Please welcome Beth DelGiacco. Hi, welcome to our Boston Innovation Hub. It's looking very transformed today. Welcome to our second R&D spotlight event. Today, we're going to focus on autoimmune myositis and the opportunity for VYVGART to have a meaningful impact on patients' lives. We have a full house today. We have many investors and analysts. We also have our argenx colleagues here, and during that mix and mingle, we encourage you to get to know each other. We also have a lot of people joining on the webcast, so a big welcome to them as well. Autoimmune myositis. We've actually transitioned from calling this disease, or what is really a group of different diseases, away from idiopathic inflammatory myopathies, because idiopathic means of unknown origin. The reality is, today, we know what drives myositis, which is our immune system, and you're going to hear from us about autoimmune myositis. We're going to be making forward-looking statements, the details of that are here. We've held several of these topical-focused events, it's really core to who we are as a company. We're grounded in science. The patient is our North Star. All of this is guiding our future. What you're going to see today is an agenda that covers the full spectrum of that value chain. We're going to hear from Karen Massey, our Chief Executive Officer. She's really going to connect the autoimmune myositis opportunity to Vision 2030. You're going to hear from Leentje De Ceuninck, the principal scientist on the autoimmune myositis team, about the biology rationale of why we selected the subtypes that we selected. You're going to hear from Luc Truyen, our Chief Medical Officer. I've heard the rumors that we're going to have phase III data today. The update is that we're firmly on track for 3Q, not today, but we will be able to add context around all the phase II data we've shown and the path forward. We have Sandrine Piret-Gérard, our Chief Commercialization Officer, who's going to talk about our evolving view of the commercial opportunity for autoimmune myositis. We have a great panel of external speakers today, that's going to be a fireside moderated by Josh Bryson, our Head of U.S. Medical Affairs and Evidence Generation. They're going to talk about the unmet need, the treatment burden, lack of treatments, the opportunity for VYVGART, much more. What I wanted to flag as I introduce our external speakers is that we have three physicians with three different specialties. Actually, that is very reflective of autoimmune myositis as a disease. We have Dr. Avery LaChance from Harvard. She's a dermatologist. We have Dr. Arjun Seth from Northwestern. He's a neurologist. We have Dr. Rohit Aggarwal from the University of Pittsburgh, and he's a rheumatologist. Actually, if any of you had attended our virtual 2021 R&D Day when we unveiled myositis as an indication, Dr. Aggarwal was a speaker there as well. We're going to make it very easy for you today. We know that we're going to share a lot of information, so we'd like to just start with what you need to know right up front. First off, autoimmune myositis is a white space opportunity, and it has the attributes that are perfect for an argenx indication. Strong biology rationale. We know IgGs are present and they're also driving disease, and we have data to support that. We also know there's a very high unmet need in autoimmune myositis. In IMNM, there are no treatment options approved. In DM, there's been limited innovation. You're going to hear from Larissa today. She's an IMNM patient. We have an urgent call to action as a company to bring forward our medicines, and we have strong conviction that when we enter these markets, we're going to shape them and we're going to expand them. I think this is a playbook that you probably recognize. ALKIVIA enabled us to take a data-rich approach to development, and it's guiding our path forward. Remember, ALKIVIA was designed as a basket trial. We believe that IgGs are driving IMNM, DM, and PM. You'll hear from Luc today on the phase II data. You'll hear about the phase II enrollment and also how that drove the phase II response. Enrollment was led by IMNM. We said we enrolled it fast, and we did. We also saw that IMNM drove the statistically significant response we saw and supported our receiving Breakthrough Designation from the FDA in IMNM. We also saw a clear signal in DM that gave us the confidence and the conviction to move forward in this subtype. PM was the smallest contributor to our phase II enrollment, and also a similar smaller contribution to phase III, and this actually makes sense. Alongside our evolving understanding of PM, PM is continually being reclassified into different subtypes. Today, we no longer see a path forward to approval in PM. What started as a basket study is now a big opportunity in IMNM and DM. Based on this learning, we're refining our U.S. regulatory filing strategy. We will update the analysis of the primary endpoint, and I just want to say this again. We are not updating the primary endpoint. We are updating the analysis of the primary endpoint. We're going to assess each indication on its own merits, ensuring there is a strong benefit-risk profile for approval. Of course, we still have the experiment ongoing. We have to see the data, but if we have positive data, we see a clear path forward for approval in one or more subtypes. IMNM and DM are strategic entry points for argenx and for VYVGART into rheumatology. We have the opportunity here to be first in class, and we know what that means. Building long-term relationships with HCPs, launching with strong evidence, and doing it without other FcRn competition, and that's meaningful. We've seen the power of this position from the MG and the CIDP experience. It also feeds into our Vision 2030. First, IMNM DM as the foundation, followed by Sjögren's and future indications to come. I think all in all, for number five, we are well-positioned to achieve our two goals. Near-term label expansion and long-term leadership in autoimmune myositis. We have strong phase II data, clear signals in both IMNM and DM. We've had active collaborative discussions with the FDA for alignment, and we now have a filing strategy that sets us up for the clearest path to approval in one or more subtypes. This is what supports that near-term goal, label expansion. We also see this as a foundation for our future leadership in autoimmune myositis, that's really about that second goal, long-term leadership in autoimmune myositis. With that, let's get the event started. We want to start where we always start, which is with the patient voice. Let's hear from Larissa. I'm Larissa Webster, I'm from Portland, Oregon, and I have necrotizing myositis. I describe it as your muscles dying. It weakens your body. I started feeling symptoms for sure in 2023. I probably was feeling symptoms before that but wasn't realizing what they were. I would be going to the gym, and I wouldn't be able to lift the weights that I normally was lifting. I couldn't barely walk the treadmill. I was falling. I was falling outside. I was falling in the house. I had my primary, talked to him about it, and he ran all these different tests like CT and MRI and blood, and nothing was coming up, and I just felt worse and worse. I kept on pressuring my doctor like, there's something wrong. He said, I'll send you to a gastroenterologist. Maybe he can see something, so I took the tests that he had required, and it was the CK test that was at 22,000. He told me, go to the emergency room right now. We don't know if your organs will shut down. The neurologist came in and said, from everything that you've been telling me and what's going on with you, I think you might have a myositis. We don't know if we will have to incubate