Good morning. I'm Pete Salzmann, Chief Executive Officer of Immunovant. I'm excited to welcome you to Immunovant's R&D Day, where we have an opportunity to dive deeper into our asset, our program, and our opportunity. We'll be making some forward-looking statements over the course of the day. Investors should carefully read this slide available on our website and in the 8-K we filed this morning. Before we jump in, I'd like to cover some housekeeping for how we'll handle Q&A from the audience. We're very interested to address any questions that you may have. Throughout the day, please use the chat function to submit your questions, which we will address at the end of the program. If you'd like to submit them anonymously, that's okay too. I'm going to kick things off today with a brief company and asset overview. After which we'll cover information related to our three announced indications. As most of you know, Immunovant was established with a dedicated purpose to advance the development of batoclimab, a fully human monoclonal antibody in the very exciting anti-FcRn class. Batoclimab has a unique combination of attributes, in particular the ability to deliver deep IgG reductions via a simple subcutaneous route of administration and thereby enable tailored dosing. We believe that this unique combination of attributes, together with the potential, the broad potential of the anti-FcRn class, as well as our strong balance sheet, make for quite an opportunity. We're in the process of initiating our phase III trial in myasthenia gravis, and we're on track to start two additional trials, pivotal trials in 2022. We also plan to announce two new indications in August, as previously disclosed. With this in mind, our cash is expected to fund our development plans into calendar year of 2025. In this first section, I'll briefly dive a bit deeper into the anti-FcRn market and into batoclimab special features. For those of you who don't know Immunovant, our vision as a company is to enable normal lives for people with autoimmune diseases. In other words, we want to make a big difference for people with these conditions. We love trailblazing, and you will see some unique development plans coming from our teams. These plans are informed by understanding many voices, many perspectives. In addition to understanding regulatory pathways and physicians' perspectives, we work hard to really understand what people with these conditions need and desire. These insights are often the most important when crafting a differentiated development program with the potential to deliver unique treatment solutions. At a high level, the needs described on this page may seem straightforward, even obvious, but we've spent a lot of time listening to people with autoimmune diseases, and I believe we've identified some unique and actionable insights, especially when combining some of the ideas. For example, in the upper left corner, we've noted that people want reliable treatment options and that some of the older therapies, especially steroid-sparing immunosuppressants, can take a long time to work. In the lower right corner, we've noted that improving symptoms is important for quality of life, but so is reducing uncertainty. In the lower left panel, we've noted that symptoms often wax and wane. By themselves, each of these three insights may not seem very unique nor very actionable. Put them all together, and we realized a real tension that people with MG face. When their symptoms are getting worse and their treatment needs to be escalated, people with MG are often anxious about the uncertainty created by prior experiences when they changed medications and then had to wait repeatedly to know if it was working. When their symptoms are worsening, many desire rapid and deep symptom control. Understanding this, we are introducing a unique element into our phase III MG trial, specifically induction with our highest dose. If successful, we believe this will be a very differentiating part of our overall data package. I expect we'll take a similar approach in other conditions and indications, tailoring the dose or dosing regimen to the unique needs of each disease. For those of you who are newer to the anti-FcRn space, it's important to first understand the role IgG antibodies play in mediating autoimmune disease pathogenesis. The immune system is made up of both cellular components and immunoglobulins. IgG is an immunoglobulin. It's also a protein. It has a very long half-life, and that's because IgG is recycled, which I'll show in a moment via the Fc receptor. An interesting characteristic of diseases mediated by pathogenic IgG or autoantibodies is that in many cases, disease severity may correlate with the absolute autoantibody burden. This potential correlation may then create a unique opportunity for more potent FcRn inhibitors like the higher doses of batoclimab. If pathogenic IgG can cause disease, how does FcRn inhibition help? We need to start with the role of the Fc receptor in general and how it prolongs the half-life of IgG. Here you see a Fc receptor noted in dark blue binding to an endogenous IgG antibody in green. This binding prevents the IgG from being shuttled to a lysosome, where it would normally be enzymatically degraded along with other proteins in the blood. The FcRn recycles IgG back into the circulation. On this slide, our monoclonal antibody 1401 or batoclimab, shown in purple, binds the FcRn shown in dark blue. This binding prevents endogenous IgG, shown in green, from binding to the FcRn. When that happens, the endogenous IgG is shuttled to the lysosomes where it is degraded. That's the fundamental biology, which is pretty straightforward. Interestingly, most autoantibody-mediated conditions do not have any targeted therapy available. Hence, there are many potential indications with high unmet need that are promising targets for FcRn inhibition. Sometimes a list like this from other therapeutic categories or mechanisms of action is primarily a list of indications that might be studied. In the case of anti-FcRn, specific studies in more than 17 indications across a variety of therapeutic areas have already been initiated or announced. The announced indications across several assets include classic autoantibody-driven diseases like myasthenia gravis and several others on this list. Most of these classic indications already have positive clinical data from one or more anti-FcRn. Recently, a range of studies in the exciting immune complex-driven group have also been initiated. We believe that batoclimab has a unique combination of attributes that will allow us to compete very well across a wide range of these indications, whether classic or immune complex-driven. More on that in a moment. First, just to put some numbers around the market opportunity. This slide shows the estimated market size in the U.S. and Europe related to the three indications that we've announced to date on the left for batoclimab. Factoring in the broader range of indications being explored by the FcRn class generally, the size of the potential market opportunity grows substantially. Okay, this slide provides some really important detail regarding batoclimab's unique combination of attributes. Let me start in the bottom right. Batoclimab was designed from inception with the patient in mind, with pharmacological properties and formulation that enable simple subcutaneous injection. How did that happen? Well, very early in the antibody development phase, when there were multiple candidate antibodies from which to choose, the inventors of batoclimab selected the final candidate not only based on potency for binding to the Fc receptor, but also based on ease of solubility. They actually made all the finalist antibodies in small aliquots, which is quite challenging at this earliest phase of antibody development, and tested them for solubility. Batoclimab, as the final lead antibody in this family, possessed both of the desired properties. It binds the FcRn receptor well, and it was soluble at a high concentration needed for simple subcutaneous delivery. Moving to the top right, this preparation of batoclimab in a subcutaneous form has demonstrated deep IgG reductions. As previously reported, the 680 milligram dose yielded a 78% reduction after 4 doses in our phase I MAD study, and an 80% reduction with longer dosing in the thyroid eye disease phase IIb study. Taken together, these two features yield a very nice benefit in the middle right side of the slide, specifically the potential for tailored dosing. In fact, we expect three different doses, 680 milligrams QW, 340 milligrams QW, and 340 milligrams every second week to provide a wide range of therapeutic reductions in IgG and thereby enable tailored dosing. This last point is important enough that it gets its own slide. We believe that continuous dosing, coupled with the ability to fine-tune the dose based on controlled data from clinical trials, has the potential to meaningfully advance the quality of care for people with IgG-mediated disease, both in comparison to older therapies and in comparison to other anti-FcRns in development. Recognizing the broad range of potential applications and the substantial unmet needs in these conditions, we are moving forward with an aggressive development program. We expect to start three pivotal trials this year, and by the end of the summer, we will have announced five indications in total. This is possible based on the broad potential of the anti-FcRn class and also based on the unique attributes of batoclimab, plus our strong balance sheet. Transitioning now to specific indications that we're studying, we'll begin with thyroid eye disease or TED. We're going to hear from two experts, one an oculoplastic surgeon and one endocrinologist. This section covers a lot of ground and begins with a pre-recorded fireside chat moderated by our Chief Medical Officer, Dr. Bill Macias. Bill, take it away. Thanks, Pete. Good morning. I'm Bill Macias, Chief Medical Officer at Immunovant, and I'm very pleased to be joined today by Dr. Andrea Kossler for a discussion on thyroid eye disease. Dr. Kossler is the Director of Oculoplastic Surgery and Orbital Oncology and an Assistant Professor of Ophthalmology at Byers Eye Institute at Stanford. Good morning, Dr. Kossler, and thanks for your time today. Hello, everybody. Thank you for having me. It's such a pleasure to be here talking about one of my favorite conditions. Thank you so much. Thanks. I'll get started. Can you give us your insights on how our understanding of thyroid eye disease has evolved over the last several years? Sure. Thank you so much. Yes. In the last couple decades, there have been significant advances in our understanding of this disease, and it has really resulted in a paradigm shift in the way that we treat another change. It's been really remarkable to be an oculoplastic surgeon during this time. Before the last few years, you know, I've been treating thyroid eye disease for about 13 years, and we previously Did not have good treatment options for this condition. It's a complex heterogeneous condition, and I did enjoy treating it, but sometimes I felt deflated with the treatment options that I had available. In the last, you know, decade or so, we feel that we really understand the pathophysiology to a point that we have new treatment options for this condition. We've really learned a lot about the autoantigens involved in this condition. For a long time, we did understand that this was an autoimmune condition where antibodies or our body would recognize the thyrotropin receptor as foreign and would form these antibodies against the thyrotropin receptor. We now understand the important role of the IGF-1 receptor. By understanding the pivotal role of the IGF-1 receptor and also understanding how the IGF-1 receptor colocalizes with the TSH receptor on the orbital fibroblast cell membrane, we better understand how autoactivation of this receptor complex can really drive the pathophysiology of the disease. I think understanding that really important part of the pathophysiology has led to new treatment options, and we can talk about those treatment options shortly. We also better understand that this disease occurs mostly in patients that have hyperthyroidism. We understand the risk factors. Of course, we've always known that women are at higher risk, but now we understand things like patients that have vitamin D deficiency are at higher risk. Smokers, patients that receive radioactive iodine, even patients that have hypercholesterolemia may be at higher risk. Even I think patients that have sleep apnea or diabetes could be at risk for more sight-threatening disease. We're understanding the pathophysiology, we're understanding risk factors, we're developing better treatment options, and more than likely, we will find that the prevalence of this disease is grossly underestimated. For a very long time, we've always thought that it was about maybe 40% of Graves' patients can develop this disease. Studies have shown that up to 70% of patients with Graves' disease have changes in their extraocular muscle size on imaging. I think now with this wave of education and marketing and awareness that has occurred in the last, you know, five years or so, patients are coming into my clinic telling me that they have thyroid eye disease. They're seeing commercials during the Super Bowl. They are self-diagnosing themselves, and I think that once we do new prevalence studies, we will find that it's actually much higher than was previously reported. We're learning a lot about the condition, and it's been a very exciting time as an oculoplastic surgeon now that I have better tools in my toolbox to treat these patients and a better understanding of the molecular basis of their condition. Wonderful. The disease presentation is variable, and there's growing evidence that Rundle's curve is an oversimplification. In your opinion, what's the best way to evaluate and address the various manifestations beyond proptosis? Well, certainly thyroid eye disease is not a black-and-white condition, and I think that was one of our errors, was that we were trying to really fit it into this box of either active or stable. Where I went to medical school, we had this culture of treating the patient and not the disease, and it was called cura personalis, treat the entire patient. I think that's really important for thyroid eye disease. I think it's really important that we understand that this is a heterogeneous disease, and it affects our patients in different ways, both functionally but most importantly, emotionally. I think that we really need to consider that in each patient. When I evaluate a patient, I'm really trying to understand what I'm seeing in my clinic and relating it to the pathophysiology of the disease. We know that when the orbital fibroblast is activated, we know that it can release cytokines and hyaluronan and create this inflammatory cascade. If I have a patient in my clinic with pain and