Good afternoon, and welcome to the Nektar Therapeutics Investor and Analyst event. At this time, all attendees are in a listen-only mode. A question-and-answer session will follow the presentations. As a reminder, this call is being recorded, and a replay will be made available on the Nektar website following the conclusion of the event. I'd now like to turn the call over to Vivian Wu from Investor Relations and Corporate Affairs at Nektar Therapeutics. Please go ahead, Vivian. Thank you, and good afternoon, everyone. Thank you for joining us today for our webcast event with Type 1 diabetes experts. On today's call, we expect to make forward-looking statements regarding Nektar's proprietary drug candidates, the timing of the start of enrollment for ongoing or planned clinical trials with partners, therapeutic potential of our drug candidates, the timing and outcomes of regulatory decisions, and future availability of clinical trial data. Actual results may differ materially, and these statements are subject to important risks detailed in Nektar's filing with SEC, including the Form 10-Q filed on November 8th, 2024. Nektar undertakes no obligation to update forward-looking statements as a result of new information or otherwise. Webcasts of this call will be available on the IR page of Nektar's website at nektar.com. With that said, I would like to hand the call over to our Chief Research and Development Officer, Jonathan Zalevsky. J Z. Thank you, Vivian. We're very pleased today to announce an additional clinical collaboration between Nektar Therapeutics and TrialNet. As you know, we've been developing rezpegaldesleukin in multiple indications, including a Phase 2b study in atopic dermatitis, as well as a Phase 2b study in alopecia areata, and today, we announced a future upcoming clinical trial using rezpegaldesleukin for the treatment of new-onset Type 1 diabetes. We're very pleased today to be joined by an expert panel of Type 1 diabetes experts: Dr. Daniel Moore from the Vanderbilt University Medical Center, Dr. Megan Levings from the University of British Columbia, and Dr. Kevan Herold from the Yale School of Medicine, all deep experts in Type 1 diabetes and also members of the TrialNet group. In today's presentation, we're going to cover three important elements of our work. First, Dr. Moore will give an introduction on Type 1 diabetes, the disease in general, what we know about its epidemiology, pathology, and treatment. And then Dr. Levings, an expert in the role of regulatory T cells, will discuss the role of Tregs in Type 1 diabetes. And then Dr. Kevan Herold will speak about TrialNet, the group, and also the concept of the rezpegaldesleukin clinical study. It's a very interesting session, and I hope you all enjoy the discussion today. And without further ado, I'd like to hand it over to Dr. Moore. Again. Thanks, Jay Z, so I'm excited to talk with everyone about diabetes pathology and epidemiology and some of the things that motivate us to develop new and improved therapies, so I think many people would know that diabetes is a collection of diverse disorders characterized by excessive urine output, and in diabetes mellitus, including Type 1, there's sugar in the urine. All forms of diabetes mellitus result from an imbalance of insulin supply, and the needs for insulin in Type 1 diabetes result from adverse interactions between the immune system and beta cells, ultimately leading to an ongoing loss of insulin production. This is just like 104 years ago. The child with Type 1 diabetes looked like this, and everyone with Type 1 diabetes died for all of human history up till about 100 years ago, which is amazing. The presentation is often very difficult to discern. People with and developing Type 1 diabetes will have fatigue, weight loss, polydipsia, polyuria. And unless someone tests them, it can be mistaken for all kinds of other illnesses. Even in the acute phase, people may appear to have gastroenteritis, appendicitis. We've seen children in our pediatric endocrinology clinic that were thought to be having an asthma attack but really had elevated sugars and acidosis leading to abnormal breathing. This is very difficult. And of course, children may die with a new-onset Type 1 diabetes if it's not detected. Worldwide, there's about 8.4 million people living with the disease and about 500,000 new cases a year. In America, there are 2 million Americans and over 300,000 children. It's estimated in the next 20 years the population living with Type 1 diabetes will nearly double or more to 17 million, with the prevalence increasing about 0.3% each year. The disease has genetic factors, environmental factors, and also stochastic or just bad luck factors leading to the diagnosis. There are rapid increases in all populations. Many minority populations, including the Hispanic population, are experiencing the greatest current increases. In the U.S., there's about equal numbers of new cases in children, but under age 20 and those over, about 30,000 new children and 30,000 new adults each year. If you have a family member with Type 1 diabetes, your risk of developing the disease is increased by about 15-fold, which is data that TrialNet and other organizations have contributed to. Type 1 diabetes incidence continues to rise about 3%-5% per year, with the highest incidence in Scandinavia and Sardinia, but with individuals with Type 1 diabetes being found in all ethnic populations all over the world, including South Europe and the U.S., and even in China and Japan. Treatment of Type 1 diabetes has looked basically for the last 100 years very similar, especially in children, where basically all the treatment is insulin therapy. You can see in the upper left-hand corner in the 1970s, Kevan and I probably both remember this as we were both living with Type 1 diabetes around then. All the insulin came from animal-derived, was basically squeezed out of animal pancreas. Insulin improved over time. But in those time periods, you basically peed on sticks and got animal-injected insulin in order to keep yourself alive. All sorts of follow-up technology or follow-up medical therapy from that has basically been derived from these kinds of insulins, with the insulins improving, the purity improving, and other clever engineering designs made to have them act with different kinetics to provide different qualities of life, but for a child with diabetes, basically the treatment is still insulin. The pinnacle of this kind of treatment is what we see today with the closed-loop therapies and closed-loop technologies, where people have wearable sensors and wearable insulin pumps, so the sensors can detect blood sugar every three to five minutes, and wearable insulin pumps can pump those very same insulins underneath the skin to control blood sugar, so while those are very effective and very good for the people that can wear them, it's still a challenge for most people to manage their Type 1 diabetes. Even people that are doing a very good job. This is a tracing you can see here that shows average blood or shows blood sugar throughout the day. The little squares are sort of meal times. And so people might run a normal blood sugar under 5, which is about a blood sugar of 90 or 100. They might run normal blood sugars at meal times, but they might exceed blood sugars of 180, 200, even up to 300 in between meals, even when they're using