you because things are dying, and we don't have it under control. That's when I realized it was serious. I just cried. I felt like my dreams went poof. Once I checked out of the hospital, I actually got worse before I got better. I fell several times in the bathroom, scared my husband half to death. His dreams too had went poof. We had plans. Adjusting everything in my life, slowing way down, walking with a cane, not being as active as I used to, not being outdoors, hiking and walking, I miss that. That was really hard. The medication obviously changed me. The prednisone, I gained 40 lbs, and there's nothing you can do about it. It's just the most awful feeling. It changed my personality too during the time. It totally changes your brain and your body. It's been a long road. It's been a really long road. It's been tough. What I would tell somebody is their story's going to be different than my story. I would tell them also that it's okay to cry. It's okay to be upfront with your doctor, to say that you need more information. Ask for it. I am so grateful that I'm getting the opportunity to share this because I think it's really important, and I think that there's a lot of people that have my condition that they don't know that there's a community out there, and if we can reach them, that would be so great. Please welcome Karen Massey. Thank you everyone. It's great to see you. I've watched that video obviously a few times. Every time I watch it, when you hear, my muscles are dying, can you imagine the feeling that you have and how she describes, my dreams went poof, and the dreams of my husband went poof. Her whole life impacted by this disease. I think what you hear from Larissa and what we hear from patients is myositis is more than muscle weakness. It takes away people's identity. It takes away their independence. It takes away the ability to live their life that they want to lead. For us, as Beth said, that's a call to action, and that's a call to urgency that you'll hear throughout the presentation today and why we're so focused on turning over that data card and hopefully getting VYVGART out to patients as quickly as possible. By the way, what's also really important to note is that myositis is deadly. Myositis has three times the mortality rate of the general population. This is not just about muscle weakness, this is not just about symptoms, this is also about a severe, rare disease that has a high mortality. We have an urgency to act, and what we want to share with you today is our clear path forward for autoimmune myositis. Autoimmune myositis is a quintessential argenx opportunity. What do we mean by that? Well, at argenx, we always start with the biology. We always start with the science first. I want to make sure that it's clear today, what you'll hear from Leentje is we have as much conviction in the biology for IMNM, for DM, even for PM today as we did when we started this trial in 2021. It's very clear that pathogenic autoantibodies are driving this disease. With VYVGART, we have a targeted option to remove those central drivers of the disease. Second is we always focus on disease areas that have high unmet need. We just talked about that. We just heard from Larissa. What you'll also hear about today from our KOL panel is healthcare professionals are frustrated treating myositis. They feel helpless. Sandrine will share some market research from neurologists, from rheumatologists that share that they don't feel that they have the tools in their toolbox to treat these patients the way they want to. They have blunt tools. They have tools that are not approved for the indication, that are not treating the underlying disease. They feel frustrated when they're sitting across from the patient. The opportunity is clear. We can help these patients, we can provide these tools, targeted precision tools, to healthcare professionals. As Beth said, we've prioritized two opportunities here, IMNM and DM. That's based, yes, on the biology. It's based on regulatory feedback. It's also based on the phase II studies data. You'll hear more from Luc on that as our path forward. The opportunity is very clear. IMNM, roughly 20,000 patients. There are zero treatments approved today. There are no treatments on the horizon. The unmet need was recognized by the FDA with Breakthrough Designation, and we believe that IMNM is a blockbuster indication on its own. DM is the second opportunity. It's larger, around 40,000 patients. It's a more heterogeneous disease. There are limited treatment options available here as well. Of course, IVIG is approved, but we know what that comes with, especially in terms of treatment burden for patients. We see DM as another blockbuster indication on its own. What you'll hear today is that we have prioritized IMNM and DM. We have a clear path forward, assuming positive data. Let's turn over the data card and see in Q3. If we get positive data, we'll be moving as quickly as possible for a fastest path to market for both IMNM and DM. Let's talk about the ALKIVIA trial that set us up for success in myositis. I'm really proud of the team that designed this study back in 2021. I think it's exactly the right trial, and has set us up for success today because it's an adaptive design, it's flexible, and it's allowed us to evolve as the disease and the understanding of the disease has evolved. It's bold, and it's innovative. By the way, ALKIVIA is the first study to actively include IMNM patients. To date, I think it's the only study to actively include IMNM patients. The phase II data are very convincing. You're going to hear more from Luc on the phase II data, but just at a high level, to pull out what I think are some of the most important points. You all already know there were 89 patients. It's a phase II study. On the primary endpoint, TIS at 24 weeks, the P -value was 0.0004. That is a strong P -value on 89 patients. What you saw in the data is a rapid separation of efgartigimod versus placebo. We published data recently that you see that all the way out to 52 weeks, sustained efficacy. That's a classic signature of VYVGART, and that's what these patients need. Of course, the safety reflects what we see in the real world, that strong safety leads to a benefit when you're looking at chronic therapies like in autoimmune myositis. That gives the prescribers confidence. What gives me confidence for phase III? Well, phase III is twice the size of phase II, and it's twice as long. It also includes additional endpoints that patients and prescribers really care about, in particular on the steroid tapering. This seamless phase II, phase III design is exactly the right study to lead us to the position that we're in today. It's the right trial, it's the right design, and it's going to unlock the myositis opportunity for us. What are our goals, and what does success look like for argenx, a nd for patients in myositis? You'll be able to see the playbook in action that we've applied in MG and CIDP, as we think about autoimmune myositis. Our filing strategy, focused on IMNM and DM, gives the clearest path to label expansion. We're focused on getting there fast and broadening access to reach more patients with VYVGART as quickly as possible. The reason that strategy is so powerful is that this is our first step into rheumatology. Remember how we succeeded in neurology. We were first to market. We were able to win the loyalty of prescribers based on the innovation that we brought, but also the world-class team behind VYVGART. We now have the same opportunity to do that in rheumatology. This will be the first-in-class FcRn, launching with rheumatology and setting the stage ahead of what we have Sjögren's data reading out later next year. That combination of first in class alongside that