redness and swelling, and their symptoms are worsening, then I can understand what is happening on that molecular level in that patient. If I have a patient whose proptosis is worsening or their extraocular muscle restriction is worsening, I can understand that adipocyte proliferation or that myofibroblast proliferation that we know occurs when the orbital fibroblast is activated. For me, I try to just understand the clinical presentation based on the understanding of the pathophysiology, and I try to treat the patient. How does this impact their quality of life? How does this impact their function? If their disease is progressing and it's severe enough to impact their lives, then I feel that I need to treat them. The old dogma of categorizing patients into the activity of the disease and the severity of the disease, I think is a good one, but I think there's a little bit more to it than that, and there's a lot of overlap. What we need to remember is that our clinical judgment and our patient's experience trumps any algorithm that we may have. As we learn more, we're better understanding that it's not just active and stable. It may be a large variety of different phenotypes, more like active and chronic. It doesn't ever go away, and by better understanding the different phenotypes of the disease, I think one day we will be able to treat the patient in a targeted fashion for their specific disease rather than trying to develop a one-drug-fits-all type of treatment scheme. Very interesting. From a patient perspective, what bothers the patient most? What do patients see as their greatest unmet need, or does it vary by patient? I definitely think it varies by patient. I think that from what I can tell in my patients, I think it's the uncertainty that is the most challenging for them. If you could imagine looking in the mirror and seeing somebody else, you know, seeing the person that you've seen every single day slowly change, and feeling helpless and feeling like you didn't know when this would end, how severe would it be, and you see these disfiguring changes, and you also worry, am I going to lose my vision? Also the frustration of sometimes not finding someone that knows how to help you. I think the uncertainty and the disfigurement is usually the most anxiety-provoking. We know that our patients, about 50% of them, develop significant anxiety and depression over the disfiguring changes. We know that our patients have quality-of-life scores on par with patients that are living with emphysema and cannot breathe well or heart disease or inflammatory bowel disease or diabetes. We know how impactful the, both the functional but also the disfiguring sequelae can have on our patients' emotional health. I really think that's the hardest part for these patients. Has our understanding of the treatment paradigms for acute and chronic TED, has that changed now over the last couple years? I don't think that we know exactly the best treatment for the chronic patients at this time. At least I don't know. Maybe, maybe someone else knows. I think for a very long time, we have known that most patients have a biphasic condition where they start with this active inflammatory phase, and then they burn out into this more chronic phase. That's pretty typical of most autoimmune diseases. I think that most of us would agree that we should intervene early during that active phase so that we can prevent the orbital and the ocular sequelae that can happen from the condition. I think that most people agree we should treat patients early in that active phase. Now, the chronic phase is now uncharted territory. For forever, we have had this dogma that we treat patients after the active phase, once they've entered into this chronic or stable phase after they have been stable for six months. That's kind of been the way we've always been taught. The treatment options for the stable phase have always been surgery. Once patients have stable disease, you wait six months, you ask them to wait and wait and wait, and then when that magic six-month comes around the corner, then you do this rehabilitative surgical plan for them. Are there specific patient types that are in need of new innovative treatment approaches? Well, I think that we would have to touch on the current treatment options to really talk about what is lacking at this point. Of course, in January 2020, teprotumumab was FDA approved for the treatment of thyroid eye disease, the only FDA-approved treatment option at this point for this condition. I think that it is certainly been a game-changer for our patients. Not only has teprotumumab, the company and its release brought awareness, education, financial interest, and so many other important aspects to our understanding of this condition. I'll always be thankful for that because now patients, providers understand this disease, and investors are interested in this disease. You know, I think that's the patient wins every time when people are interested in treating the condition. Teprotumumab is certainly, at least in my experience, the most effective drug that I've used for this condition. We know with the clinical trials that it does seem to be quite effective in the active moderate to severe phase. It doesn't work in everyone. The studies show quite clearly that about 83% of patients have an improvement of 2 millimeters or more in their proptosis, but that is not 100%, and 2 millimeters is not enough for everybody. I think it's an amazing step in the right direction. It's certainly better than other treatment options like IV steroids or radiation, in my opinion, for the correctly selected patient. We still need more studies to understand other groups. We talked about this being a heterogeneous disease. You know, what about the sight-threatening patients? What about the mild patients? What about patients with terrible dry eye disease? What about patients with terrible restrictive strabismus or eyelid retraction? The studies have not really shown that teprotumumab is extremely effective, either in these populations or studies just haven't been done in these populations. I think that there are still so many unanswered questions. There are still so many patients that are in need of treatment. I think it's just one step in the right direction, but we need so much more in this area to treat the various phenotypes of this condition, the various severities of this condition, and then the patients that just don't respond to this type of treatment for some reason. That's a great point. When drugs like teprotumumab get approved, patients win. Not only do they get access to the medication, but it raises the awareness of the disease with other patients, with physicians, with other healthcare providers, and even with payers. I'm not surprised to hear you say that you see a large amount of unmet medical need remaining. It's pretty rare for a single medication to be the best drug for every patient. Building on the answer to the last question, what are you looking forward to seeing from the next wave of therapies and development? Well, I think that question is obvious, but I will say that, right now, if you were to look at all of the drugs in the pipeline. The only exciting ones either are replicating the same mechanism of action as teprotumumab. We have a couple subcutaneous IGF-1 monoclonal antibodies, and we have a couple oral or one oral option, monoclonal antibody against the IGF-1 receptor, and a couple IV options. I think that a lot of people are trying to do a similar thing as what has already been accomplished. I think it's exciting that there are going to be other options out there because that'll drive down the price. It'll probably, hopefully allow us to find better options that potentially are safer for our patients, or maybe it'll open up access for our patients. That's always going to be good for our patients. It's unlikely that we're going to find a significant improvement in the efficacy of the drug if we're trying to just change the affinity or the duration or the dosage or the approach of the same mechanism of action. I'm excited about the variety of drugs that are out there, for the reasons that we just discussed. I think that what I'm excited to find out about is going to be the results of the FcRn inhibition, and to see if perhaps by using a different approach, if we might be able to have a better safety profile and if we might be able to treat upstream of the autoantibody activation. If there is a way to treat these patients before the orbital sequela happens, that would be, you know, the holy grail. I'm excited for anything that's going to help my patients get better treatment, more cost-effective treatment, safer treatment. But I also am interested in maybe thinking outside the box and maybe rather than waiting until they are significant enough that it's impacting their life, maybe if we just prevent it from the get-go, or have just a better safety profile, then that will also be really exciting. Well, Dr. Kossler, thanks for spending time with us, and thanks for these valuable insights. Thank you so much. Thanks for having me. I always love talking about thyroid eye disease. It was such a pleasure. Thanks, Bill, and thanks, Dr. Kossler, for providing that overview of thyroid eye disease. I think you'll agree with me that Dr. Kossler did an excellent job painting a picture of TED. Not only capturing how much we've learned about this condition in the last few years, but also highlighting the variable nature of the condition. Moving forward with this discussion on thyroid eye disease, I'll share some research our team conducted to better understand the needs of people with TED. To start, as you heard from Dr. Kossler, TED is a condition with variability. This slide includes pictures of two different people with thyroid eye disease. Both have excess proptosis, but the degree of inflammatory features differs quite a bit between these two people. The patient in the top panel has much more eyelid edema and conjunctival redness than the patient in the bottom panel, and this highlights just one dimension of variability from patient to patient. Now, sharing some of our market research. In this survey of patients currently being treated for TED, we found that even with treatment, patients with active TED expressed that they still make substantial lifestyle modifications. In fact, 80% of participants in this survey reported moderate or major lifestyle modifications that they were making despite ongoing therapy. The patients ranged in age from 29 to 60, reflecting a prime working age range consistent with the broader TED population. The impact on work life was highlighted as particularly challenging. Patients expressed difficulty working on electronic devices, driving, and engaging in social situations. The other insight that was apparent from this survey is that different people with thyroid eye disease have different needs. Consistent with Dr. Kossler's commentary, TED's a heterogeneous disease, and improving proptosis by 2 millimeters is clinically significant and very important. There are other symptoms that can be even a higher priority for certain patients. We believe it's possible that medications with different mechanisms of action will address different symptoms differently and therefore be complementary in the treatment paradigm. To build on this last point, I'd now like to turn over the next portion of this thyroid eye disease module to Dr. George Kahaly. Dr. Kahaly is a professor of medicine, endocrinology, and metabolism, and is chief physician of the Endocrine Outpatient Clinic at the University Medical Center of the Johannes Gutenberg University Mainz located in Mainz, Germany. Dr. Kahaly's lab specializes in the characterization and analysis of autoantibodies and endocrine disorders. In addition, Dr. Kahaly is the lead endocrinologist on a multidisciplinary team treating patients with thyroid eye disease. Dr. Kahaly is kind enough to join us to present current insights into the pathogenic antibodies implicated in the etiology of thyroid eye disease, which may inform new approaches to treat this multifaceted condition. Dr. Kahaly, thanks for joining us, and please proceed. Thank you so much for the kind introduction. It's a pleasure to contribute to this R&D day. In the next 10 to 15 minutes, I would like to introduce you to the pathophysiology of thyroid eye disease, as well as introduce you to the mechanism of action of batoclimab. Now, we do know that the TSH receptor autoantibodies or immunoglobulins are the biomarkers of Graves' hyperthyroidism. This autoimmune thyroid disease occurs very frequently with an associated eye disease called thyroid eye disease. The anti TSH receptor immunoglobulin, which are shown here, are the biomarker of Graves' hyperthyroidism as they bind to the ligand, which is a TSH receptor localized on the surface of the thyroid follicle. Once these autoantibodies, which are specific for the disease, bind to the TSH receptor, they activate the thyroid follicle, leading to increase of volume, to activation of the cell metabolism, and to release of thyroid-related hormone T3 and T4. This is not the end of the story since these TSH receptor antibodies also circulate in the blood and bind to several target cells expressing the TSH receptor. While they bind to this TSH receptor, they activate the orbital fibroblasts as one of the target cells, leading to proliferation of the orbital tissue and differentiation of those fibroblasts. At the end of the day, we do have the clinical phenotype of proptosis and thyroid eye disease. Now, these TSH receptor antibodies target specifically the orbital target cell. The fibroblasts will, once activated, release proinflammatory cytokines, mucopolysaccharides like hyaluronic acid, and the hydrophilicity of these mucopolysaccharides leads to edema, to attraction of water, and to extraocular muscle swelling. These cytokines and these mucopolysaccharides are also secreted from the orbital fibroblasts with the extracellular matrix protein and fibronectin, leading to fibrosis of the extraocular muscles. Fibrosis of these muscles, as well as edema and extraocular muscle swelling, cause diplopia and impaired muscle movement. In severe cases, we do also observe compression of the optic nerve through the swollen tissue. Another changes, and one of the crucial changes in the orbital space, is the differentiation of the orbital fibroblasts in pre-adipocyte and later on in adipocytes called adipogenesis. This differentiation in adipocytes will lead to extracellular fat expansion, to increase of the fat volume within the orbit and of course, to proptosis and lid retraction. All of these changes are caused, o. Course, by the binding of the TSH receptor autoantibody to the TSH receptor. However, we do know in the meantime that besides the TSH receptor, another receptor, the IGF-1 receptor, which is adjacent to the TSH receptor, also plays a major role in the pathophysiology of the disease. Once the TSH receptor immunoglobulins