these devices and doing their very best to care for their Type 1 diabetes. Historically, we understand from the Diabetes Control and Complications Trial, which concluded in the early 1990s, that we should control Type 1 diabetes and optimize blood sugars. In this trial, you can see on the left, people were divided into two groups. They got conventional treatment, which ran an A1C of about nine, and intensive treatment, where they received phone calls every day and multiple injections to achieve an A1C of around seven. On the right, you can see the progression of complications like retinopathy, and if they receive the intensive treatment, their chances of developing future complications were drastically reduced, motivating that we very much should control Type 1 diabetes as best we can. The average teen, though, despite all this, is still living basically with 1970s diabetes control. Despite all these advances, most young people with Type 1 diabetes still have A1Cs in the eights and nines, putting them at substantial risk for future complications, so they really do need something better than the therapies we're able to currently deliver, and you can see here the diabetes control is the prevention for every possible complication. So if you have retinopathy, if you worry about retinopathy or kidney disease or nerve pain or other losses, every point you lower your A1C is worth a substantial reduction in your risk for a future complication. So it's very important to control it. At the same time, controlling it comes with substantial risks. Once you achieve an A1C below about 7, you have a very substantial risk of having a severe hypoglycemic event. This doesn't just mean a little low blood sugar where you have a snack. This means people that cannot take care of themselves and require someone else to intercede on their behalf so they don't die from the low blood sugar. So while it's imperative to control the diabetes, controlling the diabetes continues to come with its own risks due to the use of insulin therapy. And despite all that, even if you do a great job with your Type 1 diabetes control, you can see here, less than 6.9, your risk of developing a future cardiovascular event and dying from that is still about threefold over the healthy population. So even if you're doing excellent with your diabetes control, your life expectancy is still lowered by almost a decade. So again, we need better treatments and better interventions to maintain people earlier. I think probably the clue to this is that preservation of C-peptide, that is, preservation of endogenous beta cell function, preservation of endogenous insulin secretory capacity, is very valuable to you. In the Diabetes Control and Complications Trial, they found people that they called responders, which were people that could still make some C-peptide that you could measure, and then people that were non-responders who had C-peptide levels, that is, insulin secretory function so low that it couldn't be measured. If you're a responder, your chance of getting a future complication was cut by more than in half. That was great if you were lucky enough to have your own endogenous C-peptide remaining. Similarly, your risk of having severe hypoglycemia was cut by almost threefold if, again, you were lucky enough. There wasn't anything you could do at the time of the Diabetes Control and Complications Trial to make this happen. If you were so lucky that you had C-peptide, your quality of life and your risk of future complications was drastically improved. So again, that can become a goal. Patients can be identified today prior to the onset of symptomatic T1D. Preservation of insulin secretion, which means beta cell function and C-peptide response, is the key to improving their long-term health outcomes and their quality of life. People will feel better. People will live longer. People will be better off if they maintain their beta cell function. Immune targeting therapy is probably the key to this. It's likely to achieve this outcome, but it needs to be optimized, tailored, simple, and free of sort of adverse effects for people to adopt it. With that, I'll turn it over to Dr. Megan Levings so we can talk about Tregs and Type 1 diabetes. Thanks very much, Dan. So I'm an immunologist, so I'm going to focus more on the basic science and concept of how the immune system goes awry and how we can potentially intervene in Type 1 diabetes. So my lab works on regulatory T cells. They are a subset of CD4-positive T cells present throughout our body. And they're like the police of the immune system. So it's their job to control various types of other immune cells, keeping them from causing autoimmunity and other unwanted things like allergies. They're characterized by high expression of a protein called CD25, also known as the IL-2 receptor, and a transcription factor called FOXP3, which is their lineage-defining transcription factor. More recent work shows that they also highly express another transcription factor called Helios. And so now we often characterize these cells as expressing these three proteins, CD25, FOXP3, and Helios. Unlike conventional T cells, another defining feature of Tregs is that they don't produce pro-inflammatory cytokines, most notably IL-2, and in this way, they act as an immune balancing factor, keeping other immune cells under control, so Tregs have multiple mechanisms of action, which makes them a very attractive target for a drug therapy because you're basically getting a lot of bang for your buck because they can do so many different things. We think about their ability to suppress the immune responses in three different phases. They are a T cell, so they express their T cell receptor like all T cells would do, and so the first phase of their suppression is to activate these cells, which would happen either in the lymph node or in the tissue. They would interact with an antigen-presenting cell, where they then down-modulate the ability of those antigen-presenting cells to go off and prime and stimulate other T cells. At the same time, the Tregs themselves are getting activated, which allows them to enter the second phase of the suppressive function, where they start making suppressive molecules, making regulatory cytokines like IL-10 and TGF-β, producing proteins like CD39 and CD73 that can generate the immunosuppressive molecule called adenosine, and even up-regulating further their expression of CD25, which allows them to act as a sink for IL-2, depriving other T cells from its source, and through these mechanisms and the creation of a suppressive microenvironment, the cells can achieve what we think of as long-term tolerance, so through molecules like TGF-β, they can actually convince other T cells that were not previously Tregs to turn into Tregs themselves. And of course, the Tregs can expand. And through a combination of expansion and de novo Treg induction, you can have this long-time, long infectious tolerance, which goes on to sustain immune regulation throughout the life of the person. So in Type 1 diabetes, there's been a lot of work to try and understand the role of regulatory T cells in Type 1 diabetes. And this is a schematic diagram showing the general concept for what we think is happening. So normally, in a person who doesn't have Type 1 diabetes, you would have a favorable balance between your regulatory T cells and your