world-class team builds a moat that is hard for competitors to penetrate. In true argenx style, the work doesn't stop when we turn over that data card in Q3. We will continue to generate evidence, we will continue to shape the market, and we'll continue to expand the market. Just like when we launched VYVGART in MG or in CIDP, we fully expect that with a new treatment option and a new innovation, the market won't just switch to VYVGART, the market will expand. We'll start to see earlier diagnosis, we'll start to see earlier treatment, we'll start to see patients staying on therapy longer, and we'll start to see, importantly, better outcomes for patients as a result. These two strategies in parallel allow us to deliver both short-term leadership in myositis as well as long-term leadership in rheumatology. As we get into the details for the rest of the afternoon, one thought that I want to leave you with is that we are confident in our clinical trial. We're very clear on our path forward, and we're very much looking forward to the data readout in Q3. With that, let me bring to the stage Leentje, who will take you through the biology and our conviction in the biology of autoimmune myositis. Thank you, Leentje. Thank you, Karen. Good afternoon, everyone. In this session, I would like to highlight how 50 years of autoantibody research has transformed our understanding of myositis. Back in time, now almost 50 years ago, when the first myositis-specific autoantibody, Mi-2, was discovered, it was thought that autoantibodies were just bystanders of disease. Over the years, more than 30 different autoantibodies have been identified, and these autoantibodies nowadays are important diagnostic tools for physicians. Over time, we also learned that myositis is not just one disease. In this animation, which is actually courtesy of Dr. Ku and Dr. Chinoy, it nicely illustrates how evolving classical diagnosis or evolving evaluations of the classical diagnosis has led to a split up of polymyositis and dermatomyositis, and actually into splitting out polymyositis even further in newer myositis subtypes such as IBM, IMNM, overlap myositis, and antisynthetase syndrome. This actually also nicely reflects that there is not that much left of what was originally identified as polymyositis. Each of these myositis subtypes are also associated with specific autoantibodies. They can also lead to a whole spectrum of clinical symptoms. On the top left, you can see how antisynthetase syndrome autoantibodies such as Jo-1, but also certain dermatomyositis or IMNM autoantibodies can lead to a higher chance for patients to develop complications of the lung, such as interstitial lung disease, while other autoantibodies are associated with the development of symptoms that are associated with, for instance, the joints, the heart, the skin, or the gastrointestinal tract. What my patients with IMNM, DM, and antisynthetase syndrome have in common is this specific proximal muscle weakness, as we also heard from Larissa. This common feature actually allows to evaluate the therapeutic effect of novel treatments on muscle function across these different myositis subtypes, which we actually did in the ALKIVIA trial. The biggest question in myositis was always, are these autoantibodies just a presence? Are they just markers of the disease, or are they actually being pathogenic? Well, most of these myositis autoantibodies, actually all of them, they target autoantigens that are present inside cells, which would argue against the fact that they would be pathogenic. Pioneering research from the NIH has shown that autoantibodies can actually enter muscle cells and skin cells in myositis patients. On top, you can see here the muscle biopsies of some patients. You see in green, IgG autoantibodies lighting up in green inside the muscle cells across the different myositis subtypes, which is not the case in muscle biopsies of healthy patients. Further research showed that when autoantibodies enter muscle cells, they can bind to their target antigen and disrupt the normal function of this antigen. This can, for instance, lead to interferon overproduction, lipid accumulation, or disruption of transcription and translation, eventually leading to cellular damage and inflammation. Yes, autoantibodies are pathogenic. Autoantibodies, they can cause cellular damage in a dual way. As I just showed you, autoantibodies can have this intracellular effect, but autoantibodies can also bind extracellular antigens. This can lead to the formation of immune complexes or activation of the complement system. This triggers interferon and cytokine production, JAK-STAT signaling, and inflammatory cell recruitment. One example of this, for instance, this pathway on top, is the clearest example of how in IMNM patients, autoantibodies can bind to autoantigens that are expressed on the cell surface of muscle cells. This causes the activation of the complement system and leads to perforation of the muscle cells and the leakage of muscle enzymes such as CK. This explains, for instance, why myositis, or specifically IMNM patients such as Larissa, have these extremely highly elevated muscle enzyme levels of CK. The clinical success of JAK2 inhibitors further confirmed that suppressing downstream interferon and JAK signaling could dampen autoantibody-driven inflammation. Our hypothesis is that efgartigimod could act one step earlier, more upstream, and could actually remove the pathogenic IgG autoantibodies that leads to this cellular damage. Importantly as well, on the right, you see that the cellular damage that is caused by the autoantibodies leads to more exposure and more release of autoantigens in the environment, which causes a feedback loop, further driving inflammation and damage. Two preclinical models actually support the hypothesis that efgartigimod could break this cycle of damage. When autoantibodies that are isolated from IMNM patients that are positive for an autoantibody are injected in mice, we see that these mice develop muscle weakness and necrosis. On the left picture, you see in the muscle biopsies of these cells that the mice develop necrosis, which is indicated by the black triangle. This is also clearly reflecting what is seen in IMNM patients. When these mice are treated with efgartigimod starting on Day 8, which is once the disease is established in these mice, the mice show reduced muscle necrosis. We saw this increased muscle generation present. Oops, sorry. There is no pointer. As you can see by these clusters of regenerating muscle cells indicated by the white stars. We also see on the right that treatment with efgartigimod, indicated in green, leads to a restoration of the muscle function in these mice compared to non-treated mice, which are indicated in black, and which keep on having a clear loss of muscle grip strength. In a second model, when we immunize mice with a Jo-1 autoantigen, these mice develop excessive lung fibrosis. On the left picture, you can see accumulation of collagen in the lungs of these mice. There are clear deposits of collagen which actually disrupt the architecture and the function of the lungs in these mice. This picture reflects as well what happens in patients that have Jo-1 autoantibodies, which, as I previously showed, can develop severe lung damage, such as interstitial lung disease. When these mice are treated with an efgartigimod mouse analog, we saw that these mice had clearly improved lung fibrosis, restoring the normal architecture of the lungs. Oops, sorry. In the past two years, we have had the hypothesis that actually by reducing the autoantibody levels, we could bring therapeutic benefit to patients. What was, just in the beginning, just a plausible hypothesis, is now supported by more mechanistic evidence