bind to the TSH receptor, there is a crosstalk between the TSH receptor and the IGF-1 receptor, which is mediated by beta-arrestin 1, and the activation of both receptors leads also to activation of several IGF-1 receptor- and TSH receptor-dependent intracellular pathways leading to release of acidic mucopolysaccharide like hyaluronic acid and to, of course, orbital edema. This crosstalk is crucial to the pathophysiology of the disease. Now, a few words regarding the mechanism of action of the monoclonal antibody targeting the FcRn called batoclimab. Additionally to the extensive explanation by Dr. Pete Salzmann, I would like also to show you how this monoclonal antibody is interfering with the pathophysiology of the disease. Now, batoclimab mechanism of action is designed to inhibit the FcRn, potentially fostering the degradation of circulating pathogenic autoantibodies. In details, in the absence of batoclimab, as shown in the left panel, FcRn binds to the anti-TSH receptor antibody, inhibiting their degradation and returning them into the circulation. However, once you add batoclimab, FcRn is blocked from binding to anti-TSH receptor antibody. Subsequently, these anti-TSH receptor antibodies are transported to the lysosome for degradation, decreasing their levels in the circulation. Now, having said this, since we have a degradation actually of these TSH receptor autoantibodies in the lysosome, we do observe less circulating TSH receptor antibody in the blood, less TSH receptor antibody binding to the TSH receptor on the surface of the orbital target cell, less activation of the orbital fibroblasts, less release of mucopolysaccharides and pro-inflammatory cytokines, and of course, inhibition or blocking of the swelling of the orbital tissue. With the help of this monoclonal antibody, we are clearly inhibiting the pathogenesis and the severe course of the disease, inhibiting the release of pro-inflammatory cytokines, inhibiting also the swelling of the eye muscles, and inhibiting, of course, the development of proptosis. This monoclonal antibody, although not tested yet, could play an important role in the management of thyrotoxicosis, of autoimmune thyrotoxicosis, since the treatment of Graves' hyperthyroidism is indeed to remove these pathogenic stimulatory TSH receptor antibody, inhibiting the activation of the TSH receptor and the activation of the thyroid follicle. Thanks, Dr. Kahaly, for providing an overview of the pathogenesis of thyroid eye disease and the proposed mechanism of action of batoclimab as a potential treatment for TED. Now I'd like to kick off a review of selected exploratory analyses from our TED 2B study with batoclimab. As an important reminder, this study was terminated early, and the primary endpoint was not significant. I'm going to share a few exploratory endpoints that we believe are encouraging. While these analyses are not definitive, they do increase our confidence in the anti-FcRn mechanism of action for patients with TED, and they provide part of the basis for our interest in moving forward with further development in TED. To start, in this trial, we observed that batoclimab reduced the total IgG concentration in serum. The observed reductions were dose-dependent over the 12 weeks of treatment, and the changes observed with the 340 mg and 680 mg QW doses were similar to other trials that included these doses. The 255 mg dose was new in this 2b trial. Now, this next slide shows some new analyses. Whereas the prior slide showed reductions in total IgG, this slide shows reductions in the stimulating anti-TSHR antibodies specifically. These stimulating antibodies are quantified using a cell-based assay. The curves show the% change from baseline over time for the three dosing groups. The numbers in the table show something else. Specifically, the table shows the percentage of subjects in each dosing group whose anti-TSHR stimulating antibody level normalized by week 12. Normal here is defined as less than or equal to 140 in this particular assay, where the units refer to the activity in the cell-based assay for the test serum relative to control serum. This data suggests not only a dose-dependent decrease in general for anti-TSHR antibodies but also suggests a dose-dependent response in terms of the percentage of subjects whose anti-TSHR antibodies at levels normalized. Numerically, the dose dependency for this normalization analysis may be stronger than the dose dependency for percentage change from baseline. This suggests that deeper reductions of IgG may be particularly important in thyroid eye disease. Next, I'll review some exploratory proptosis data from the same study. Now, the data on this slide is from week 6 of our TED 2B trial. Although the primary endpoint for this prematurely terminated trial was at week 12. We selected week 6 for this post-hoc analysis because it represents the latest time point with the largest amount of patient data available prior to dosing being stopped due to the voluntary pause. We believe these data suggest a dose-dependent proptosis response at week 6, with a greater than 40% response rate observed in the 680-milligram batoclimab group. This next slide shows CT scan data that I find very intriguing. CT scans were done in a few centers and were interpreted by a specialized central reader. This graph shows data for all subjects who had a baseline CT scan and a week 12 CT scan after completing 12 weeks of dosing. As you can see on the y-axis, the bars show% change from baseline in total extraocular muscle volume. Looking at week 12 CT scan data on this slide, we observe a suggestion of a dose-dependent effect on muscle volume, with a 30% reduction of total muscle volume observed in the 680 milligram batoclimab group. We observed numerically smaller decreases in other batoclimab groups, while placebo subjects increased slightly on average. Diving a bit deeper here into the specific extraocular muscles, we observed relatively consistent CT scan changes at week 12 across the board. These data are from a small number of patients, just those where CT scans were performed at their center, and only for those subjects who completed 12 weeks of dosing. This data, like the prior slide, does show all of the patients who had CT scans at baseline and at 12 weeks. Of course, the primary objective of this study was to measure the effect of batoclimab versus placebo on proptosis response rate at week 12. The endpoints I reviewed today, I'm reviewing now, are post-hoc and exploratory. Nevertheless, we believe that these data are encouraging for continued development of batoclimab in thyroid eye disease. We also believe that these data suggests that higher levels of IgG suppression may be necessary, as suggested by the anti-TSHR data, by the proptosis response data at week 6, and by the changes in extraocular muscle volume at week 12. Based on all this information, what do we see as the potential market opportunity for batoclimab in TED? The answer is that we believe there is an exciting opportunity with an addressable market size similar to other rare diseases driven by pathogenic IgG. The estimated annual incidence of TED in the U.S. ranges from 15,000 to 20,000 new patients per year. We believe this is the minimum addressable market size for teprotumumab in active TED. I say minimum because epidemiologic studies may be underestimating this active population. As Dr. Kossler mentioned, the availability of a highly effective treatment in teprotumumab is leading to market development and to increased recognition of TED. In fact, we believe that the use of teprotumumab will continue to grow, partly due to this increasing awareness among people with underlying Graves' disease. Now, the interesting thing about treatments for TED is that they are likely to be labeled for a specific duration of use. This is true of teprotumumab in its label, and we expect it will be true for new therapies as well. We believe this creates a need for complementary therapies in TED. Taking all this together, we see a nice range of potential market sizes for a complementary therapy with three distinct categories of unmet need. The first group is made up of patients with moderate to severe active TED who are on the milder portion of the spectrum. The second group of patients are those who achieved a good response from the teprotumumab, but whose symptoms are still severe enough that they require additional therapy even after responding to teprotumumab. The third group is made up of patients who respond well to teprotumumab, but then whose symptoms relapse after some period of time off medication. Taken altogether, these three groups of patients with active disease represent an addressable market size that we estimate is between 7 and 18,000 patients for complementary therapy. Said another way, that represents 47%-90% of the incidence value for moderate to severe TED in general. Just to make an important point again, the reason this number and percentage are high is that we believe many patients could benefit from both medications taken serially, not taken concomitantly. This is a big part of what this slide shows. In summary, we're encouraged by recent innovations which have fostered increased awareness and improved understanding of the biology in TED. Armed with deeper insights into our own product profile, as well as a solid understanding of remaining patient needs, we're enthusiastic about the potential for batoclimab in this disease space. We heard today that TED is a complex heterogeneous disease with varied presentations. Given this variability, as well as the likelihood of fixed-dose duration and product labeling, we believe that there are many patients who could benefit from complementary treatment approaches. As we heard during this session, batoclimab constitutes a potentially novel treatment option. The serological, clinical, and imaging data, though exploratory in nature, make us enthusiastic to continue to develop batoclimab in thyroid eye disease, especially given the deep IgG suppression that has been observed with batoclimab. We believe thyroid eye disease is likely an indication that requires an anti-FcRn capable of delivering top-end IgG suppression. With that, I'd now like to transition our next section of today's agenda, which is myasthenia gravis. We'll begin with a panel discussion and then have a chance to hear directly from someone with MG. After that, I'll review how we're planning to differentiate batoclimab and MG. Let's start the panel discussion now. In this next section, I'm excited to be joined for a discussion on myasthenia gravis by Dr. Katherine Ruzhansky and Dr. Nicholas Silvestri. Dr. Ruzhansky is a clinical neurologist, associate professor of neurology, and director of the EMG lab at the Medical University of South Carolina. Dr. Silvestri is a clinical neurologist, associate professor of neurology, and assistant dean for student and academic affairs at the University at Buffalo. I want to thank you both for taking some time to discuss myasthenia gravis today. Dr. Ruzhansky, I'd like to open with a question for you. Myasthenia gravis is a condition characterized by voluntary muscle weakness. Of course, that is a gross generalization, as the actual clinical presentation of myasthenia gravis is so varied. Recognizing that not all muscles are impacted equally in all patients, what are some of the common patterns that you see clinically? Some of the common weaknesses that we see could be limb weakness, so such as arm or leg weakness, or axial weakness. Somebody may have trouble holding their neck up, and then patients who may have bulbar weakness, so that's trouble with speaking, chewing, or swallowing. Some patients have all of those symptoms, and some have more bulbar predominant, some have more limb predominant, and that just depends on the case. Among the limbs, is there a variation, upper versus lower, or is it usually one or the other, or what do you see there? It could be, you know, in some people it may be more predominantly the legs, in some it may be the arms, and in some it may be both. Sometimes the weakness varies as the day goes on, and people may experience more arm weakness one time during the day and then more leg weakness another time. It's characterized by fatigable weakness and by the fact that it can change as the day goes on. Yeah. That fatigable piece, that's interesting. I've heard people with myasthenia talk about that they have to be careful sort of not to use too much of their energy. They might be okay at the beginning of an activity and then towards the end feel very weak. Is that something you see commonly? Yes. They both experience fatigue, which is the generalized feeling of, you know, inability to go on, just fatigue, but also fatiguability. With repeated activities like raising arms up, they may experience more arm weakness. For example, if somebody tries to, you know, reach over to put luggage in an overhead bin, for example, if they try to do that, they may have trouble because their arms become fatigued with that activity. Yep. Yeah. Makes sense. Dr. Silvestri, turning to you. I recall fondly from medical school that neurologists are sort of the masters of the physical exam. Are there particular components of the physical exam that you find especially helpful in diagnosing myasthenia gravis or in assessing its severity? Yeah. Thanks for the compliment, Pete. Yeah. I think, you know, much like we just talked about fatigue and fatiguability, we can see that on exam. You know, as Dr. Ruzhansky pointed out, you know, certain muscles tend to be more affected than others in myasthenia. The ocular muscles, the bulbar muscles, the limb muscles. It differs from patient to patient. On exam, looking for things like eyelid ptosis, or dysconjugate gaze in the eyes, looking to see if, as you hold a finger up, to see if people's eyelids droop a little bit more or their gaze becomes a little less centered, and they start to see double. And then again, looking at their muscle strength. Ordinarily, when we do an exam for most patients, we're just kind of evaluating strength at one time. In the cases of myasthenia, we often check for that fatiguability. We often have people try to hold their arms up or hold their legs up while we push on it for several seconds to see if there's that element of fatiguability. When I see those things in the appropriate clinical context, that makes me really think about myasthenia. Another neat little trick we can do is we can do what's called an ice pack test. We can put an ice pack on a patient's ptotic lid, for example. If the lid transiently improves, the droopiness transiently improves, that's also very suggestive of myasthenia. What's the basis for that improvement with the cooling? Yeah. The thought is that it reduces the action of acetylcholinesterase, which allows acetylcholine to sit in the synaptic cleft a little longer to transiently improve strength. That's the leading theory. I think that some basic scientists may take issue with