pathogenic autoimmune T cells. Interestingly, we all have autoreactive T cells in our body, but normally, it's our Tregs that are keeping them under control. But for some reason, in people who have the genetic risk or who have some environmental trigger or other stochastic factors like Dan talked about, that balance can start to become dysregulated, and people can start entering down the pathway of the different stages of Type 1 diabetes progression. So in an early stage, stage 1, you still have a favorable balance between Tregs and other types of effector T cells. And so you don't have any clinical symptoms of diabetes. But nevertheless, as this disease progresses and your Treg balance starts to become less favorable, you can get the development of cytotoxic CD8-positive T cells that can then traffic to the islets. That little circle at the bottom there is a representation of a beta cell islet. And those CTLs can start to progressively kill those insulin-producing beta cells. And progressively, there's more and more loss of tolerance. Patients will go from stage 1 to stage 2, where they start being dysglycemic, although they do not yet have a very acute diabetes, finally entering stage 3, where there's the full clinical presentation of hyperglycemia that Dan talked about. At this stage, in stage 3, which we think of as new-onset Type 1 diabetes, we have this imbalance between regulatory cells and effector T cells. But the patients have not completely lost their islet cell function. So there are still some islet cells there capable of making C-peptide. So why are Tregs defective in diabetes? And is there really definitive evidence that this would be a good target in terms of therapy? Probably the most definitive evidence that Tregs are really essential for controlling autoreactivity to islets comes from this rare genetic mutation called IPEX, which are children who have mutations in FOXP3, the lineage-defining transcription factor for Tregs. Essentially, if you do not have functional Tregs, you are born with Type 1 diabetes. This is very definitive evidence that these cells are essential to control islet autoreactivity. In the more common polygenic form, there's been multiple studies over the last decades showing that there's many different possible pathways that you can lead to an inadequate function of Tregs. There's some studies showing there could be inadequate numbers. They could be abnormally selected in the thymus. They could have decreased proliferation survival, potentially an unstable phenotype. And there could also be situations where the effector T cells are resistant to the effects of Tregs, overall resulting in this undesirable balance between the various cell types. So how can we reverse that? And the strategy that we're talking about today is really honing in on this unique property of Tregs to express this transcription factor called FOXP3, which has dual functions as both a transcriptional activator and a transcriptional repressor. And so at the same time, it is a transcriptional activator of CD25, the high affinity chain of the trimeric IL-2 receptor. And in parallel, it is suppressing IL-2. So these cells end up wanting IL-2 but not being able to make it themselves. And so they need to find IL-2 from the exogenous environment. And this is fundamentally different from a regular T cell not expressing FOXP3 because they would simultaneously be expressing CD25 and IL-2. So the idea is that we could potentially boost the Treg axis by finding ways to deliver IL-2 specifically to Tregs that are constitutively expressing this high affinity trimeric IL-2 receptor. And this would be in contrast to other T cells in the body, which only express CD25 under certain situations and overall tend to more predominantly express the low affinity receptor. So there's been multiple different strategies described for how you could preferentially modify IL-2 to deliver it specifically to regulatory T cells. So the historical way was actually to just use wild-type IL-2 on its own. And rather than delivering it in the high doses that are used for cancer immunotherapy, to deliver it at low doses repeatedly. And this, we'll come back to this in a couple of slides. This has been tried already several times in Type 1 diabetes. But there's now more sophisticated engineering-based ways to improve the wild-type cytokine, which has a lot of issues related to dosing and short half-life. The one we're going to be talking about today is this pegylated form of IL-2. But in the research setting, there's also other strategies, for example, modifying IL-2 by coupling it to antibodies that change its affinity and interactions, actually the creation of new versions of IL-2 with point mutations called IL-2 muteins. And then a full genetic engineering strategy would be to use this orthogonal IL-2-IL-2 receptor system, where you can actually engineer cells to express a new receptor that only binds to a new form of IL-2. So evidence that we can successfully boost the Treg IL-2 axis in Type 1 diabetes comes from several mouse studies. And I'm just going to highlight a couple of them here. This is the first study that showed this was possible from the Jonathan Sprent's lab several years ago. And he used the strategy of coupling IL-2 to an antibody, the JES6-1 antibody, which changed its properties so that the IL-2 was better able to signal through the trimeric IL-2 receptor. And you can see in C57BL/6 mice, if these mice are administered this combination of IL-2 and this antibody in the dark squares, you get this very rapid boost of Tregs, which then gradually decline over time. And this was functionally successful at improving the outcome of islet transplantation. So in the bottom graph, these are mice that are getting an allogeneic islet transplant with or without either just wild-type IL-2 therapy or the IL-2 antibody combination therapy. And you can see only in the antibody IL-2 combination therapy did we get this preservation of long-term graft survival. Injection of the wild-type IL-2 was not able to do that. Moving on to the autoimmune model, again, there's several science studies that have shown that this is successful. I've just pulled one of them here from Marc Gavin and Dan Campbell, showing that in this case, they're using a mutant form of IL-2, so a mutein coupled to an Fc region. And if you deliver this mutein to NOD mice, so these are the mice that are genetically susceptible to Type 1 diabetes, you can see that they preferentially have an expansion of Tregs in red. So going from left to right, we have higher Tregs. We have a better Treg to CD8-positive ratio and a better Treg to NK ratio, showing that this mutant form of IL-2 is actually able to preferentially expand regulatory T cells. And they're also able to significantly delay the incidence of diabetes. You can see each one of those little arrows is an injection of the product. And whereas just doing nothing, the mice will eventually get diabetes, the vast majority of them. Whereas if the mice get these repeated injections early in their life, we get this significant suppression of diabetes incidence. So the disease course in F, and then you can see the improved histology in H at the bottom. So what about in humans? This is a very complicated slide, but I'm just going to take you through a few of the highlights. So in humans with Type 1 diabetes, until now, only the