by preclinical data and as well by clinically controlled data. In the ALKIVIA trial, we saw that patients that were treated with efgartigimod showed clear clinical improvements across different myositis subtypes compared to the control group. Importantly, in the biomarker data of patients that show a major clinical improvement, we saw that the improvement was also reflected in their biology. We saw that improvement in clinical symptoms, in muscle strength was paralleled by reductions in autoantibody levels. In individual DM patients, we saw also reductions in interferon production. In individual IMNM patients, we saw clear reductions in CK levels. Together, this indicates that targeting autoantibodies underlying the disease holds strong potential for targeted therapy to improve the muscle and extramuscular symptoms, and the quality of life of patients like Larissa. I will now hand it over to Luc, who will further elaborate on the phase II clinical results. Thank you, Leentje. Isn't science cool? In case you see me limping, I bought new shoes and I regret it. Most of you were at our R&D Day in New York in 2024, where we talked about this particular study and how it, for us, was an example of the best argenx could do, trying to minimize white space and accelerate our path to patients by utilizing an adaptive study design. We built this on, the whole story Leentje has shared with you, the biological insight that autoantibodies are the drivers, not bystanders, and that these lead to destruction of muscle, as you could see in these preclinical models. As we then design this, how do we reveal this biology in patients? We also want to recognize that we need to know what patients care about. We need to know how physicians would assess effect, we chose a primary endpoint, the TIS, which is a composite endpoint that encompasses six dimensions relevant to this disease. I'll go in a bit more detail later. The core feature is, of course, the muscle strength, as we already had said, that proximal muscle weakness is a core feature across the subtypes. Another very important aspect of these diseases is their high frequency of utilization of steroids. Larissa, in fact, talks about this, where she says she gained 40 lbs under high steroid treatment. That is the least, I think, of the problems she encounters with this sort of treatment. We also built in the program, a systematic approach of steroid tapering. Where does another part of the innovation lie is that we said, and I said that on the stage there, one of our core approaches, we want to minimize white space. In this particular case, how can we do phase II/ III development as time efficient as possible? We developed an operationally seamless design, and I will show that more on the slide. Also as a first, and this was already indicated, but repetition is the mother of something. It is the first time that three different subtypes were included in the same trial, and that also the first time that IMNM was in fact included in any study because it was prior an exclusion. What does this look like? This slide now, in 2024, there were no numbers in there because of course this was ongoing. Here you can see that in the 90 patients approximately that entered the 24-week phase II study. The operation is seamless here, just to be clear, is from when we fulfill screening in phase II, we started enrolling in the phase III. The adaptive aspect of this study was that we could stop a subtype should data warrant it. That was the adaptive part of this study, and this is maybe relevant for the Q&A later. As I already said, the TIS tries to capture holistically the impact of this disease and how an intervention could improve it. Muscle strength, physical function, patient and physician assessment, muscle enzymes, and Leentje already showed some of the, stole my thunder there, basically, but okay, w e measure those, and extramuscular activity. These patients, and in our phase III trial, we have up to 175 patients we are following for 52 weeks. What is important to realize as we talk about this is that we on purpose did not have a target per subtype of enrollment. The moment you do that, then you are basically in a convoy situation where the slowest enrolling cohort determines the overall speed of the trial, and we did not want that. Again, speed to patient was essential. Of course, they all had to have active muscle weakness, right? We wanted to have something that could change. The tapering protocol I already talked about was actually only executed in phase III. Why is that relevant? The phase II data I will show you are on top of standard of care. Okay. The primary analysis, this has already been talked about, is that we are really going to look at the individual risk-benefit in each subtype, and the reasons why will come in the next slide. You have seen this slide, Leentje just showed it, to me it is still remarkable that over 24 weeks we could see this sort of effect on active. It is already, as said, highly robustly significant. A very simplified way to think about this is that this is an improvement score, and it is a derivation of percentages, and I can go in a very complicated explanation. It goes between 0% and 100%, and over 24 weeks, the patient on active reached 50% improvement from their condition they were at baseline. Pretty neat. I am very excited about that data. Where did those data come from? Here is the beginning of the story of the change, which is, given we did not have a target enrollment, first come, first served, we saw that we very quickly enrolled IMNM patients to about 2/3 of the study. DM, about a 1/3. PM, quite low. During the panel, we can come back on some thoughts why that is. PM, I'm going to say it maybe wrongly, could be going the way of the dodo. Because as it's recognized that different antibodies are driving, you get more individualized identification, and it's no longer just polymyositis. You can see steroid dose in phase II. There was no tapering done, age, et cetera. 85% had autoantibodies, 15% were seronegative. The majority of this effect you see on the left side, logically, was driven by the IMNM subset. In fact, if you do an analysis, it was statistically significant on its own. DM showed a clear signal, but with that, 30% part of the sample did not reach statistical significance, but a clear signal. Another feature that is common across all the indications with efgartigimod is speed of onset. This shows you that on actually a responder analysis, because if you take the continuous one, it actually starts separating earlier. This is reaching TIS ≥20. Another feature, depth of response, which we all should care about, is that if you take higher and higher thresholds of what you want to achieve, the separation between active and placebo becomes bigger. In this particular case, TIS ≥40, to us, is particularly encouraging. The TIS, as I said, is a composite. Here is just the message that each of the composite parts improved. Look at the muscle dimension. It improved significantly. This is very rewarding for us because this is, again, biology at work. This just shows you again the fast time it does it. Not only does this MMT8 score, the patients feel it on the right very fast. Right. Blue is efgartigimod. From early on, patients feel there's something different. Very exciting to see. What are the risks? By and large, the risks are as we know them very well from our overall safety database. If you look at the event rates per 100 patient years, which is in each column, the furthest to the right, there's not really that much difference. We currently have 25,000 patient years of experience. I was sensitized to this by Dr. Aggarwal. Is that in these particular indications, infections and serious infections are of course always of