that, but that's the one I'm sticking by. That's a little, I don't know, a little physical chemistry in the clinic there, huh? Exactly, yeah. It's going back to your, college days, right? Oh, that's interesting. Dr. Silvestri, although people with an autoantibody to the acetylcholine receptor represent most people with MG, there are other autoantibodies that have been identified. Of course, also there's a population of true seronegatives. Do you see different clinical presentations based on the specific autoantibody present? Yeah. You know, speaking generally, because every case is a little different, every patient's a little different, those patients with MuSK myasthenia, which probably comprises about 7% of the total population, tend to have a more severe form of disease that tends to affect the bulbar muscles a little bit more predominantly. In fact, in severe cases, these patients can almost look like they have ALS. Mm. until they're diagnosed and treated. It's interesting, there's a little bit of a geographical variation of the incidence of MuSK myasthenia. Both in North America and Europe it's been known to occur a little bit more commonly in southern latitudes than northern latitudes. It's almost like the opposite of MS, actually. Yeah, MuSK is about 7%. LRP4 is a more recently diagnosed or recently described antibody, which tends to actually have a milder phenotype than your typical acetylcholine receptor positive patient or your MuSK patient. The seronegative patients, so LRP4 is about 1%. The seronegatives comprise the rest, again, probably about 7% of the total. The acetylcholine receptor antibody is making about 85% of the population. That's variable. I think that probably they resemble the acetylcholine receptor positive patients the most. They're the more challenging diagnoses to make. I mean, you know, if you have a patient with acetylcholine receptor, MuSK receptor, LRP4 receptor, we can check those in blood. We can check those and get those results back in about 10 to 14 days. The seronegative patients, we have to do the blood work, and then, if we still have a high index of suspicion of the disease, we rely on sophisticated electrodiagnostic testing, specifically single fiber EMG, and that's how the diagnosis is made in those cases. Right. 'Cause I guess the general EMG doesn't really help you too much. You have to do the more specific EMG. Is that right? Right. Yeah. Your kind of standard variety or standard nerve conduction studies, EMG, patient could have severe myasthenia, and that would be normal. You have to really do the more sophisticated tests like repetitive nerve stimulation or single fiber EMG. Dr. Ruzhansky, switching maybe gears a little bit to treatment. Thinking about someone who is moderately to severely impacted by MG and needs more than just symptomatic care. How do you decide between the various treatment options? We do have one set of guidelines, which is, it was published in 2016, which is the International Consensus Guidance, and it was recently updated in 2020. Overall, the general approach is that once somebody has moderate burden of disease, we do entertain corticosteroids plus or minus a nonsteroidal immunosuppression, and we have oral agents for that. They are not FDA approved for the indication, but there's studies that show that they are effective in myasthenia. That was our general approach to care, and we would also treat patients with intravenous immunoglobulin and therapeutic plasma exchange because the nonsteroidal immunosuppressant drugs that are taken orally do take a long time to become effective. Some take up to a year. That was the general approach to care up until a couple of years ago when other therapies became available. We have complement therapy, the commercial one, eculizumab, which I do reserve for patients that are quite severe and have the AChR antibody. Also efgartigimod, which is an FcRn drug, became FDA approved a couple of months ago. So those are newer agents, but overall, we do like to have patients on oral medication or on treatments that are not such a treatment burden with frequent trips to the infusion center or, you know, IV access. But it really has to depend on the patient. You know, is there a contraindication to the nonsteroidal immunosuppressant? Is there a contraindication to some sort of infusion therapy? Are there concerns about infections or compliance? It's actually a very complicated thing to pick a therapy for each patient. We do have the guidelines, as I mentioned, but it's an overall general approach. Really, it comes down to picking a treatment and individualizing care for each patient, depending on other comorbidities and various other factors that come into play. Yeah, that makes a lot of sense. I know from some of our prior conversations, where we've spoken about mode of administration or route of administration, that can play a role. You recently shared with me a little story, maybe you don't mind sharing it again for the group, about you sort of spent a little bit of a day in the life of, I think one of your patients going to infusion centers, and maybe if you don't mind sharing that experience. I thought it was really instructive. I actually did it again today. I have a patient who's on infusion therapy every two weeks, and I just went down there to say hi and do a very quick assessment. I've been doing this every two weeks for six months, and I'm exhausted going there just to say hi every two weeks. This person gets an IV every two weeks, has to come drive here to get this infusion. I thought to myself, "Wow, this is how they live their life. I'm just here saying hi once every two weeks, and I'm exhausted just doing this. It's on my calendar. It's a to-do." The treatment burden with these infusion therapies, although a lot of them are very effective, this gets old very quickly, as you may imagine. The unmet need is certainly treatments that are effective, but the treatment, the mode of administration is something other than intravenous access. Maybe kind of talking about the same question from a little bit different angle, Dr. Silvestri. I think you had mentioned, you know, some of the other considerations that you take into account when choosing a therapy, comorbidities, patient age, things like that. Can you talk us through a little bit your process for selecting therapy in moderately severely affected patients? I think, you know, I echo what Katherine said earlier in terms of, you know, the consensus guidelines. Frankly, you know, for those of us treating patients with myasthenia on a regular basis, those more or less just codified what we've been doing. The great thing about treating myasthenia gravis is it's not really a cookbook. It's not a recipe for every patient, right? You have to take other things into consideration, patient age. Younger patients, especially women of childbearing age, you have to take into account, you know, if they wanna become pregnant or if they accidentally become pregnant. Some of these agents are not great for people to be on when conceiving. On the other end of the spectrum, older patients with a lot of medical comorbidities, a lot of these medications can, you know, exacerbate or even cause some comorbidities, or interact with the medications that people need to be on for these comorbidities. You know, overall patient quality of life, right? You have to balance the severity of the disease. How is the disease actually impacting one's life? And how are the treatments impacting one's life? You know, if we're able to make the myasthenia better, but it's at the cost of creating comorbidities or leading to inconvenience, such as what Katherine talked about with you know, routine repetitive infusion therapies or perhaps the need for a port placement and people that need infusion therapy that have poor venous access and the like. These are all things that have to be taken into account, when you know, you're coming up with a regimen for a particular patient. Makes a lot of sense. Thinking about the way people think about different treatments, we've conducted some market research with people who have moderate to severe MG recently who are on therapy. The goal of this research is really just understand how both the disease and the therapy impacted their lives. They run a lot of different treatments, not surprisingly in a diverse group like that. Perspectives varied a lot. There was one area where their perspective was pretty uniform, and that was that a fairly large majority of people with MG said they would prefer continuous medication to control their symptoms, maybe going up and down a little bit as the disease waxes and wanes versus intermittent treatment only when their symptoms got worse. Dr. Ruzhansky, does that resonate with your clinical practice? I think so. I think what the patients meant is they don't like to have maybe peaks and valleys, but like to have steady improvement and also to take out that uncertainty, you know, when will I get worse if they're off therapy. I think that makes sense and that was the sentiment that they wanted to be on something because if the disease is active, they don't want to wait until it becomes very, very active and then get a whole bunch of medications. I think that makes sense, and I think the way that question. I don't know how it was asked, but you know, I think most patients don't want to be on anything. They wanna not have the disease. I think what the question was asking is they want to be on a steady regimen of medication to keep the disease under control and not have, you know, like these peaks and valleys. It makes sense what the answers were. Yeah, you're right. I mean, this was a group that was fairly affected, and I think the days of them thinking they might get off all their medications, you know, was probably in the rearview mirror. It was a matter of sort of the more intense therapies. Do they take a continuous medication at some level or only intermittently and when we dug into it a little bit, it really seemed to be this uncertainty of a flare that was driving the reluctance for intermittent therapy. As I think you pointed out as one of your reasons why that might have been the case. Maybe just one other question on study design, Dr. Silvestri, for you, and it's in, you know, with this idea of dose titration. We have a unique design element to our phase III trial, and namely, we're using an induction maintenance approach. Most of the phase III trials to date have been done with a single dose or single dosing regimen kind of straight across, either get randomized to treatment or placebo, and, you know, whatever the treatment is, it's sort of the same for everybody who gets randomized to the treatment arm. What we're doing instead is initially treating people who be randomized to sort of two higher doses during the induction period and then in the maintenance period. The one of those sort of medium dose will be carried through, and then we'll have a lower dose as well. The thinking is that in the initial period when somebody has worsening symptoms that are requiring changing their therapy or enrolling in a trial, the main goal is getting the symptoms under control. Then once the symptoms are under control, the main goal shifts to benefit risk and sort of getting as much benefit with the least amount of medication, more tolerable, maybe better long-term safety. Hence studying that step down in dosing. Does that sound like information that would be valuable to you as a treating physician? I mean, absolutely, Pete, and I think, you know, to an extent, that really resonates with me because we're doing a lot of that already, right? We do that with steroids, for example. A patient comes in with myasthenia that's quite severe. We wanna safely put them on a decent dose of steroid to get them to well-controlled, but, you know, long-term steroids is not tenable, so we do taper over time to try to find that right balance. Same thing really with IVIG for myasthenia and for other autoimmune neurological disorders. We're typically starting with a higher dose, and then over time, you know, reducing the dose or spacing out the intervals. Really in some work that I've published and others in other centers too, even with some of the oral immunosuppressants, we know that with perhaps longer-term disease control, we can reduce doses to try to balance that risk and benefit. I think the approach you've taken really, you know, has many parallels with what we're doing. Certainly if the medication is efficacious and safer than some of the medicines I mentioned, that's a very welcome addition to the armamentarium. Excellent. Well, we can probably go on even longer. This is a really fun discussion. But we've managed to cover many, I think, interesting topics around myasthenia gravis, both the diagnosis of the condition, some of the root causes from a pathophysiology standpoint and the treatments, and also brought in the perspective of people living with MG through your eyes as treating clinicians. I really appreciate your time today, Dr. Ruzhansky and Dr. Silvestri. To expand on the discussion with Dr. Ruzhansky and Dr. Silvestri, we're very pleased to share a short video that features the experiences of someone living with myasthenia gravis. In this video, Johnny was kind enough to share some personal accounts of her journey with MG. Hi, I'm Johnny, and I have myasthenia gravis. It's a constant battle to figure out what it is that your body needs. The symptoms that I manage now are shaking. My fingers get weak if I use them too much. Things like pulling, twisting. My neck and mouth are weak. I have problems sometimes swallowing or speaking clearly, and then overall weakness. The way that I set myself up for success is breaking my day into pieces. I always try to have a plan B. I try to use things that are the most efficient in the house, things that are lightweight and not too heavy. Those little things make a really big difference in the amount of energy that I have left at the end of a task. There are certain things that will wear me out, and I'm okay with that. It's a cost-benefit thing all the time. Wow. I'm so grateful that Johnny shared her experience with MG with us. She's truly inspiring. I was struck by her tenacity and positive outlook. Even though that video is short, Johnny does an amazing job of helping us look beyond the technical scales like MG-ADL and QMG. Her story clearly shows the types of daily adjustments that many people with MG need to make. She said at one point, it's a constant battle to figure out what it is that your body needs, and that statement captures the uncertainty that many people living with MG have described to us. Fortunately, neurologists are very well-trained in nuance. Their diagnostic expertise plays a key role in treating neuromuscular disease generally, and in treating myasthenia gravis specifically. In this context, the traditional approach of selecting a single dose or a single dosing regimen to study in phase III seems too blunt, too one size fits