pro-inflammatory cytokine induction. We would thus anticipate seeing a reduction in pro-inflammatory chemokine, such as CXCL13, that are induced during co-stimulatory activation. The second important biomarker assessment looks specifically to assess a reduction in the inflammatory component of ALS using inflammatory biomarkers. We will be assessing a range of biomarkers previously reported to be upregulated in ALS, including TNF alpha and RAGE, MCP-1, IL-1B, and others, and looking at the effect of tegoprubart in reducing the inflammatory signature in these patients. The third biomarker assessment is exploratory and will assess the effect of tegoprubart on neurofilament light chain. We consider this assessment exploratory since in a trial of this size and duration, changes in this measurement may be difficult to detect. Similarly, the study collects data on clinical indicators such as the ALS Functional Rating Scale. As with NfL, in a trial of this size and duration, changes in these measurements may be difficult to detect. Success for this trial would be demonstrating safety, target engagement, and a reduction in pro-inflammatory signature. Next slide, please. Moving to kidney transplant. This 52-week trial will evaluate the safety of a tegoprubart-based regimen in up to 12 kidney transplant recipients. Each study participant will receive standard induction with RATG and maintenance with tegoprubart, MMF, and steroids. We are primarily interested in assessing tegoprubart as a replacement for tacrolimus in this regimen and ensuring that this approach is not only safe at the exposure levels of tegoprubart, but is also effective at preventing acute rejection in the absence of a calcineurin inhibitor. Only a few patients are needed to be able to begin assessing the prevention of acute rejection in the absence of CNIs, which have been the mainstay of immunosuppression regimens to prevent acute rejection for the last 25 years. We will also look at graft function, patient and graft survival, safety, including the incidence of new onset diabetes, as well as biomarkers. These data will help inform and support future larger trials. Next slide, please. In islet cell transplantation, we are looking at patients with type 1 diabetes and hypoglycemic unawareness who experience significant swings in glucose levels that are associated with serious risk and comorbidities. Our goal here is to evaluate tegoprubart as the backbone of a maintenance anti-rejection therapy, similar to what we just discussed with kidney transplant. For islet cell transplant, we are evaluating the number of patients that achieve insulin independence, and we are also assessing the number of cell transplants required to achieve this independence. Our hypothesis is that by removing CNIs, which are directly toxic to the islet cells, and replacing with tegoprubart, more patients could achieve better control with fewer transplants. Next slide, please. Thank you. Finally, our IgAN trial will assess the ability of two different doses of tegoprubart to reduce urine protein in patients with IgAN. This is an open-label trial in patients on stable doses of ACE inhibitors or angiotensin receptor blockers who continue to have high proteinuria levels. The primary endpoint is change in urine protein from baseline. The study is designed to provide a 24-week urine protein readout and to treat patients with tegoprubart for up to 96 weeks in order to assess long-term kidney function via changes in estimated glomerular filtration rate at 96 weeks as well. Change from baseline in urine protein is an endpoint that could support approval, so this study would inform the program and could potentially enable a pivotal trial as the next study. Thank you very much, and I'll turn it back over now to David-Alexandre. Thank you, Jeffrey. We will now transition to the Q&A session. Get everyone on. Thank you. I appreciate everybody sending questions. We've received a number of questions around ALS biomarkers, and I'd like to thank Thomas Smith from Leerink Partners, Matt Kaplan from Ladenburg Thalmann, and Pete Stavropoulos from Cantor for their questions on biomarkers in ALS. Stanley, the first question is going to be for you. There are two parts to this question. The first one is what biomarkers in the current trial that we're running would give you the most confidence that the program should move forward? When we ultimately look at the data, what biomarkers would give you the most faith that we should move towards a larger trial? That's one question. The second question is how would you weigh a reduction in inflammatory biomarkers versus a reduction in NfL light chain, for example? Well, can you hear me okay? We can. We hear you well. Good. Let me answer the second question first. I know a lot of my colleagues are very excited about NfL light. There are certainly data out there that indicate that NfL light as a structural component would be very meaningful to monitor. We're all in favor of monitoring it. I like the fact that as we heard the presentation from Jeffrey, that NfL light is not at the top of the list that's gonna be monitored. I'm a big fan of neuroinflammation, as I expressed. Here we have a compound whose major goal is to cut down neuroinflammation with elegant data that has been reviewed by Steven that it can accomplish this. From my perspective, there are three sets of biomarkers. One that we've heard about, namely MCP-1, which is now known as CCL2. TNF alpha, which is going to be measured. The problem is that in our hands, interleukin six and one beta, unfortunately, IL-1 beta, they're not easy to measure in the blood unless you use very, very high-powered Quanterix type of assays. With routine ELISAs, TNF alpha, MCP-1, and the ones that are being measured here, I think are very exciting and I think are the ones that we should be looking at going forward. One of the things that I mentioned in my talk is, everyone looks at the so-called clinical guide ALSFRS. The problem is that ALSFRS is unfortunately not as good for most of us in double-blind trials and unfortunately, it's the cemetery where lots of trials have been buried, and I'm concerned about that. But I do like, one, safety and tolerability. Two, the fact that inflammatory biomarkers are gonna be monitored