wild-type form of IL-2 has been tested. And I would say the big challenge in all these studies is that wild-type IL-2, it's very unclear what the right dose is, and it has a very short half-life. Most of these studies have been trying to figure out if we had to use wild-type IL-2, how much would we give and how long would we give it for. The initial studies were done by David Klatzmann's lab in adults with established Type 1 diabetes. You can see the different doses that were tried there. It was clear that this strategy caused a dose-dependent increase in Tregs. At the highest dose, they saw evidence for suppressed effector T cell responses to beta cell antigen. John Todd and others in Cambridge tried similar studies, again in adults, this time using people who had new-onset Type 1 diabetes. They did dose-finding trials to try and figure out, OK, what would be the best regimen for IL-2. They did identify a regimen that could establish a steady-state 20- to 50-fold increase in Treg frequency. They also had some mechanistic evidence that this increase in Tregs was associated with prolonged improvements in decrease of pro-inflammatory cells. Then finally, there's another study in children from the Klatzmann group using yet another dose and yet another regimen, which had some correlations between people who were having the best responses for those who had actually a Treg deficit to start with. They did see improved maintenance of C-peptide at one year in seven of the high Treg responders. The overall summary from these studies is that delivering IL-2 to people with Type 1 diabetes, including children, was safe with very few adverse effects. Because of the undesirable properties of IL-2, it makes it a very difficult drug to deal with because of the uncertainty and the optimal dose and the optimal schedule of delivery. That brings us to the concept of today. If we were going to try and boost Tregs in Type 1 diabetes, where would we start and how would we do that, so going back to that schematic diagram, the concept we have is to intervene at stage 3 using a way to boost Tregs with an IL-2 drug with the REZPEG molecule, such that we could rescue the Treg to effector cell balance at this stage of diabetes and prevent the ongoing loss of tolerance, so I'm not an expert on REZPEG, but I'm just going to briefly go over these two slides on the molecule we're talking about, so as I mentioned, these versions of IL-2 are specifically designed to preferentially stimulate the CD25-containing trimeric IL-2 receptor so that you have expansion of regulatory T cells without affecting undesirable islet autoreactive T cells. And the goal would be by boosting these regulatory T cells, we then come back to that favorable balance, so we have downregulation of conventional T cells, suppression of antigen-presenting cells, and the induction of more Tregs, and the big advantages of REZPEG compared to IL-2 is that it has an extended half-life, and so the dosing regimens are much more straightforward, and it has shown activity in various animal models of autoimmune diseases, such as lupus, and has been tested in several clinical trials with very consistent effects on boosting Tregs, and just ending here with one slide showing the preferential expansion of Tregs in mice comparing to the wild-type form of IL-2, so in this experiment, black 6 mice were injected either with wild-type IL-2. Those data are shown on the far right. You can see wild-type IL-2 does boost Tregs, but not nearly to the same extent as a single dose of REZPEG shown on the left. You can see much higher boost in Tregs as well as a longer effect, really illustrating the benefit of this strategy in comparison to the low-dose wild-type IL-2 that's been tested so far. And as I mentioned, the selective stimulation of Tregs has been observed in humans as well across multiple clinical studies of healthy people and people with different types of autoimmune disease, including lupus, dermatitis, and psoriasis. So I'm going to end there and hand it over to Kevan, who's going to talk more about the trial design. Thanks very much, Megan. So my name is Kevan Herold. I'm a professor of immunobiology at Yale. And I'm also the chair of NIDDK TrialNet. So I'm going to just summarize what TrialNet is for those who are not familiar. TrialNet is a group of 18 clinical centers that are supported by the NIH, specifically NIDDK, to identify and test therapies that can delay or prevent the development of Type 1 diabetes in individuals who are at risk. The TrialNet's trials to stop beta cell destruction and enhance beta cell survival in persons with residual beta cell function also have clinical benefit for participants and provide information relevant to more durable and effective prevention therapies. In other words, in many cases, we need to first trial agents in patients with new-onset Type 1 diabetes in order to figure out how to go into earlier stages of the disease. And as I'll mention in just a moment, and as Dan and Megan have brought up already, we are able to identify individuals who are at risk for Type 1 diabetes and who we may be able to prevent the development of the disease. The knowledge gained through clinical research. Our mission is using that knowledge to build on our successes so therapies can be clinically meaningful. In other words, preventing the development of diabetes or improving it in people who've already been diagnosed with the disease. And our goal is to reach all patients who are at risk, including those in the past have not been involved in research studies. So TrialNet has actually accomplished a number of things. One of the most important is the approval of the first drug to delay Type 1 diabetes, namely teplizumab, an anti-CD3 antibody in individuals who are at high risk for developing clinical diabetes or what we call stage 3 Type 1 diabetes. We've also used samples from our clinical trials to understand the pathophysiology of the disease and to enable us to target specific pathways that we think are involved in the disease mechanism. And Megan has already discussed one particular pathway that we think is quite important in preventing development of Type 1 diabetes. We're very eager to collaborate with other funders, industry, nonprofits, and others who are interested in helping us to prevent Type 1 diabetes. We try to build on what we've learned already, including developing trials that, as I mentioned already, target specific pathways involved in the disease development. So here's sort of an org chart, so to speak, about how TrialNet is set up. There is an executive committee that includes representatives from the NIH, NIDDK. There's myself and a co-chair, Linda DiMeglio from Indiana University. There is a coordinating center, which we call the TNCC, that's led by Jeff Krischer at the University of South Florida, and a hub that's responsible for outreach to patients and communications that's led by Carla Greenbaum at Benaroya Research Institute. We have a collaborative mechanistic panel. All of our trials are designed to answer important questions about the mechanisms of the disease, how these agents that we trial fit into changing that mechanism, and so that we learn with every single trial that we do. There is the clinical network, and I mentioned already the work of the hub. There's a data coordinating center that exists at the University of South