all. On the other hand, an intermittent on and off approach may not provide the certainty of a continuous treatment approach. With all this in mind, we designed our phase III trial to be unique and to differentiate batoclimab. For someone with moderate to severe MG who is a candidate for a new medication or for a clinical trial, we believe they want a few things. First and foremost, they wanna get better. People in this phase of their disease course are quite impacted by MG, and so they want to achieve a big improvement quickly. We designed the induction period of our trial to maximize speed and depth of batoclimab's efficacy, which we believe has the potential to be best in class. Patients will receive 12 weeks of continuous dosing during the induction period. Efgartigimod was observed to have separated nicely from placebo with 4 weeks of initial dosing. We believe continuous dosing can do even better, particularly when it comes to the percentage of subjects experiencing a larger clinical response. Once people with MG have improved on treatment, they wanna stay better. They wanna avoid flares. Many patients would appreciate the option to lower their treatment dose a bit during the chronic phase to minimize the potential for side effects associated with immunosuppression, which can occur with a wide range of medications used to treat MG. Physicians also shared with us that maintaining disease control can be easier than getting the disease under control initially. As I discussed with Dr. Silvestri, this leads to a common approach for many immune modulating therapies, namely in an induction and maintenance approach, where higher induction doses are used to maximize initial clinical control, while lower maintenance doses are often used to optimize benefit risk during the chronic phase of therapy. Finally, after a period of steady disease control, often at a lower dose, we expect that many patients and their physicians would really appreciate having multiple approved doses or dosing regimens to enable fine-tuning to match the waxing and waning course of MG. Our phase III trial is uniquely designed to generate this data and thereby differentiate batoclimab. This next slide summarizes our overall program approach. The induction and maintenance design is actually a well-established approach for new therapies and other autoimmune diseases, and it's common clinical approach, as we heard from Dr. Silvestri, for many older medications used in MG. At the same time, it's actually a first among recent trials in myasthenia gravis. This approach provides the potential for maximum initial and potentially best in class efficacy driven by deeper IgG suppression. It allows this to be realized compared to other anti-FcRns that are approved or still in development. Having then achieved maximum initial efficacy, we believe that lower doses have the potential to maintain this efficacy. We also expect these lower doses will reduce the impact on LDL. Finally, during the long-term extension of the trial, flexible dosing will be studied to optimize treatment over time as the disease waxes and wanes. We're not aware of any other anti-FcRn program designed to generate this kind of data package. We also believe batoclimab is uniquely suited to demonstrate this differentiated patient-centered approach based on the broad range of IgG suppression that may be achieved via simple subcutaneous injection device. Moving now from the conceptual to the specific, this slide provides more detail on our design. Approximately 200 subjects will enter the trial and be randomized into one of three blinded arms. 680 milligrams of batoclimab delivered weekly, 340 milligrams of batoclimab delivered weekly, or placebo delivered weekly. Period one will last for 12 weeks, and the primary efficacy endpoint will be measured as the mean change in MG-ADL through those 12 weeks. As is common with induction and maintenance trials, subjects will then be re-randomized at the end of period one. Periods one and two are fully blinded, with all subjects in each period receiving the same number of weekly injections. Whereas period one tests the ability of two doses of batoclimab to deliver higher efficacy than placebo, period two tests the ability of two dosing frequencies of batoclimab to maintain efficacy. The primary endpoint for period one and the key secondary endpoint for period two will both be restricted to AChR antibody positive patients with additional analyses run for the entire population and for AChR antibody-negative patients. Bottom line is that we believe this design has the potential to optimize batoclimab's specific attributes, namely the broad therapeutic window and simple subcutaneous administration. The trial was designed around 340 milligrams delivered weekly as the anchor dose, but also tests a higher dose in the induction period and a lower dose in the maintenance period. If approved, we believe batoclimab will have unique and differentiating data for clinicians to optimize the treatment of their patients with MG. With that, I'm excited to introduce our next speaker and move the discussion to warm autoimmune hemolytic anemia. Dr. Tucker is a consultant hematologist at the Royal Cornwall Hospitals NHS Trust. He's a fellow of the Royal College of Pathologists and a member of the Royal College of Physicians. Today, Dr. Tucker will review warm autoimmune hemolytic anemia, an autoantibody-mediated condition that lacks any approved therapies. Dr. Tucker, please proceed. Hello, my name is Dr. David Tucker. I'm a consultant hematologist at the Royal Cornwall Hospitals NHS Trust in southwest England in the United Kingdom. I am here to give you an overview of warm autoimmune hemolytic anemia, which is sometimes abbreviated to WAHA. These are my conflicts of interest, and the picture is just to give you an idea as to where I live in the southwest of the U.K. Warm autoimmune hemolytic anemia really does represent a very complex but fascinating and challenging disease. It is an autoimmune disease. It's caused by antibody-mediated destruction of red blood cells. It can be unpredictable and potentially life-threatening diagnosis. It's a relatively rare disease. There are relatively few large data sets to guide our management of it. The mainstay of management initially is with immunosuppression, with corticosteroids, and these are usually effective at getting the disease under control, but they carry significant toxicity burden. Patients are often unable to get off steroids in the long term or relapse after the steroids have been discontinued. And beyond steroids and a monoclonal antibody called rituximab, there really is a lack of data and evidence for other therapies. Therefore, we would regard clinical trials as recommended to enroll patients to identify the optimal choice and sequence and combination of drugs. Before I go into autoimmune hemolytic anemia, I thought it would be nice just to give you a bit of background on red cell physiology and biology. As you know, red blood cells are made in the bone marrow and then travel around the circulation, transferring oxygen and carbon dioxide, for around 100 to 120 days before they are recycled in the liver and spleen. The red cell is a unique cell in the body, because it has a very unique shape. It's a, what's called a biconcave cell, which is to increase its surface to volume ratio. This is an electron microscopy slide showing a red cell in comparison with a platelet in the middle there and a lymphocyte to the right. In order to maintain this shape, it has a very complex and elegant membrane structure. Here we have the phospholipid bilayer on the outside, and then underneath that is underpinned by a very sophisticated scaffolding layer. That is often damaged in autoimmune hemolytic anemia. The idea behind this membrane is that it allows the red cell to pass through very small gaps, what's called tank treading, through very small capillaries, and remain intact. If you look down the microscope at a red cell, you would see this nice pink circular cell with a pale center, where there's less hemoglobin. If a cell is damaged in autoimmune hemolytic anemia, the antibody damages the outside of the cell or destroys it completely. What happens is the cell loses its elegant scaffolding and becomes spherical, which is herein demonstrated on electron microscopy and on plain light microscopy. These cells are called spherocytes. How does warm autoimmune hemolytic anemia work? It's antibody-driven, and the antibody is an IgG antibody, represented here in this top window here, which is a cartoon showing where these white blood cells inside the bone marrow are generating IgG antibody. Most of the time, IgG antibody is directed against microbes or parts of infectious microbes or viruses in order to protect us from infection. Occasionally, one of these antibodies can be directed against our own tissues, such as the outside surface of a red cell membrane. That is the culprit in autoimmune hemolytic anemia, warm type. What happens is the antibody coats the red blood cells. The red blood cells then circulate through the body and enter the spleen and liver, the main sites of the immune system, where they are recognized by macrophages, which recognize any cell coated in antibody. The macrophage then engulfs the red cell and destroys it, releasing its contents. Occasionally, one of these red cells will get through, damaged but intact, and those are called spherocytes. This causes anemia, and it causes new red blood cells to be made in large numbers, what are called reticulocytes. It causes an autoimmune test called a direct antiglobulin test, which is a positive test for this disease, as well as release of the contents such as bilirubin, enzymes, lactate dehydrogenase, depletion of scavenger molecules which go around the body mopping up free hemoglobin from the red cells, and of course, the generation of spherocytes. One of the interesting new breakthroughs in this area of research is the recognition that as well as this process going on and antibody being generated, antibody is actually recycled. Antibody is recycled from macrophages by being removed from the damaged red blood cell in these little vacuoles here attached to what's called a neonatal Fc receptor, and then recycled back into the body for further red cell destruction. The molecule, the monoclonal antibody batoclimab works by blocking this neonatal receptor and preventing the IgG antibody from reentering the circulation, therefore, really depleting the amount of antibody in circulation. What causes warm autoimmune hemolytic anemia, and who is affected? Well, actually, for 40%-60% of cases, we don't really know what causes it. It's what's called idiopathic. For the rest of the cases, there are a variety of diseases which are associated, either other autoimmune diseases like systemic lupus erythematosus, immune thrombocytopenia, or even rheumatoid arthritis. Occasionally, other hematological diseases, such as chronic lymphocytic leukemia or lymphoma. Sometimes infections can trigger an autoantibody, such as mycoplasma. Who does it affect? Well, it's a relatively rare disease, about 1-3 per 100,000 people are diagnosed with it per year. It carries a prevalence of under 1 in 1,000 in the population. Which is equal to around about 40,000 people in the US at any one time who might be diagnosed with the disease. In terms of what the patient experiences and how they present, it's often quite a pernicious, gradual onset. It presents with anemia, essentially. This is often a gradual increase in fatigue, shortness of breath, and sometimes patients say that it's been commented that they're becoming a little jaundiced around the eyes. That's a mild onset with a hemoglobin level of above 10 grams per deciliter. As more hemolysis takes place and the bone marrow is less able to compensate for those red cells being destroyed, the anemia becomes more profound, and breathlessness and fatigue on moderate exertion might occur. Patients sometimes develop signs such as ankle swelling, palpitations or more obvious jaundice. As it becomes more severe and uncompensated, the breathlessness and fatigue becomes present at rest, and patients often become light-headed on standing. Occasionally, it can become life-threatening, where there is not enough red cells to carry oxygen to key tissues such as the cardiac muscles, causing chest pain and cardiac ischemia. Because warm autoimmune hemolytic anemia is a relatively rare disease, there are few large trials, clinical trials to guide exactly how we manage it. Therefore, management is mainly based on expert opinion. The cornerstone of management is with immunosuppression, with corticosteroids such as prednisolone in the first instance. Because immunosuppression is used, and because the disease does carry other complications, it does have some serious effects. There is historically a treatment-related mortality rate between 8%-15%. The major issue that we have with our patients is that most patients become dependent on immunosuppression, often steroid dependent, and that can be a real challenge, obviously, for the patient and for the physician. This gives you some idea as to how patients respond to first-line treatment with corticosteroids. High-dose corticosteroids, around 80% of patients will respond and their hemolysis will improve, but only around 20% will remain in remission when the steroids are discontinued, sometimes a year after starting. about 40% of patients remain in a sort of a long-term control, but with long-term steroid use. These side effects of steroids are significant. As we can see here, the side effects are anything from new onset or worsening of diabetes to thinning of the bones causing osteoporotic fractures. Peptic ulcer disease is more common in patients on steroids, as well as the unpleasant side effects such as insomnia, weight gain, and mood disturbance. As you can see from this graphic here, this is a graphic of patients on long-term steroids. Even at low doses, which are represented by the green diamonds here, they do experience increased risk of side effects, even at low doses of complications of steroids over time. Where steroids work for a bit, but then may stop working or where the patient relapses their disease, a second-line treatment which is often employed these days is a monoclonal antibody called rituximab, which acts by suppressing the production of antibody in the B-cells, the lymphocytes in the immune system. Again, a lot of patients will respond initially, about 70%, and take a few weeks to respond. But relapses are common. Forty to 50% of patients may relapse after 30 months or, you know, two or three years. Many patients then go on to requiring further therapy. The long-term remission rates are also not well known because this is a relatively new therapy. As you can see here, this is a Kaplan-Meier curve to show the relapse rates. In blue are the patients who remain in remission on rituximab. As you can see, the level reduces with time, although perhaps less so