interest. There is on the more than Grade 3, three patients that's had that in the whole study. I think that stands for the known safety profile. We can discuss this further, but overall, in the context of this, this does not take away from any benefit observed. This is supported by an extensive database and gives us the confidence that we can have a reliable risk-benefit assessment here. What have we learned? What are we doing with it, and why does it matter? We have learned that IMNM drove the phase II result. DM showed a signal, but due to the low sample size, could not reach the significance in the phase II. We went to the FDA with our data package and talked about Breakthrough Designation, and they granted it for IMNM. The reasons being no available treatments and clinically relevant results package in the phase II. The baseline characteristics of phase III, I can tell you, without divulging too much, this is an ongoing trial. We don't want to cause any problems before we close the database. What I can tell you is that the baseline characteristics in phase III are very close to phase II. What does that lead us to? We have an emerging strong data package in IMNM and the potential for a strong data package in DM. That positions us for, of course, overall it must be positive, we can file for at least one of these subtypes with urgency, because thinking again about our principles, speed to patients, and that's why it mattered in the way we designed this program. With that, I give the floor to Josh. Thank you. Thank you, Luc, good afternoon, everyone. Over the last part of the session here, I think you've heard that we have a really exciting opportunity to impact patients with autoimmune myositis. Today, we're really fortunate to have three leading experts across dermatology, neurology, and rheumatology to come up here and talk to us about the landscape, the unmet need, the treatment paradigms, and what's exciting about innovation in this space. With that, let's meet our panelists. Our first panelist is Dr. Avery LaChance, who's an Associate Professor of Dermatology at Harvard Medical School, she's the Director of the Connective Tissue Disorder Clinic at that institution. We have Dr. Arjun Seth, who's an Assistant Professor of Neuromuscular Medicine in the Department of Neurology at Northwestern. Dr. Seth brings deep experience in neuromuscular disease, treating both MG/CIDP as well as autoimmune myositis, was a site in both phase II and phase III. We have Dr. Rohit Aggarwal, who joins us. He's a Professor of Medicine at University of Pittsburgh Medical Center, he's the Co-director of the UPMC Myositis Clinic. He's been a key advisor, I think, as you heard earlier, on this study and on this program. We are absolutely delighted and privileged to have this expert panel, I would like to welcome the three of you up to join me. Thank you. Lovely. Why don't we kick it off with Dr. Seth, I think we're going to talk a little bit about the disease burden and the unmet need in this space. I want to start by anchoring to the patient we heard from earlier, Larissa, specifically a necrotizing myopathy patient. Can you talk to us a little bit about how these patients come into your clinic and present to you some of the struggles they go through? That's a great question. I think a lot of the patients come in exactly the same way that you heard Larissa's story, which is they present with weakness. They're not able to work out or do their normal activities of daily living, so getting up off a toilet, climbing stairs, they go to their primary care providers and explain that they're having symptoms. They're told sometimes that they're just getting a little bit older, and it actually takes a few months to actually end up seeing someone, so a neurologist or rheumatologist, to actually then do this testing to evaluate for a CK, and then discovering that they actually have an immune-mediated necrotizing myopathy. That story is very, very common. Just to follow up to that, even thinking about her disease course, but the course in IMNM in general, right, is we know it's very aggressive. Could you talk to us a little bit about how you think about the urgency to treat there? Immune-mediated necrotizing myopathy, in particular, can be quite aggressive, as can dermato, immune-mediated necrotizing myopathy, typically, patients progress quite quickly over the first three to six months and are initially able to just notice some slight difficulty with, let's say, running or getting up out of bed. Over six months are really in sort of can end up being in wheelchairs. Most of the patients that I've ended up seeing have been coming to me basically in wheelchairs, and they're not able to get up and walk and ambulate independently. That's the sort of burden. These patients have a privilege of getting to you in a very specialized sort of tertiary center. I would imagine that could be somewhat disparate depending on where you are and your access to care. Absolutely. Most patients actually end up coming into the hospital, their first admission is actually into the hospital where they end up seeing a specialist, then get diagnosed, and then initiated on treatment while in the hospital. Excellent. Shifting gears, we'll go to you, Dr. LaChance, and I want to ask specifically a bit about DM. We know even from some of the science we went through and everything else that this is a very heterogeneous disease, I guess. Could you talk a little bit about sort of the variety of presentations that patients come to you with. Sure. I think for dermatomyositis, we've really been anchoring and hearing a lot about the impact of muscle on patients, and certainly we can see a similar thing in dermatomyositis as well, where patients have difficulty walking, getting upstairs, et cetera. But as the dermatologist in the room, like the Lorax speaks for the trees, I'll also speak for the skin and say that actually in dermatomyositis, dermato skin, myo muscle, that inflammation in the skin and the muscle is a really big thing to know about in dermatomyositis. In fact, for a lot of our patients, the burning pain, discomfort can keep them up at night, can prevent them from sleeping, and that skin can have just as big if not bigger impact for those patients as well. About 80% of patients with dermatomyositis are going to have skin and muscle involvement where they're battling both, and about 20% of patients are going to have skin-only disease, so amyopathic. Layered on top of this can also be a multi-system disease where we have to think about interstitial lung disease and other internal disease manifestations as well. This is not really just impacting the muscles, but really is a multi-system inflammatory disease state. Thank you. Dr. Aggarwal, shifting over to you, now thinking about sort of all the unmet need in myositis, I guess, what do you think are the greatest unmet needs today? Well, I think the biggest unmet need is we need more efficacious treatment that are safe and tolerable, and I would add in today's world, that can limit the use of steroid. I think we do not have a treatment that encompasses all three, maybe IVIG in one subset, but overall, in the whole disease, we do not have that, and specifically, we do not have that for IMNM. There is a huge unmet need. The reason that you see a lot more IMNM in your trial is because that's what they're telling you. That's what the subset has the highest unmet need. I think overall, I would say overall IMNM itself needs efficacious, safe, and tolerable treatment, but amongst those, IMNM patients have the highest unmet need. Very helpful. A question about, I think Leentje did a really nice job of showing how symptomology has evolved the subtypes over time and how we've learned more about autoantibodies