very carefully. Three, yes, let's see if ALSFRS can show some stabilization. I think the direction we're going in that has been articulated for CD40 ligand inhibition is absolutely correct. Thank you. Second question, also regarding ALS came from Rami Katkhuda at LifeSci Capital, and it's for both you, Steven, as well as you, Dr. Appel, which is how does tegoprubart limit central inflammation if it does not cross the blood-brain barrier? Well, let me answer that directly because I think Steven showed this beautiful model of peripheral neuroinflammation. One of the major points I wanted to make is that inflammation in ALS is not limited to the CNS. It is systemic. In point of fact, number one, the antibody does not have to cross the blood-brain barrier to influence the immune system in a way that should be beneficial to the patients. No question about that. Number two, what we and others have documented is there is site-specific alteration in the blood-brain barrier, and antibodies will get in at the site of inflammation, and we and others have documented that. I think both things say that the appropriate antibody targeting and if it hits target, such as, hitting CXCL13, et cetera, as well as, altering the inflammatory biomarkers that we're gonna be on target. Thank you. We've received some questions around xeno, including from Matt Kaplan at Ladenburg Thalmann. That's for you, Dr. Vincenti. The question- Yes. Considering the recent xenotransplantation human experiences that have been publicized, you know, how close do you feel that we are to xenotransplantation? There's a second question around what is Eledon's Xeno strategy. Maybe I'll add that as a question for you, which is, you know, how do you see a potential role of an anti-CD40 ligand like tegoprubart in xeno? Well, you know, for the past 20 years, I'm hearing that xenos were around the corner. You know, in fact, for years coming to the transplant meeting, the American Transplant Congress, whenever there was a symposium on xeno, I tried to avoid them because I felt that the same stuff was being repeated year after year. However, now we've entered a completely different era with the addition of new, newer technology, the CRISPR technology, where genes can be deleted as well as genes can be added. I think realistically one can see that within a year or two, maybe the first clinical trials with xeno kidneys may occur. I think we're much closer than we've ever been. I think the prospect of being able to have an unlimited supply of organs is very exciting to the 80,000 people who are on the wait list for kidney transplant, but also, of course, in the future for heart and other organs. You know, I think that's why it's an opportune time to start thinking how we translate the studies in non-human primates to humans, and how do we put together an immunosuppressive regimen that will fit xenotransplants. Great. Thank you. The next questions are around islet cell transplant. Thank you, Pete Stavropoulos, from Cantor. Pete asked, so this is for you, Piotr. What are the hurdles to adoption? Tied to that, received a question asking what type of clinical data would be necessary to drive broader adoption in the United States? Of the islet transplantation, right? Islet cell transplantation for type 1 diabetes. As I highlighted in the presentation, the major two obstacles is the lack of sufficient source of islets for transplantation. We've been utilizing deceased donors, but more recently there are clinical trials with good outcomes when islets are manufactured from the stem cells, and this might be unlimited source of the high-quality islets. The second obstacle was toxicity of the tacrolimus, which we highlighted. If anti-CD40 ligand will be as effective or even more effective in anti-rejection properties, but less toxic, this definitely will allow for broader application of islet transplantation. What's exciting is there was also some data that was showing that anti-CD40 ligand has potential for tolerance induction. What it means is that after some time, it is possible that we will be able to stop immunosuppression completely, which is ultimate goal in the treatment of type 1 diabetes, to replace the islets without need for immunosuppression. This molecule, this agent has a great potential of less toxicity, improved efficacy, and potential for tolerance. What type of clinical data do you think would be necessary to drive broader adoption in the United States? Right. The data which shows advantage over the previous clinical trials based on the calcineurin inhibitors. Basically, you know, more patients. These are the objectives of the proposed trial by Eledon, right? More patients, insulin independent, longer insulin independence, and then patient achieving insulin independence with one transplant instead of 2 or 3 or 4, like we have them today. The final question around islet cell transplant is how common do you think the procedure could become? Is there potential to go beyond brittle diabetes? Of course. Today we offer only to those most desperate patients whose life is severely compromised and because we're using toxic immunosuppression. Living insulin-free with some side effects of immunosuppression, it's still compromising patients' life. In the long term, if the toxicity can be reduced and this drug has potential for this, then it can be applied. I think, you know, I mean, the ultimate goal is to transplant the islets without any immunosuppression or tolerance, right? In the meantime, using this approach, we can help many patients and learn a lot and which can bring us closer to optimal goal, to ultimate goal in induction of tolerance. Well, thank you. Dr. Barratt had to go, so I'll follow up with the individuals that sent questions for him. With that, I would like to conclude our R&D day, our first R&D day at Eledon, by first thanking all of our presenters, as well as reiterating our vision of focusing on patients for whom anti-CD40 ligand therapeutics may provide a life-extending treatment option. With 4 open clinical trials and our first data expected later this quarter, we look forward to updating you on our progress. Thank you again for your time today and for your interest in Eledon. Thank you very much. Thank you. Thank you, everyone. Thank you. Thank you.