Florida, collects all of our data, much like a CRO. And then there are other committees that operate in parallel, including a committee responsible for publications, recruiting individuals, so on and so forth. And then each of our protocols has a separate committee that deals with developing the protocol and stick with the protocol through its full implementation and completion. Now, we've seen this slide in one form or another by the other two speakers. But basically, the notion here again is that autoimmune Type 1 diabetes begins before individuals have even immunologic markers of the disease. But when they have immunologic markers, specifically the development of autoantibodies, we know that they are on the pathway towards developing clinical disease. We call stage 1 Type 1 diabetes, which is the beginning of the disease, to identify those individuals who have positive autoantibodies that we can measure in the serum but do not have any abnormalities of glucose tolerance. These individuals are clinically silent. As beta cell function deteriorates, we may find that there are some abnormalities on a glucose tolerance test. But again, these are individuals who are clinically silent. We call that stage 2 Type 1 diabetes. The risk of progressing from stage 1 to clinical stage 3 Type 1 diabetes is about 35%-50% over five years. Whereas once glucose intolerance has developed, the risk of progressing to clinical stage 3 diabetes is about 75% in five years. Stage 3 Type 1 diabetes is what walks in the emergency room. People who have symptoms may present with ketoacidosis and in whom the diagnosis is very, very clear. So our plan here is to study REZPEG in individuals who have stage 3 Type 1 diabetes, clinical hyperglycemia, and to determine whether or not we can change the course of the disease once these individuals have presented with Type 1 diabetes. Now, when you present with the disease, we know that you still have clinically significant beta cell function. By that, I mean that those individuals have residual beta cell function that is associated with reduced risk of microvascular complications such as eye disease, kidney disease, and with reduced risk of severe hypoglycemia. But over time, those individuals will lose essentially all of their beta cell function and be at higher risk of developing these complications that Dan has already discussed during this presentation. So we've already talked about REZPEG. The objective, therefore, of this trial is to determine whether or not it will preserve beta cell function that we measure by measuring something called C-peptide in the plasma. C-peptide is produced by the insulin-producing beta cells in the islets of Langerhans together with insulin. The reason we measure C-peptide is that it's not cleared by the liver, which occurs with insulin on its first pass through the liver, so C-peptide is an accurate reflection of endogenous beta cell mass or function, so we use that as an index telling us how much residual beta cell mass is left in an individual with Type 1 diabetes, so our plan here is to enroll 66 individuals within the first 100 days after the diagnosis because we know they have clinically significant beta cell function, and we'll give the drug every other week for 26 weeks. You can see the randomization ratios two to one to active drug versus placebo. And we'll measure C-peptide response to a mixed meal at enrollment, three, six, and 12 months. And the first 18 subjects will be adults. We will do a safety analysis. And then our plan is to lower the age down to 12 and then eventually to eight after that safety analysis has been completed. And then, of course, we will measure additional immune and metabolic parameters. So the total N is 66 individuals. And the primary outcome of the trial will be the beta cell function measured by measuring C-peptide during a mixed meal tolerance test at 12 months after study enrollment. So that's diagrammed here, which is basically the flow of the trial. As I mentioned already, our plan is to enroll a total of 66 individuals, 2 to 1, into REZPEG or placebo treatment arms. We will begin with adults. They will be randomized and treated. We will evaluate their function after six months. At six months, we get a good measure, preliminary read, of both efficacy and safety, most importantly, safety. If the safety looks good, we will open enrollment to pediatric individuals, beginning with age 12 and then lowering it to age 8 and above. As I mentioned already, the primary outcome is the C-peptide response to a mixed meal at 12 months. Our secondary exploratory measures include a variety of metabolic as well as immunologic parameters that we have assays. These are fairly standard measurements in studies in Type 1 diabetes. That's what we have. I think we're happy to stop here and take any questions. Great. Thank you, Dr. Herold. Please hold for a brief moment while we pull for questions. Our first question comes from Yasmeen Rahimi at Piper Sandler. Please go ahead, Yas. Good afternoon, team. My apologies as I'm in transit. If you could just let me know if you can hear me first before I go forward with my questions. Yeah, we can hear you loud and clear. Okay, great. Thank you. Thank you so much, Dr. Herold, for the thoughtful discussion. I guess the first question is, could you provide some commentary on the dose selection for the study? What work went into picking the 12 micrograms per kg for the selecting dose and how you're thinking about the doses as you go across the different cohorts? And then secondly, if you could comment on what type of a change in C-peptide across the three cohorts could establish validation and warrant further development. Appreciate color on sort of these multi-part questions. And I'll jump them back into the queue. Yeah, Dr. Herold, would you like to begin? And I can add also a few words on the follow-up. Why don't you, Jay Z, why don't you add about the, I mean, obviously, we're interested in the dose level, sure, in the dose that causes complete efficacy and no adverse events. But Jay Z, maybe you want to answer that. Yeah, I'll start with that one. Yeah. Yasmeen, when we looked at the design of this study and we looked across the entire REZPEG program, it was pretty clear that what we learned from the lupus study was much more applicable and relevant to this patient population and also what we learned about the dose range and activity profile. As you recall in that study, the 900 microgram flat dose was the most effective dose that we studied. That translates to a 12 microgram per kilogram dose, assuming a nominal body weight of 75 kilograms. Very much as Kevan said, that dose level was really an optimal dose level to study in this population. We get a very effective elevation of Tregs at that dose level. As Kevan said, it's a great balance of all of the other parameters as well. So a very good dose for this type of study for signal seeking. And then your next question was about the kind of MMTT C-peptide levels that one could consider as being a sign of success. And Kevan, maybe I can turn that one over to you. Yeah. So we are going to take advantage, first of all, for the safety review, we're going to take advantage of methods that have been published from TrialNet that basically tells us if we know your age, your sex, and where you're starting with your first C-peptide response, we know where in controls