distinguishing subtypes over time. I guess, how has it evolved from your perspective when you think about practicing in this space? In the last 20, 25 years, what has happened is nicely put by the slides that how the DM and PM was combined and then they took apart and how the journey of the myositis diagnostically. All of that has been influenced heavily by autoantibodies to begin with. Diagnosis and classification has been heavily influenced. We know autoantibodies define a unique clinical phenotype, so we know that for sure. Lately, we have been using autoantibodies to drive our management itself. What has happened in the last about 5- 10 years, we are seeing increasing data about pathogenic role of autoantibodies, largely to multiple scientists across the world. I would say NIH has really shown convincingly that how these autoantibodies are playing a direct role in pathogenesis, which so far was thought about, but we didn't have a direct proof. Now we really have these direct proofs that lowering these autoantibodies should get to the improvement. Even in 10 years ago, when we did studies where the antibodies level will go down, disease get better, antibody levels go up, disease get worse. We knew their clinical association, but having a direct pathogenic experimental proof was not there. I'm really happy to see that coming through now. Dr. Seth, I want to sort of ask you a similar question. I guess thinking about how you've seen it evolve and also around autoantibodies in your experience in this space. I think the autoantibodies, you're absolutely right. It really does help guide our management, especially if we find an HMGCR antibody or an SRP antibody. We know sort of what the phenotype looks like, so what patients will present with in terms of their weakness, their sort of clinical course, and can actually change our treatment strategy based on that. There's also a whole subset. The HMGCR antibody was only discovered 16 years ago. There's a lot of these other novel types of immune-mediated necrotizing myopathies, what we call seronegative, without known antibodies that probably exist. They present very similarly. We do send to other labs to look for actually different types of novel antibodies that will present in the same way. Dr. LaChance, I want to ask you a very similar question. In dermato, which we know that autoantibodies, depending on your phenotype, have a profound impact on your comorbidity risk and other things. Love to hear your thoughts. Yeah. I think a couple things to nail home is that in dermatomyositis, first off, the autoantibodies are not needed for diagnosis. Your diagnosis is really based on what you see clinically for patients, and I think it's a really important thing to know that actually the sensitivity of some of these assays can really vary by institution and where we send these labs off for. Historically, if you look back at a number of the different studies that have come out, some say X number of patients did not have a positive autoantibody. Probably if you had a better assay, you are going to detect that autoantibody, and I think now more and more we're realizing, and I think the dermatomyositis kind of purists and experts for a long time have really thought actually those autoantibodies are there, we just need better assays to detect them. I think that's one thing that's important to nail home. Secondly, in dermato, although you don't need those autoantibodies for diagnosis, exactly as has been mentioned, it can be really critical to help prognosticate what you're going to expect to see for patients in terms of comorbid disease. Some patients, their autoantibodies, MDA5, you're going to be very worried about rapidly progressive interstitial lung disease. Other patients may have very NXP2, mild skin disease, very aggressive muscle involvement. Those autoantibodies, seeing that they play a role really in driving this heterogeneous disease state and the different things that we see in terms of how they present clinically helps us also understand of the role of these autoantibodies as truly pathogenic. Excellent. Shifting a little bit to the treatment landscape and then the FcRn rationale, and maybe this is a question for the group. When we were reflecting on the data we saw in phase II, and we're going to see in phase III, it's not a true placebo group, right? These patients are on a background of steroids and DMARDs. Obviously, I know the three of you are experts and are doing a lot for complicated myositis, but when we think about the limitations of what's in the toolkit right now, I would love to hear some perspectives. Maybe, Dr. Aggarwal, we'll start with you. Yeah. I think we have been using the toolkit that was prescribed to us from rheumatology per se, which is DMARDs, methotrexate, mycophenolate, tacrolimus. None of these are really proven, and none of them really works on its own. They need s teroids, plus these immunomodulators, would work. If you look at the overall outcome in our studies, in our center for 10 years, only 20% of patients had any major outcomes in the past when we didn't have more immunomodulatory therapies. In dermatomyositis, we are fortunate now to have IVIG that does take it to the next step. That's it. That's all we have. I think the unmet need from that standpoint is huge, and I think we have nothing. When our IMNM patient comes in, we know that in three months, this patient is going to be wheelchair-bound and have nothing to really push the treatment forward other than keep bombarding them with steroids, next immune suppressive agent, next immune suppressive agent, and nothing else. I think that's a really significant unmet need that we feel that needs to be fulfilled by hopefully the drugs like FcRn receptor blockers. Excellent. Dr. Seth, I don't know, anything to add? Oh, that's a great answer. Yeah. I totally agree. I think there has been a huge unmet need, no FDA-approved drugs for IMNM, I think that's where this space and this trial actually fills that space. Dr. LaChance, I want to ask you slightly differently, right? These patients are going to be chronically immune suppressed for a long time. How do you think about that, and specifically, how do you think about steroids, and they may have to be on high doses of steroids? Yeah. I think for a really long time, exactly as the docs up here have mentioned, that we've been having to rely on our DMARDs, so methotrexate, mycophenolate mofetil, can you imagine coming into your doctor and saying, I can't walk, or I have this burning rash, we say, okay, I've got a drug for you, but it's going to take three to six months to kick in. Then the eyes get wide, you say, okay, but while that's ramping up, we're going to turn this off really quickly with a fire hose. That's where the corticosteroids have come in to really turn disease off as we're waiting for those slow ramp-up steroid-sparing agents to kick in. Those steroids, we have to remember, have a really big impact for our patients as well. There are a lot of risks associated with long-term high-dose steroids. Especially when we're talking about in the myositis space, there can be muscle impacts and loss of muscle from those long-term steroids as well. Then over time, you're saying, am I dealing with a steroid myopathy? Are we still having ongoing inflammation? There are these really important things that we need to know that the steroids can do. For a while, we've had to layer therapies on, it's a really exciting time to now have some more targeted, quicker-acting agents that we can bring into this space, that's really needed to have that steroid-sparing effect and prevent long-term damage. Can I just jump in on that? I feel like sometimes I exchange the disease. Yeah. Give them tons of steroids, make me feel better that