than patients on placebo. Rituximab, again, has side effects. It is an immunosuppressant. It can cause low white blood cells as well as increased risk of pneumonia and other infections. Again, it's not always available everywhere in the world. Beyond rituximab and corticosteroids, there really is a lack of evidence for what to provide for patients third line. Historically, one of the treatments has been surgical removal of the spleen, and patients often do respond, but responses are unpredictable. Some patients won't respond to that. It's an irreversible surgical procedure and not definitively curative. There is a significant risk of life-threatening infection after splenectomy, as well as thrombotic complications. With that, it carries a significant mortality risk. Nowadays, we often employ what are called steroid-sparing immunosuppressants, azathioprine, cyclosporine, or mycophenolate. The evidence for these is very unclear, often from small case studies or case series, and no large trials really are available. For more severe refractory cases, occasionally, chemotherapy or even stem cell transplantation has been used, although these are based on case reports, and they come with quite high levels of complication rates and mortality rates. There is certainly a need for new therapeutic options in WAHA. In long-term studies of patients over three to four years, we know that less than half of them remain in remission off treatment. About a quarter of patients remain on low-dose steroids, and another quarter have ongoing diseases requiring higher doses of steroids or other immunosuppressants. This comes with serious risk of ongoing complications. The risk of deep vein thrombosis and pulmonary embolus is significant, as well as an excess mortality rate. In summary, warm autoimmune hemolytic anemia is a rare disease. There are a few large datasets to guide our management. Because of that, there is an unmet need because a large proportion of patients remain on immunosuppressants long term. These have a significant side effect burden to the patient, and there really is a lack of evidence base beyond second-line treatment. That's why, as physicians, we would encourage patients to enter clinical trials at a relatively early stage in this disease. This is a list of my references for this talk. I would like to thank you for your attention. This is an example of Another example of Cornwall, where I live, taken from my canoe. Thanks a lot, Dr. Tucker. I'd like to highlight now why we're really excited about the potential clinical benefit for batoclimab in warm autoimmune hemolytic anemia. In thinking about the treatment paradigm, as Dr. Tucker mentioned, you're really looking at primarily high-dose steroids, which work but need to be tapered because you can't treat patients long term with high doses of steroids. This steroid tapering leaves many patients with recurring hemolysis and the associated symptoms. Repeated steroid tapers can also be very unpleasant. After a steroid taper with a relapse, many patients end up in this zone where they're on a moderate dose of prednisone or other steroid, with all the risks associated with steroids, and they still may need occasional blood transfusions. They're still not back to normal from the standpoint of their hemoglobin. Really a long way from their treatment goals. As Dr. Tucker described, this appears to be a pretty classic autoantibody-driven disease. Based on this biology and based on the large unmet need, we're excited about the potential for batoclimab in this condition. Now I'll pass it over to Bill to introduce our next topic. Thanks, Pete, and good morning again. Recognizing that across indications, patients want reliable treatment options that can deliver on both efficacy and safety, we've engaged multiple scientific leaders in lipid metabolism to understand how and when hyperlipidemia is best managed in clinical practice. To start, I'd like to introduce Dr. Michael Davidson to present an overview of cholesterol management. Dr. Davidson is a clinical professor of medicine and director of preventive cardiology at the University of Chicago Pritzker School of Medicine. Dr. Davidson, please proceed with your presentation. Yeah. Thank you very much. To begin with, I want to put in context that LDL is a risk factor and why we think about it when it comes to the effects of different drugs or how we modify the risk with our therapies. It's one of the most modifiable risk factors for cardiovascular disease, but it's not the only one. We also think about tobacco, sedentary lifestyle, high blood pressure, diabetes, and those things we can modify in addition to elevated LDL cholesterol. We understand that from the epidemiological perspective, it's one of the most powerful predictors of cardiovascular risk. It's well understood that the cholesterol does accumulate in arterial wall, leading to atherosclerosis, but this is a process that occurs over many years. It's now well-recognized that it's actually ApoB-containing lipoprotein particles, LDL being the most predominant of the type of ApoB particles. They penetrate the arterial wall, they stimulate a foreign body immune response leading to macrophages engulfing these oxidized LDL particles, leading to foam cells and ultimately to atherosclerosis. When we lower LDL, we reverse this process, and we ultimately can significantly modify the development of atherosclerotic cardiovascular disease. Here's a timeline of the process. As I mentioned, it's a process that occurs over many years, ultimately leading to plaque rupture and thrombosis and cardiovascular events. It's still the leading cause of death by far is cardiovascular disease. Here's a slide that summarizes about 70 years of research. Observational data showing the higher the LDL, the higher the cardiovascular risk. Came experimental data showing that when you fed animals cholesterol, you developed atherosclerosis. When we reversed that process, you reverse atherosclerosis. Came the interventional studies, which showed that lowering LDL with certain therapies, statins and others as well, lead to reduction in cardiovascular risk. Ultimately, more recently, been genomic studies confirming that no matter how you affect LDL by different mechanisms or targets, it's associated with a higher cardiovascular risk. Came the understanding about how do we modify risk, and the statin trials were, in hindsight, over the last 20, 30 years, has been a tremendous breakthrough in how we have modified risk of elevated LDL cholesterol. Starting in 1994, the 4S trial being the most prominent, showed that lowering LDL with simvastatin resulted in a total mortality reduction. Subsequently, there's been many other trials to show that statins do, in fact, reduce cardiovascular events. The lower we bring LDL down, the lower the cardiovascular risk. This is a well-documented linear relationship between the on-treatment LDL levels and cardiovascular events, but also the magnitude of the absolute LDL lowering and cardiovascular risk. The genomic data, the more recent data, what's important about that is it does highlight that it is not just statins that reduce risk, but other genomic polymorphisms that are associated with lower LDL have the same associated cardiovascular benefits. It doesn't matter how you lower LDL, but what matters is getting the LDL levels low to reduce cardiovascular events. The other important element, we can almost model this out exactly, is the absolute LDL lowering in milligrams per deciliter and time, how long we treat or how long the LDL levels are elevated, the so-called cholesterol years phenomenon. It's a very long duration before you see both the benefits and the risk of LDL cholesterol. This slide highlights that both of those factors, you can model almost exactly what the adverse event would be of higher LDL over time and the other way around with the absolute benefit of lowering LDL over time. Lastly, this is how we establish guidelines, is that we wanna match the intensity of LDL lowering to the risk of the patient. Everyone has a different risk profile, and the higher the absolute risk, the greater the absolute benefit of lowering LDL cholesterol. That's how we think about each patient. It's in context of what their risk factors are, their age, and then we can decide, you know, what approach we should have when it comes to LDL-C reduction. The guidelines have stratified these four high-risk groups, most important being those with established clinical atherosclerotic cardiovascular disease. We wanna get their LDL levels down at least 50%. Now goals have started to reemerge as targets of therapy. We have the primary prevention, which is more complicated because we take patients' LDLs over 190, wanna treat them. We think about how we do a calculated risk using a risk calculator to determine which patients should be more intensively modified. This is a discussion with the patient in which we do discuss what their preferences are regarding treatment. Here's an example of absolute risk and how we determine the benefit. This is a 45-year-old female, non-smoker, non-diabetic patient, low blood pressure. LDL is 8 millimoles or roughly 320 milligrams per deciliter, so very high LDL. Over 10 years, her risk of an event is only 2.3%. If you lower that LDL, we drop that risk by 0.8%. It's a very modest benefit because the risk is so low to begin with, you know, for this particular patient. That, that's the discussion we have with each patient to understand, you know, when we should consider statin therapy initially and then any more intensive therapy added on if necessary. Here's another example. This is an older gentleman, 74-year-old male, non-smoker, non-diabetic, same blood pressure, same LDL. You can see the risk of an event is now 15.4% over 10 years, so much higher event rate. There, the benefit is 5.1% who would benefit from treatment. These are the things we have to put into context when we think about both the risk and the benefits of higher LDL levels and in lowering those LDL levels with drug therapy. We move on to secondary prevention. Secondary prevention are patients that have established clinical atherosclerotic cardiovascular disease separate from those that have diabetes, hypertension, other risk factors. These are patients that have clinically evident cardiovascular disease. Here we have an algorithm to treat. The message here is we use high-intensity statin therapy to achieve a target ideally below 70 mg/dL. Finally, in conclusion, what I wanna put in context for you is that the LDL is causal. This took a number of years to establish this fact, but now it's a mantra that LDL causes atherosclerotic cardiovascular disease. The two ways to model the effects is the absolute level of LDL and the duration of that elevation measured in years, you know, so-called cholesterol years. The guidelines that we have, you know, match the intensity of therapy to the absolute risk of the patient. Statins, you know, due to their proven LDL-lowering efficacy and safety and now cost because they're all generic is the prime therapy that we use initially for patients, and then we consider add-on therapies on top of that once statin therapy has been maximized. There are other therapies, and just to put into context of what we're talking about today, we as clinicians, I'm a preventive cardiologist, lipidologist, we have other therapies that we realize do adversely affect LDL levels, and we manage through that, you know, with the patient and understand the risk-benefit that we can have with certain therapies. A couple good examples that have cardiovascular benefits, SGLT2 inhibitors and beta blockers, have proven CV benefits, and yet they raise LDL cholesterol levels. We have examples of anti-cytokine therapy, such as IL-6 inhibitors, which significantly raise LDL levels, and that's a known mechanism of where IL-6 will downregulate LDL receptors, and you know, when you modify that IL-6 level, the receptors get upregulated and can help clear LDL. Inflammation itself is driving cardiovascular risk in addition to that. This is a risk-benefit we have to establish in IL-6 inhibitors when compared to other cytokine therapies that don't raise LDL, have no increased risk for cardiovascular disease. These are things you need to balance when you're thinking about the magnitude of what LDL risk is for a specific patient. Also, just a final point, LDL elevation with a therapy should be judged in context of absolute risk versus benefits. We have a number of lifestyle interventions, like a keto diet for example, and we see this in my lipid clinic, where it does raise LDL, but we also can use that as a tool to help modify metabolic syndrome-type risk. We so therefore kind of understand the risk-benefit and how some of those diets can overall potentially reduce cardiovascular risk. I think it's important to make these points that LDL is certainly a causal risk factor. Each individual is different in how we think about it. We always need to understand the risk-benefit when it comes to how we modify, looking at drug therapy and how that can affect the patient's overall health and what that means for their overall longevity as well. Thanks very much for those insights, Dr. Davidson. Given the backdrop that Dr. Davidson has provided, I'd like to preview preliminary clinical trial results from a new currently ongoing phase I study of batoclimab in healthy subjects. The primary objective of this study is to assess the changes to LDL cholesterol for subjects treated with 680 milligrams of batoclimab on or off a common dosage of atorvastatin. This slide displays the study design. The first group of 12 subjects entered the trial and were randomized to one of two cohorts. Subjects in cohort one were administered 680 milligrams of batoclimab delivered weekly for 6 weeks, along with 40 milligrams of atorvastatin delivered daily. Subjects in cohort two received 680 milligrams of batoclimab delivered weekly for 6 weeks, along with a matching atorvastatin placebo delivered daily. I'd like to also point out that subjects in both cohorts started treatment with atorvastatin or matching placebo 14 days prior to starting batoclimab. On this slide, you can see preliminary data demonstrating that subjects on 40 milligrams of atorvastatin along with 680 milligrams of batoclimab delivered weekly for 6 weeks, represented by the purple line, reduced their baseline LDL cholesterol from a mean value of 109 mg/dL measured at week -2, to 68 mg/dL measured at week 6, representing an approximately 37% reduction over the course of the study. The decline in LDL cholesterol in these subjects was evident at week 0 prior to starting batoclimab, and mean LDL values remained relatively constant with batoclimab treatment. The blue line, the batoclimab placebo arm, demonstrated the anticipated increase in LDL cholesterol with this dose of batoclimab. To provide some context on atorvastatin usage, this slide also includes a table of atorvastatin prescriptions by dose based on a U.S. claims