from all of TrialNet studies, you ought to be at six months. So we're going to be comparing the data that we have from the drug-treated individuals to this sort of analysis. We know we're going to look to make sure, first of all, that people are not worse. And then I think that's really where the stop is at six months. In terms of getting to the endpoint and looking at efficacy, we probably then will completely, we'll need to fulfill the 66 for enrollment. But what the six-month analysis does is enables us to make sure there are no adverse events that we would be concerned about occurring. In terms of the types of improvement that we're looking for, it is, I'm sorry, I don't have the power analysis in front of me right now. But basically, we are looking for a statistical improvement in C-peptide at the one-year time point compared to the baseline. In general, these have amounted to about a 50% or so plus or minus improvement in the C-peptide levels. Just to add quickly some color there too. I think it's important to remember that everybody that doesn't get treatment, C-peptide will be worse in a year. So every single placebo individual will have substantially worse C-peptide. And the younger they are, the worse off they're going to be in a year. So even having the same C-peptide in a year that you started with at diagnosis is a remarkable achievement for people with Type 1 diabetes. Yeah. Thank you so much. Thanks for the questions, Yas. Our next question comes from Julian Harrison at BTIG. Please go ahead, Julian. Hi. Thank you for hosting this and for taking my questions. First, I'm wondering if it's well understood what happened to the teplizumab efforts in stage 3 in the United States. I'm probably playing catch-up here. But if you could point me in the right direction, that would be great. So that's still ongoing. Sanofi is working on that. There have been discussions with regulators, both in the United States and in Europe. So that is still moving forward. Okay, great. And then a related question. With that construct forging the path forward in stage 2, do you think that opportunity maybe becomes easier to pursue by others with time? You mean, do I think that delaying onset, yeah, that opportunity? Yeah. I mean, I do think that that becomes, first of all, the teplizumab experience would indicate that you can do it. And it's achievable. And I think that the experience would also say that the endpoint in stage 2, which is conversion to stage 3, is approvable. And yeah, ultimately, that's where we'd like to go with this. Great. And then a final question for the panel. I'm wondering what you think makes pegylated IL-2 maybe a more enabling construct in Type 1 diabetes compared to some others like Fc fusions or muteins. Megan, can I ask you to kick that one off? Yeah. The Fc fusions, of course, have. They're a much more complex molecule to make. They have potential for immunogenicity. The muteins also have potential for immunogenicity. So I think from an immunological perspective, that's where wild-type IL-2 is attractive. And there's probably lots of manufacturing aspects that are attractive as well. Jay Z, you probably want to expand on that. Sure. But maybe, Dan, would you like to comment? I can go last. Julian's heard me answer this question before anyway. Absolutely. Yeah. I think the key really here that Megan talked about earlier is the kinetics and tolerability and sort of duration. I guess you think about area under the Treg curve, right, which has been not very favorable with at least native IL-2. And then pegylated IL-2 seems very simple. When I first heard about this, it seemed like, "Wow, that seems really simple. How's that possibly going to work?" But at the same time, taking advantage of the receptor and its sterics and its interaction create a situation where you just can create competition between Tregs and T-effectors. And then the pegylation also adds a long duration of activity if you compare it to what people with Type 1 diabetes know. You have your Lantus that you inject, and it lasts a long time. And it's very desirable to have something that you inject as long as it's safe, that it lasts a fairly long time, and gives you a duration of effect that's sort of manageable for home treatment. I think the duration and sort of the selectivity or what make it a very attractive idea compared to some of the other ones that are available. Yeah. And what I'll add, Julian, also is that, as you know, with our design of REZPEG, it's a full agonist, Tregs, unlike IL-2 muteins, which show a different selectivity and potency profile, but they don't reach the same amplitude of Treg activation, indicating they're partial agonists, many of those designs. And that kind of full agonist allows us to have a very broad dose range. For example, as you know, in atopic dermatitis, we're developing a higher dose, 24 micrograms per kilogram. We have a lot of experience and a lot of data with that dose level. But the pharmacology is so broad that we can use a 12 microgram per kilogram dose level here for this study in type 1 diabetes for these initial cohorts. So it's really a lot of elements that go into the design, really preserving some of the best properties of the native protein, but then optimizing them pharmacologically with polymer chemistry to improve almost like the pharmaceutics and pharmacological properties of the IL-2 protein. All right. Excellent. Thank you again. That's very helpful. Thanks for the questions, Julian. Our next question comes from Jay Olson at Oppenheimer. Please go ahead, Jay. Oh, hey. Thank you for providing this innovative update on type 1 diabetes. We have a few questions maybe to start with regards to the heterogeneity of type 1 diabetes patients. Would you be enrolling patients with Treg deficiency in your clinical trial? What is the ideal ratio of Tregs to T-effector cells you'll be targeting in your study? Dan, do you want to start that one? And then maybe Megan, you have some additional color. Yeah. I think generally the T1D population has heterogeneity in Treg function, as Megan was indicating. That's sort of all over the map and not exactly directly genetically determinable. So that'll be part of the mechanistic studies, potentially, to think about how do these individuals respond to native IL-2 or to REZPEG, say, in culture. What were their relative expansions of Tregs to T-effectors? And then what are the role of antigen-specific Tregs and T-effectors that can be measured by methods that TrialNet has? But a priori, we probably won't really know what their ratios are going to be going in. But on the back end, we'll get some exploratory data. We won't have randomized people based on their Treg and T-effectors and antigens, but we'll be able to begin to get some signs as to what happened there. Yeah. And just to add on that, I think one of the huge benefits of doing a study like this with TrialNet is the collaborative mechanistic studies working group that Kevan mentioned, where it's really bringing T1D immunologist experts from around the world, essentially, to brainstorm and come up with the best assays possible, build upon an existing platform of standard assays, but then add in these very specialized antigen-specific assays, for example, to more precisely track what happens to not only just bulk Tregs, which has all been done so far, but really drill down on the