their myositis is better. I show the numbers, the CK is going down, but I'm exchanging a big long-term disease with them, which includes diabetes, cardiovascular disease, bone health, muscle health, kidney. I feel like I feel better, but I'm not sure I'm really doing a good job by giving them long-term morbidity and mortality risk. Very helpful perspectives. Thank you. I guess shifting gears a little bit and thinking specifically, I've heard a lot of your talks in DM and complex DM, and then learning from you about how you think about it in your clinic, but we know there's a lot of innovation in this space. How do you see the role for multiple MOAs in the DM space in the future? Yeah. I think as a dermatomyositis doctor, it's a very exciting time to be caring for these patients. Actually, it's not like we have just been waiting for the one magic bullet to come through and treat these patients as the only thing. A lot of times, first off, we've heard how these are complex disease entities. There are multiple pathogenic drivers of disease. Actually, to date we've been using JAK inhibitors off-label, we've been using IVIG, we've been using our DMARDs. It's really not uncommon for us to need to layer different therapies together. In fact, we use DMARDs and IVIG, we use IVIG and JAK inhibitors off-label still currently in combination, because exactly like I said at the get, for dermatomyositis, a lot of these patients, you may control their muscles with one thing, but their skin is still burning or their interstitial lung disease may still be progressing. It's not uncommon for us to need to layer therapies for patients. Actually, having multiple MOAS, multiple targeted agents, all in the name of getting patients off of steroids is very important, very exciting. I think we will be using these therapies in combination moving forward. To keep up with that same theme of the last answer we heard from you, Dr. Aggarwal, and the way you finished your answer, Dr. LaChance, let's talk about the steroid taper in phase III and how you think about that. What is that going to accomplish? Why could that be meaningful when we see the data? Yeah, I think really if you think about 10 years ago, we were not doing steroid tapering in myositis trial because at that time we didn't have any treatment available. There was nothing available. They said if we do steroid tapering, it may jeopardize the treatment outcome. Now the thinking has evolved. What we are seeing is studies after studying long-term effects of these steroids, specifically in myositis, coming out. Doctors are now worried about giving long-term steroids. I think that's one of the reasons. The clinical reason is so huge because doctors are seeing burden of these long-term steroids when they follow these patients 5- 10 years down the line. Their myositis might be better by now. Now there's a lot of other problems. That's the clinical reason. Also from the regulatory standpoint, the FDA has learned through various other studies that, look, this is a very critical area for regulatory bodies to make sure the drugs are effective on their own, not because they're on the background steroid, because that's what has been happening till now. Now they want newer drug, novel therapeutics, or targeted therapies to be effective on their own, not requiring steroid help, and now steroid has done this much job, let's move it to here. No. The whole thing has to be traveled by that drug so that the steroid can be tapered off to large extent. How do you see FcRn inhibition fitting in to that potential? In phase II, we did not do steroid tapering because it's more proof of concept, but my expectation is in phase III, we should see robust steroid decrease in patients who got the drug versus who got the placebo. That's my expectation, that's my hope, and it will bring a lot of hope and excellent outcome for our patients. Thank you. Dr. Seth, I think you have an interesting perspective here as a neuromuscular physician who has been using efgartigimod in CIDP and MG and have a lot of experience, as well as being a trial participant, right? Having subjects enrolled. I'm curious, what is your outlook on sort of the mechanistic rationale here, and how do you think this is going to fit in, specifically in IMNM? I think we know that these are IgG-mediated disorders. We have good evidence to say that. I think depleting the IgG and those pathogenic immunoglobulins does play a role. We've seen that in myasthenia quite robustly and also shown steroid-sparing effect. It reduced the amount of steroids that patients have needed. CIDP similarly have shown benefit in that. I think the same thing will happen with this study as well. I have two patients enrolled in the phase II, they have been fine and doing pretty well on their background immune suppression, and have tolerated the drug really well. Very helpful. Thank you. I just wanted to make one more point. The fact that we have one drug approved, that's going to be all it, this is an autoimmune disease. The median mean age is 50 years. They're going to live another, let's say, 30 years. It's 30 years of drugs. A single drug will not going to cut it. Even in DM, I would say we need at least three or four or five drugs to really be able to serve about 90% of our patients. I think the fact that one drug is approved, now this is a second drug, is a wrong understanding. This is not a second drug. This is an option for the patients that could be even the first line in future. I know you shared sort of an interesting insight earlier about how we've seen that in some of the more complicated spaces where innovation has taken place in the last decade, like RA. RA is a perfect example. We have 20 drugs approved in RA, I still struggle with some of my RA patients. These are lifelong diseases, that one drug may work for one year, two year, maybe 10 years, but it may fail because autoimmune disease evolve and overcome that mechanism of action, you may need a second mechanism of action to counter the disease. I think this autoimmune space is a chronic disease space where these drugs are going to be used for long term. Very helpful. I want to shift gears more towards data impressions, specifically from the phase II ALKIVIA data. I think we saw some nice details from Luc earlier about some components of that. Dr. Aggarwal, I'll go ahead and start with you on this. Let's talk a little bit more about the Total Improvement Score, because this is a complicated sort of multi-component score. There's a lot to unpack. Could you tell us a little bit more about how you think about sort of the six core attributes and why they're meaningful? I think before talking about Total Improvement Score, I want to take you to rheumatoid arthritis, because that has been the major disease that revolutionized rheumatology in the last 25, 30 years. The reason that rheumatology has been revolutionized by the RA field because of these clinical trials that use composite response criteria called ACR 20/50/70. Some of you may be familiar. Rheumatologists are very familiar with composite response criteria. Why? Because in rheumatology, it's not a single disease, it's not a single organ, a straight manifestation. It's a complex disease, a heterogeneous disease. We need composite response criteria so that we can hit multiple aspects of a heterogeneous disease. Same in myositis. We need to know how's the patient feeling. We need to know how the physician feeling. We need to know how the biomarker is doing. We need to know how the skin is doing. We need to know how the muscle is doing, how's the function is doing. You get a better overall picture. If we use a single outcome, we will not be successful in any of these clinical trials because of highly heterogeneous nature of the disease. Some