database. Commonly prescribed doses of atorvastatin range from 10 to 40 milligrams. In fact, 40 milligrams of atorvastatin was the most prescribed dose in this database. To close this section, based on the data from our trials as well as discussions with KOLs. We believe that LDL changes are an on-target effect mediated by reductions in serum albumin. As we previously reported, the changes we observed in our trials have been reversible with discontinuation of dosing. We believe that short-term changes in LDL would not be problematic for most patients. Elevations that may occur with chronic administration of batoclimab may require batoclimab dose reduction and/or treatment depending on the LDL level, the patient's age, presence of comorbidities, risk factors for cardiovascular disease, and of course, whether the patient is benefiting from batoclimab treatment. The preliminary results that I shared today suggest that batoclimab-induced changes in LDL may be negated by 40 mg of atorvastatin. We plan to study additional batoclimab atorvastatin dose combinations to further characterize the potential role of statins in managing LDL changes related to chronic batoclimab therapy. Thanks very much, and now I'll pass it back to Pete for closing comments. Thanks, Bill. Before we move into Q&A, I'd like to make a few brief summary comments. Today's discussion emphasized several important points. The anti-FcRn space is definitely an exciting area of innovation. We've heard today that there is not only a high unmet need across a variety of autoantibody-driven conditions, but also a lot of variability in the pathophysiology and in the clinical presentation of these diseases. It's very unlikely that a one-size-fits-all approach will cover all needs and presentations across indications. We believe batoclimab has a unique and compelling combination of features, in particular deep IgG reductions via a simple subcutaneous route of administration. Our development plans are designed to convert these two features into a benefit that we believe will be important for physicians and patients, namely the possibility of tailored dosing supported by controlled data from clinical trials. With that, I'd like to introduce Renee Barnett, Chief Financial Officer at Immunovant. Renee will join me now to facilitate the Q&A section. Dr. Macias is also joining by phone. Great. Thank you, Pete. It's great to join you and Bill here today at our R&D day. First, thanks to everybody who joined, and thanks for sending in some really good questions throughout the presentations and the discussions that we've heard. Let's go ahead and get started. Well, given the amount of time that we spent at the beginning of our event on thyroid eye disease, we have several questions about our plans to continue development in TED. Specifically, will it be one of the pivotal studies you plan to initiate this year? Why or why not? Thanks, Renee. That's a great question. I think you definitely sense our enthusiasm for the potential of batoclimab in thyroid eye disease. It's certainly in the running to be one of our pivotal trials. We haven't made a final decision yet. We do have an upcoming engagement with the FDA that's scheduled, and we'll be discussing with the ophthalmology division our trial design and some other elements of a potential pivotal program. After that, we'll make a final decision, but it's clearly in the running. Thanks to Sam Slutsky from LifeSci for this question. Given all the various settings in TED where batoclimab could be used, do you plan to run studies in each of these settings to support use? Right. I think this anti-FcRn market is very large. As I mentioned, there are 17 indications that are currently being studied. Some of them are a little bit smaller and maybe complementary to some of the main indications. There's a large group of indications that are important in terms of their size relative to rare disease addressable populations in general and the degree of unmet medical need. You know, we'll be working our way down that list using those two characteristics, as well as looking for conditions where we believe deeper IgG reductions may be advantageous for patients because that's an advantage that we believe we'll be able to deliver. That allows us to prioritize which indications to do and in what order. Makes sense. We have a question from Robyn Karnauskas at Truist in regards to how you see both batoclimab and teprotumumab or TEPEZZA being used in the TED treatment paradigm. Can you speak to that? Yeah, definitely. It's a great question from Robyn. You know, as I highlighted at the end of the thyroid eye disease section, speaking about the addressable market, I think this is a unique market. It's a very interesting market in the sense that there's a real need for complementary therapies. I think eventually, should batoclimab prove successful and be approved, there will be many patients who end up being treated with both medications. A lot of that has to do with the fixed duration of use that we anticipate being maintained in all labels for medications approved in this condition. But also has to do with the variability in the condition. While the regulatory endpoint is fixed, it's the there are many other symptoms that will be important. As Dr. Kossler was mentioning, I think many physicians like Dr. Kossler and Dr. Kahaly will use the variability in clinical presentation to decide perhaps which medication they use first. I think at the end of the day, many patients will end up being treated with both. I think a treatment paradigm leads to both of them being used in many patients, and the order will be, you know, be individualized by physicians in consultation with their patients. Great. Thinking about the heterogeneity of the population and switching to some of their unmet needs for TED patients. We have a question from Yatin Suneja from Guggenheim. If 2 millimeters improvement in proptosis is not enough for some patients, what are the ranges in proptosis that are needed for clinical benefit based on the heterogeneity observed across all TED patients? Yeah. This is very interesting, and this is an area I've learned a lot in speaking to oculoplastic surgeons in particular. You know, I think when I first began to learn about thyroid eye disease, obviously one of the first things I was made aware of was the regulatory endpoint of proptosis responder rate and the definition of a 2-millimeter improvement. As I've had a chance to speak with a lot of oculoplastic surgeons, what I've learned is that the baseline excess proptosis can vary a lot. There are population norms, and those can be used to define whether someone is abnormal for their group. There's differences by gender and race. Individuals have their own baseline, and of course, that's not known unless they would have, for some unusual reason, had their proptosis measured before they got Graves' disease. The reason that's important is there are some patients who are in the population norm for proptosis, but they have proptosis relative to where they started. Then you have other patients that have really profound proptosis, both relative to the norm for their population group and relative to where they started. How much improvement an individual patient needs can vary a lot. In addition to that, as Dr. Kossler was pointing out, in particular, proptosis is just one of many features of thyroid eye disease. The other features that are captured in the clinical activity score, to a large degree, sometimes correlate with proptosis and sometimes don't. At a pathophysiologic level, you have both muscle edema causing various symptoms, including proptosis, diplopia, pain, strabismus, a variety of conditions. You can have proliferation of adipose sites and adipose tissue, and that can cause symptoms as well. At the end of the day, you know, 2 millimeters is a great standard for as a regulatory endpoint. But what an individual patient will need, how much proptosis improvement they'll need, how much symptom relief in other areas they'll need, that's going to vary based on where they started and kind of how their flavor of thyroid eye disease is playing out for them clinically. This is why we see a real benefit to having two different mechanisms of action potentially available for treating physicians. This one from Tom Smith from SVB Leerink is in regards to the TED data we presented today. Can you comment on the mean proptosis reduction over time in the study? How closely related were IgG and TSHR antibody reductions with proptosis improvement and improvement in clinical activity scores? Yeah, great question. In terms of correlation, at the population level, you know, I think you see a pretty good correlation in the data we showed today in the sense that we have groups of, you know, cohorts based on their treatment assignment. You have patients who were assigned to 680, 340, 255, and a placebo. The data that we reviewed today, whether we were looking at total IgG, whether we were looking at anti-TSH receptor stimulating antibodies specifically, whether we are looking at proptosis responder rate at 6 weeks or muscle volume of the five of the six extraocular muscles at week 12. All those things seem to show a dose dependency with greater than grade improvements in the higher doses and lesser improvements or no improvement in the lower doses or placebo. Those things all correlate well at the group level. At the individual level, you know, you have just a small number, so there'll be some variability whether every single one of those correlates at the individual levels. It'll be hard to tell in the study at this time, but at the population level, we saw that correlation. Thinking about our development program more broadly, Derek Archila from Wells Fargo asks, for the indications where you are not planning pivotal studies this year, does that mean you will initiate a phase II trial instead, or is the timing of the pivotal study intended to be next year? Trying to understand whether you plan to go directly into phase III trials for all future indications. It's a good question. A little similar to Sam's in terms of how we decide, you know, how to sequence our development program and what the potential overall scope of that development program will be. I think there are many indications where we can go straight to pivotal because the regulatory path is well described. Our degree of conviction on the probability of technical success is high, and the unmet need we see remaining, even with potentially another anti-FcRn in play, is meaningful. And we have an opportunity with our unique profile to add something new. In cases like that, certainly from a long-term value creation standpoint, the sooner we get to pivotal, the sooner we get to approval and launch. That makes a lot of sense. For some of the other indications which are less classic autoantibody-driven to the maybe complex related conditions, I think there's an opportunity to still hone the scientific understanding of which population of patients in some of those groups are going to respond best to an anti-FcRn. There may well be some subgroups of those conditions, some of which are much larger than normal rare disease conditions. But there could be subgroups of some of those conditions that are of similar size to a typical rare disease IgG-mediated condition. That's really where your bang for the buck with an anti-FcRn is going to be the highest. In cases like that, I think it's wise to first consider a smaller phase II study to define the perfect patient population or the best patient population before going forward. Those are the kind of considerations that we're making when we decide whether to go, you know, straight to pivotal or do a pre-pivotal study to better define the best population for the pivotal study. Great. A related one from Tom Smith, again, at SVB Leerink. Specific to TED and WAHA, what are the gating steps to resuming those programs, regardless of which phase? Right. We had a very deliberate strategy of getting back into the clinic, and that was to first have a really robust interaction with the Division of Neurology 1 of the FDA. The reason we wanted to do that was so that we could get really a lot of questions answered that relate not only to myasthenia specifically, 'cause there's those kind of questions about the trial design, but also use that interaction as a way to work through some of the general principles for resuming study with batoclimab. Things like, you know, how we would handle cholesterol excursions during the long-term extension or something like that. I think that strategy turned out to be very successful. We were able to have really focused interactions with that division and achieved a really great outcome that we've previously described. Now, having achieved that alignment on our phase III program and the monitoring and the dosing and things like that, we're going to those other divisions that are responsible for our INDs and other indications. Ophthalmology, of course, being the division that's responsible for thyroid eye disease, the heme division responsible for warm autoimmune hemolytic anemia. We wanna have those interactions and get some of the features that are specific to those particular indications buttoned up with those divisions before we restart those trials, which we're doing now. Great. Makes sense. Thank you. Pivoting now to a few questions we've received on our healthy volunteer study. First from Derek Archila at Wells Fargo. He asks, "Given that your healthy volunteer study with statins has shown you can mitigate the LDL increases for patients treated with batoclimab, will this change how you treat excursions in the phase III myasthenia gravis trial? Will you look to dose statins concurrently with batoclimab in the upcoming phase III trials and other indications? Yeah, that's a really good question. We sort of planned our myasthenia trial with an assumption that statins would mitigate the changes in LDL. While we're pleased, very pleased with the preliminary results from this drug-drug interaction phase I trial, they're not different than what we assumed. In that sense, those assumptions are already built into the trial. When we spoke to physicians, both physicians like Dr. Davidson, who's an expert in lipid management, as well as neurologists with expertise in treating myasthenia gravis and regulatory consultants and regulators, there was really strong alignment that there was no need and actually not advisable to immediately co-administer a statin during the induction period of our myasthenia gravis trial. The reason for that is severalfold. First, as Dr. Davidson highlighted in his discussion, LDL is a risk factor over years, and the induction phase of the trial is 12 weeks. As Bill said, we don't expect that changes in LDL will be a problem for most patients or the vast majority of patients in that initial 12-week period. You don't wanna, you know, treat a problem that's not there. After the induction period, the dose will come down