antigen-specific Tregs with the hope that we'd see them increasing over time. Thank you for that. And then can you talk about whether or not the FDA has approved the study of REZPEG in pediatric Type 1 diabetics and the safety data that you have there and whether or not that would also apply to pediatric atopic dermatitis and alopecia areata patients? Dan, would you like to take that one? We haven't approached the FDA for approval for pediatrics as part of what's built into the study design with acquiring a. This is a very classic T1D study design where things go to adults first, and we'll get some safety data there and then approach. But even with classical designs, if they're not initially favorable to go to pediatric patients, we can complete the whole study in adults. Okay. Yeah. What I'll add, Jay, is in terms of the pediatric plan for REZPEG, all data is considered. It's really focused on the indications. But when you roll up the data, we'll be considering all data, so both the pediatric patients in this study as well as adolescent pediatric patients. So we'll be studying in atopic dermatitis. Okay. Thank you. That's helpful. And then will you include patients on teplizumab in your Type 1 diabetes study? And are you considering combinations of REZPEG with either teplizumab or other novel mechanisms like CTLA-4 blockade? So the teplizumab patients at this point would be people who would have been treated, who would have been at risk for diabetes, would have been treated. And if they get into this study, they failed. We generally have not included those individuals in our studies of other agents. However, the protocol committee can address that in more detail. It's not going to be a huge number of patients. Okay. Great. Thanks again for this update. And thanks for taking the questions. Thanks for your questions, Jay. Our next question comes from Roger Song at Jefferies. Please go ahead, Roger. Great. Thanks for hosting the event and a very informative presentation. A couple of questions from us, and thank you for taking the questions. So first one is I see some clinical trial for the wild-type IL-2, which is very interesting, have some effect in the Type 1 diabetes. So just curious about the level of the Treg. Is Is necessary to correlate with the C-peptide preservation? More interesting is how much variability you see among all the Type 1 diabetes patients. The two earlier questions, the heterogeneity of the Type 1 diabetes. So how are we going to see the Treg stimulated by the REZPEG be able to address the broader stage 3 Type 1 diabetes and then moving to the other stage? Thank you. Yeah. Megan, would you like to address that? Yeah. So I think the real challenge, like I mentioned in those wild-type IL-2 studies, is that the half-life of the drug is so short. It's really hard to get a handle on what's going on. And also, the dosing was extremely limited. So I think the initial studies, the patients only got like five days of the drug. So I guess consistently, wild-type IL-2 increases Tregs, but very transiently. And it's hard to know exactly what was happening in those studies. I think the overall concept behind REZPEG is that we can get away from those bad pharmacokinetics, use a drug dose that has been proven to work in other diseases where we know there'll be consistent elevation of the cells. We know the dosing regimen to follow so that we'll have a sustained increase in Tregs. And then, as I mentioned, one of the fundamental properties is this ability to induce infectious tolerance. So if you temporarily switch that balance so that you have more regulatory cells than effector cells, you can then imprint the effector cells to actually take on Treg properties. So in the long run, you don't actually need to be taking IL-2 for the rest of your life. And that would be the dream outcome of a study like this, is that you had a, say, six-month treatment period, you reshaped the host immune response, and then the host just did the work for you after that. That's a dream. But that can work in an animal model. There's lots of studies out there showing that that's possible. So we'll see. What I'll just add is that's very similar to what we observed in our atopic dermatitis study, as you know, Roger, where treatment for 12 weeks induced a lasting durability in patients. Many have characterized that as a potential remissive effect of the drug. It's very much aligned with the mechanism that Dr. Levings's just described. If we can replicate something like that here, which is our objective in the study, again, that would be a very, very exciting outcome. Can I just add, Jay Z, that there's no reason that I know of why this drug couldn't be given again? As long as we have methods for sort of tracking individuals and knowing whether or not there's progression of disease, unlike certain monoclonals where you might develop neutralizing antibodies, it's less likely to be an issue with this type of a therapy. Indeed. Got it. Yeah. Thanks for the comments, all the comments. And then, so, understanding this is a very good, well-designed trial, and then with a very good trial network to do the study. So, what will be the next step after this? And then, how should we think about the timeline to move forward? Thank you. Kevan, can I ask you to comment on that? From our point of view, we would be very keen to move this earlier in disease. I mean, from all that hopefully that we presented and explained, this is an optimal type of therapy for prevention of Type 1 diabetes in individuals at risk. Now, one of the questions was, well, what about in combination? That also makes a whole lot of sense. And so depending on where the field goes, we could think of this as a single therapy or perhaps even a combination therapy after other agents like CTLA-4 Ig or anti-CD3 antibody. Thank you. That's it from us. Thank you for the questions, Roger. Our next question comes from Mayank Mamtani at B. Riley. Please go ahead, Mayank. Yes. Thank you for the detailed presentation and appreciate you taking our questions. Just maybe a couple of follow-ups, piggybacking on the conversation from before. Just given how REZPEG mechanism stacks up against teplizumab, what relevant translational markers make sense to follow? So we understand this is maybe not as blunt, and some of the concepts around immune restoration come through. And I'm also thinking safety tolerability here, if there's anything to highlight there. Sorry if I missed this, the rationale for looking at 12 months primary efficacy when treatment duration is six months, just maybe if you can point to a prior study that was conducted and what sort of we know that that's the optimal time frame to look at for C-peptide, that would be helpful. Thanks for taking our questions. I can answer it. In terms of the 12 months, I think if you take a look at the published trials with golimumab, with b aricitinib, even with verapamil, they used a 12-month readout as showing efficacy. Now, obviously, if things are looking good at 12 months, we're going to continue to follow the patients. But I think at 12 months, we can get a good read as to whether or not this is going to be effective. And then, Megan, can you comment on some of the translational markers? Yeah. So the question was about, I guess, compare and contrast teplizumab versus REZPEG and how might the mechanistic studies differ. I mean, the two approaches are extremely different. Teplizumab, I think, as you mentioned, is sort of a blunt instrument to affect all sorts of T cells in the system. There's some evidence that potentially it could have beneficial effects on Tregs, but I think, Kevan, correct me if I'm wrong, they're mostly probably disproven by now. And most of the effects are thought to be more of an induction of this T cell exhaustion, so preventing the existing autoreactive T cells from doing their islet-destroying job. The REZPEG molecule will have a much better defined mechanism of action. We know exactly what it does. And so that'll be much more helpful in terms of designing good mechanistic experiments. And through induction and boosting of Tregs, we should be able to have sort of effects that cascade down to many different types of immune responses because Tregs are known to control CD4, CD8, B cells, and innate immune cells. So we should get a much broader effect and resetting of the immune system in comparison to a drug like teplizumab. Super helpful. Thanks for taking our questions. Thank you for the questions, Mayank. Our next question comes from Arthur He at H.C. Wainwright. Please go ahead, Arthur. Hey, good afternoon. Thanks for hosting these, and thanks for taking my questions. So I guess I have two questions. First, so I guess regarding the trial design, I just want to confirm. So the trial is going to be stratified for adult patients and the children and adolescent patients, or in the last two cohorts, it will be just a mix of the different age groups? Yes. Yeah. Dan, would you like to comment on that? The plan is to have sort of continuous enrollment with maybe some safeguards to make sure some of the youngest people get enrolled. Typically, for new-onset diabetes trials, the appetite for the trials is much quicker in the younger age groups. So typically, once the younger age groups enroll, their pace tends to outpace the adult age groups. The adults will enroll for safety, and they'll continue to enroll, and then pediatric patients will enroll behind them. Okay. Thanks for that. And for the initiation of the study, could you give us some indication of what are the gating steps for getting the study rolled out? We are in the process of finalizing the protocol. I'd say, actually, the protocol is pretty much finished. And the CTA has been completed already with the NIH. We are now preparing it for submission to the FDA and to the TrialNet. We use a central IRB. And then once we're done that, we're pretty much good to go. Awesome. So my last question is, so maybe for all the panelists, so if the REZPEG is moving to the clinical success story, how should we think about REZPEG versus the kind of stem cell or stem cell cell treatment if both of them get approved? I think I would just say they're doing very different things. If I'm correct in what you're thinking about with stem cell replacement of beta cells, that's a very promising area of research. It doesn't change the immune response. So those cells are potentially subject to either, depending on what their source is, allograft rejection or recurrent autoimmune disease. So we're looking at two different aspects here. One is replacement of beta cells, which would be necessary in someone after the diagnosis of the disease, but the other is stemming the autoimmune response that caused the disease in the first place. Thank you very much, Dr. Carroll. Thanks for taking my question. Thank you for the questions, Arthur. Our next question comes from Nick Leonard at J.P. Morgan. Please go ahead, Nick. Hey, this is Nick on for Jess. Thanks for taking our questions. Some of the other questions kind of touched on this, but you discussed the relevance of the balance of Tregs in patients with Type 1 diabetes. But is Treg dysfunction considered a primary driver in all Type 1 patients? Or maybe there's a subset of patients the therapy with this mechanism could be more or less effective in? Yeah. Megan, would you like to answer that? Yeah. So I think it's unknown. You're probably correct that in some patients, Treg could be a primary defect. I mean, not a defect as severe as somebody who has IPEX, but some fundamental problem with Treg activity in other patients that may be a further downstream consequence of whatever a primary defect may be. It's probably likely that there will be heterogeneity and that we'll see different types of patient responses. But I guess the good news is that we have a lot of depth of knowledge of mechanistic assays and a big enough patient cohort size that we should be able to drill down and really figure out if we see responders and non-responders, what is driving those groups. And in fact, we've done something quite similar recently in a trial of ustekinumab in Type 1 diabetes where we were able to pull apart responders and non-responders based on an immunological biomarker. So there could be something similar that we're able to do here. Indeed. The highest point in this individual thing, they still might be very responsive to it. So even if they don't have genetic problems, they still may benefit. Yes. Yeah. Great. Thanks. Great. Thanks for the question, Nick. Our next question comes from Andy Hsieh at William Blair. Please go ahead, Andy. Thanks for answering our questions. Just really on an early PD biomarker perspective, I'm curious if there is any correlation between the titer of autoantibodies and disease severity and whether that could be used as an early biomarker. Similarly, I've also read that a lot of these patients actually suffer from other concurrent autoimmune conditions. I'm curious if that's also another early biomarker that you could look at, is probably concurrent diminishing of other symptoms as well. Just curious on your thoughts on these topics. Thank you. I'll go. Typically, the autoantibody level is not terribly predictive of the speed or, I guess, severity of where you might define that in terms of, I guess, we would probably mostly think about rate of beta cell loss or C-peptide loss overall. You can have small amounts of antibodies. The more diverse number of antibodies, you might be a little bit closer to diagnosis. But once you have two, you're kind of in a bucket of similar individuals. People with Type 1 diabetes, most commonly, they get another autoimmune disease second. So they might get thyroid disease in up to 30% of people over their lifetime, and about 5%-10% of the people may experience celiac disease. But temporally, they're not usually so closely connected as to make it a useful monitoring. I think in long-term studies, as there's more immunotherapy, like batching everybody and saying, "Do people that get X, Y, or Z immunotherapy have delays or avoid certain autoimmune diseases?" will be very interesting. But in the short term, you're probably not going to get much biomarker mileage out of those just because of the rarity and the infrequency of the events. Great. Thank you for the question, Andy. So this concludes our session for today. I'll now turn it back over to Jay Z for quick closing remarks. Well, I want to thank everyone that joined us today. I thought this was an incredibly informative and incredibly interesting presentation. I want to especially thank our panel of type 1 diabetes experts, Dr. Moore, Dr. Levings, and Dr. Herold. Thank you for joining us today. Thank you, everyone, for attending this call. Goodbye.