for most patients, and that alone will yield a normalization of LDL for many patients. Even in that second 12-week period, as we've discussed before, when I've been discussing our myasthenia trial, we're also not treating with statins during that period because we want the LDL changes, should they have occurred in period 1, to have a chance to normalize in period 2. Even over our 24-week period, it's still a relatively short period of time in the scale of timeline they usually think about LDL changes. It's only when you get to the chronic long-term extension, if you have patients at that point who have a remaining change in LDL, that's when you start to think about ways to mitigate that risk. One of which could be to treat with a statin. We did hear from physicians that prescribing physicians, when they thought about how they might use batoclimab eventually, that the concept of, you know, induction and maintenance without worrying about the LDL changes because they're not so important for the short term, made sense. They also sort of assumed that statins would probably work, but they wanted to see data. We've always had in mind that we will have some element of describing the interplay between statins and batoclimab in longer term studies and then also in this phase I trial. That's all that's going to be built into long-term extension of some of our other trials. We're very happy with the way we have the myasthenia trial designed without statin use in the first 24 weeks, and we think that's the right way to go. Great. Another question from Robyn Karnauskas at Truist Securities. Following up on our healthy volunteer study, Robyn asks, in the healthy volunteer study, did any patients experience side effects of statins that may have in a non-clinical environment might have made them discontinue? Right. You know, look, this is a pretty small study, and we didn't have in the small cohort any statin-related side effects. There are some well-described side effects with statins that happen in a small percentage of patients, like changes in CPK. There's such a huge database of information in terms of studies with statins that I think that's all very, very, very well described. In the large majority of patients, statins are really well-tolerated. I think we kind of all know how, you know, what to expect with statins, and it's good for the vast majority of patients in terms of tolerability and lack of side effects. I think that's defined. Great. Question from Matthew Barcus at Chardan. On our healthy volunteer study, what additional batoclimab and atorvastatin combinations are you considering studying? And when would you expect to get the results from those studies and share them with the community? Yeah, that's a really good question. In terms of when we'll, you know, share the details of that, it'll be, you know, sometime in the next quarter or two. What I will say, though, about the trial design is it was designed in a very specific way, and it was to start with the highest dose of batoclimab and with a fairly high dose of atorvastatin, which is 40 milligrams. You saw on Bill's slide that 40 is actually the most commonly prescribed atorvastatin dose. There are doses at 20 and 10 which are used, and then 80 is sometimes used. We started with 680 and 40. We actually thought that we predicted a little bit what would happen. I mean, obviously we wanted to see it, but we predicted that 40 mg of atorvastatin would likely be observed to blunt any changes in LDL with 680 milligrams. We wanted to see that data before designing the next cohort. The study protocol is written in such a way that we can use the information from the first cohort to then inform the second cohort. That first cohort had to complete and have all the analyses run. Now we're designing the other cohorts. We're ultimately going to test several different combinations of different batoclimab doses and different doses of statins, which I think will provide a lot of useful information for clinicians ultimately. Again, for that longer-term phase where, you know, up front is not really needed but for the long-term, treatment. Great. We'll look forward to that. The next couple of questions are in regard to the anti-FcRn competitive landscape. This one comes from Brian Skorney from Baird. Brian asks, what are the specific weaknesses of efgartigimod that you perceive could be improved upon by other FcRn antibodies? Does the potential impact on LDL here give you pause about using batoclimab instead of efgartigimod? Right. I think, first of all, I think the anti-FcRn class is a really amazing class. I think the reason I think it's amazing is because it has such broad potential. When you look at the efgartigimod label and the data from their studies, it's a nice profile. It's a nice risk-benefit ratio. I think this is a class that's going to find a lot of opportunity across a variety of indications. That being said, there are going to be differences between the products. There always are. There are differences in terms of route of administration. There are differences in terms of depth of IgG response. Both of those could potentially relate to efficacy. The relationship between IgG reduction or autoantibody reduction and efficacy has already been described in a few indications. It kind of makes common sense. There's a chance that higher degrees of IgG reduction will lead to better efficacy, at least for some patients. That's an important element that physicians, I think, will ultimately use to decide between two different anti-FcRns. Route of administration, having a simple sub-Q subcutaneous route of administration, that's kind of the same that's been used for many, many other biologics and has been shown to be easy to tolerate for many, many years by many patients who are on different biologics in autoimmune conditions. That also relates to efficacy because if you're not able to take a product chronically because of logistical hassle or other things related to the route of administration, then you can't get the efficacy. We heard a little bit of that from Dr. Ruzhansky and Dr. Silvestri related to some medications that are available by intravenous infusion. I think this, you know, efficacy is probably going to be the biggest selection criteria within the FcRn class for myasthenia specifically, and probably for other indications as well. You know, once you have that, then I think that's going to be the main determinant of share. I expect that efgartigimod will have good share. It has good data and that batoclimab will have good share as well, and that the patients for whom each medication are used will be a little bit different. I'm glad you brought up route of administration because we have a question from Corinne Jenkins at Goldman Sachs. Corinne asked, with the recent announcement of sub-Q data for efgartigimod, what are your thoughts on its impacts on the competitive landscape? And what are the factors you are considering in selection of additional indications? Right. You know, I think the Halozyme data is we only have sort of the top line data at this point. It looks pretty good. That's not surprising. Halozyme has demonstrated an ability in short-term use to be a nice enabler of higher volume subcutaneous injections or almost infusions at that higher volume. In this case, with the 5 cc I think is what teprotumumab is using. The biggest difference that I see between the two formulations really has to do with the sort of existing body of experience. As I mentioned in the last question, there are many biologics that are available as a simple subcu, meaning they have excipients which are designed to make the antibody soluble. There isn't any other medication like Halozyme co-formulated. It's just excipients and the antibody, and they're delivered via a prefilled syringe or an auto-injector for years and years. My understanding and review of the literature for Halozyme is that they're mostly products that are used less frequently than weekly. I think there's one product that's Herceptin that's indicated for weekly use, but it has, I believe, a one-year limitation of use. You don't have that sort of years of use at a more frequent dosing interval with Halozyme than you have with the standard subcutaneous injection. I think that provides a little bit more context that the simple subcu is likely to. You kind of know how it's going to play out. A couple interesting questions from Doug Tsao at H.C. Wainwright. Specifically as we're on the topic of subcu, he asks, in interacting with KOLs, have you gotten the sense that atezolizumab subcu dosing is more advantageous in some indications more so than others? I think any indication that's chronic, the subcu is going to be really important. You know, physicians will, I think, sometimes estimate the group of patients who might prefer an IV as a meaningful minority of patients. When you talk to people with the condition, that number goes way down. When you have conditions where there is a subcutaneous option available, the subcutaneous option tends to really, really take the lion's share in chronic conditions because it's just easier. Dr. Ruzhansky was mentioning the logistics associated with an IV side in her personal experience. I think the subcutaneous format is going to be much more favorable for chronic indications, which are the vast majority of the anti-FcRn indications. Among subcu, as I already said, having a simple subcu which you can use without any sort of special preparation needed, and it's just a simple push over 8-10 seconds. I think that's something, again, there's years of experience with multiple products to show that that's something people can do easily. Thyroid eye disease is interesting. It's a fixed duration of therapy. There are competitors to teprotumumab which are going for the same mechanism of action but a subcutaneous format. Obviously Horizon has a subcutaneous program in development, I think with Halozyme. I think for that shorter period of time, that's where, you know, I think to tolerate an IV for 6 months, you know, is going to be a little bit easier. Even in that period of time, many patients who are busy and working, and there are a lot of patients with thyroid eye disease who are younger, they're in the prime of their working career, even for a six-month period, having to do IV infusions, you know, can be something they'd rather not have to, you know, accept. Yeah. Doug Tsao from H.C. Wainwright also asked a bit about our new indication selection, specifically as it relates to batoclimab's efficacy. Doug asks, as you gain more data validating the batoclimab dose pharmacodynamic relationship and as you see competitors show efficacy for FcRn therapy in different indications, does this potentially enable you to move batoclimab directly into pivotal studies? Yeah, that's a sort of a great follow-up question to the question earlier from Derek and Sam about sequencing how we're going to sequence the indications. I was mentioning that there are some particularly in the immune complex area, there's we have some opportunity to refine our learning as a you know as a group of people who are really interested in the anti-FcRn class in terms of what's the best population and the best degree of IgG suppression in those conditions. To Doug's point, there are ongoing trials, you know, some of which may read out in the next couple of years. Given the favorable profile that we believe we have with the simple subcu and the ability to deliver the high IgG reductions, we'll absolutely take our opportunity to learn from those programs, you know, where that information comes out. If it's relatively definitive, then that would be an opportunity for us to, you know, move directly to a pivotal program. Having a biomarker that's so easy to measure and even if I think it's probably quite well correlated with clinical response across a variety of conditions. Even if it's, you know, just moderately correlated with clinical response, the fact that the biomarker itself is so measurable, it really allows to go to phase III faster. Because usually what holds you up and what causes you to have to do a more extensive phase II program is that dose effect curve is just it's harder to estimate when you don't have you know as good of a biomarker as you have in the anti-FcRn class. It's a long way of saying, Doug, yeah, I agree. If there's good data from other programs, that allows us to move faster to pivotal in those areas. Back to Yatin at Guggenheim. This question relates to myasthenia gravis. Yatin asks, what proportion of MG patients would prefer a more consistent defined treatment regimen versus a cycle-based approach based on disease course? Yeah. We think it's sort of the vast majority. We have a market research that we did with people with MG, and in that research, they were all in therapy, first of all, in terms of who were they. They were people there, they had myasthenia typically, you know, for multiple years. They weren't newly diagnosed. They weren't people with myasthenia for 20 years. It was more in that 5-10-year range. They were on a variety of different therapies. None of them anti-FcRn because at the time we fielded that research, efgartigimod hadn't yet been approved. There were people on Soliris and a variety of other medications. For a lot of the questions, there was a range of preferences. There was one question where there was really strong convergence of opinion, and that was, would you prefer to be on a chronic therapy to maintain your symptoms even after your symptoms are controlled? Or would you prefer to be on intermittent therapy just when your symptoms flare? And the 94% chose to be on a chronic therapy. I think the reason for that, we got into this a little bit with the discussion with Dr. Ruzhansky, is the experience that some patients with myasthenia have had or friends of theirs who have myasthenia have had where when their myasthenia symptoms return, they come back hard. The flare is really quite significant. They can go from being pretty okay to quite sick quickly. There's a lot of anxiety around flares that leads to, I think, many people preferring a steadier treatment regimen. Now, that doesn't mean they wanna be on the same highest dose that they started with forever, and that's why this induction and maintenance approach, I think, makes a lot of sense. It allows the physician to titrate down the dose potentially and get them to the right amount of medication that they need. I think most will want to be on chronic therapy. Thank you for that, Pete. Looks like that's all the time we have. Thanks again for these really good questions. With that, I'll turn it over to Pete to say a few words in closing. Thanks, Danielle. Those were a lot of great questions. In closing, I'd like to sincerely thank our panelists and presenters in particular. Their engagement and insights have helped bring into focus the reasons we're so enthusiastic about tocilizumab for a variety of autoantibody-mediated conditions. With that, our program is concluded.