patients are worried about their skin, some about their lungs, some about their muscles. That's the power of the Total Improvement Score, encompasses six outcome measure that looks holistically the patient. Because of that improvement, you're able to see overall we feel patient improved. There is deficiencies that you see the patient improve overall, you may not be able to say what aspect of the patient improved that led to overall improvement. For that, you have to look at the core set measure improvement to see what exactly improved that the patient had an overall improvement. Just to further ask some questions about Total Improvement Scores. I think one thing we've seen across trials is that there can be a very notable placebo rate. Yes. I was wondering if you could give some insight on that, and anyone else is welcome to weigh in as well. The placebo rates are not truly placebo rates. Think about this. These are patients on one, two, or three drugs on the background immune suppression. The background immune suppression is going to improve the patient. That's one aspect. It's not placebo. Standard of care, okay. The second part I wanted to mention is the moment the patient gets into the trial, they were not taking their methotrexate earlier, they start taking their methotrexate now. They were not exercising, they start exercising now. They were not taking care of their health, they start taking care of their health. There is a second aspect which is also not placebo, which is truly treatment. The third aspect, which is true placebo, which is the bias that comes in because of the hope of being in a trial. I think the overall placebo effect would be wrong to say it's about 40%, 45%. It's about 10%-20%, which is pretty normal in any of the studies. The rest of it comes from standard of care treatment, taking the medication on time, taking care of yourself. This is not the only study where we have seen this type of placebo response. Almost all myositis studies, we have seen significant high rates of placebo response. That also speaks to the extent that if you have a positive study, despite high placebo response, that means the treatment is working really, really well. To overcome that placebo response is not that easy. I think from that standpoint, I believe that this delta of 15 mean TIS and a delta of 20%-30% is hugely meaningful. I also think added on top of that's why it's going to have the steroid taper in phase III is going to be even more meaningful because I think that's where there will be. We've just talked about all the risks associated with steroids, long-term steroids, having that layered on as a real-world thing, and also a delta already up four weeks, I think is very important because that doesn't mean we're going to have to wait six months to start to taper those steroids. I know that when you're just taking care of patients with myositis, they're not part of a trial, you're probably not evaluating a total improvement score, right? You're looking at them. I do think we saw moderate and major improvement marks up there, right? A TIS ≥40 and a TIS ≥60. I was wondering if we could maybe hear across the panel, what is that meaningful impact for the patients you see that's representative of that? Dr. Seth, I don't know, let's start with you. Sure. I think some of the big things are functionality. Getting up off a toilet, climbing stairs. I ask patients that, or simple things like rolling in bed. Patients with immune-mediated necrotizing myopathy have a hard time actually rolling around in bed and getting on their side, even to do assessments, even for the clinical trial. Those sort of simple things, or having to sit up. These patients, when they do come in, they're really weak, and those are the big questions I initially ask them. Swallowing. If their swallowing is impacted, they tend to lose a lot of weight, because they're not able to keep up with nutrition, they tend to lose around 30- 40 lbs as they're going through this whole process. If that's stabilized, their weight has stabilized, and they're able to swallow. Those are big things in terms of functionality that I look at. Yeah. From my standpoint, what I look at is TIS ≥40, because we have done studies where it shows if you hit TIS ≥40, that means your pain is improved, your function is significantly improved, fatigue is improved. If there's skin involvement, and skin is part of TIS, then your skin has improved. Overall, their activity, function, pain, fatigue, all the disability part has improved. It's really meaningful. For me, TIS ≥40 is very meaningful. If you ask me, looking at the data, would you tell somebody that 80, 90% of patients improve because TIS ≥20 improved? I would say no. I would say 70% patient or 77% patient improved because TIS ≥40 improved. For me, TIS ≥40 is my gold standard. That's what I evaluate the drug on. I think to add in the skin layer as well, what we're looking to see is decreased pain, burn, and itch, and there's actually a lot of data out there that itch is as impactful for patients as pain, and that itch and burn in dermatomyositis is a very high impact on quality of life. Patients will say, I can't sleep. It's all I think about all day. When patients are improving, they say, I feel comfortable in my skin again. That's really what patients are saying, to say it's not just the look and the appearance of their rash, it's how they feel in their skin. Excellent. I want to change direction for the last question here and talk a little bit about the implications of innovation and changing the standard of care in a space and what that really means. Knowing that you all are at tertiary care centers, you're seeing complex patients. If new innovation is in this space, how do you think that's going to change as far as how patients can access treatment from tertiary centers to the community, and how will it impact the overall amount of patients that are being seen with these diseases? Dr. Seth, why don't we start with you? The myasthenia work has been outstanding, okay? Honestly, with the ads and everything on TV, patients come out of the woodworks for evaluation for their myasthenia. I think the same thing will happen with myositis. Patients who are weak or have weakness will end up seeking additional care. With more awareness, they will actually look for care. I think some of the things that we've been doing, at least at my institution, is we have trying to disseminate information on myositis and train our trainees and others in the community about inflammatory muscle disease so that people can recognize it more. We've done a lot of work on that aspect, at least in Chicago. Everybody's next. Yeah, I think absolutely the same thing we've seen as targeted therapies are there. We see more patients coming up and even self-diagnosing and recognizing the disease. I think we're going to have to do a really good job of educating our community providers as well, our community dermatologists, our community rheumatologists. Actually, one of the benefits of a subQ therapy and oral therapies is there is an ease of prescribing that's not there with an infusion-based treatment. Actually, we have a lot of our community dermatologists feel very comfortable prescribing a whole multitude of targeted therapeutics in psoriasis, atopic dermatitis. With a clean safety label that's on the derm side, what everyone's always looking for, and subQ injectable dosing, those are two things that people are getting much more comfortable prescribing. I think as we can empower people to diagnose and start treatment sooner, more patients are going to come in, and hopefully, we're going to see a dissemination of treatment, not just in tertiary centers as well. Yeah, I agree. I think that education is key because community doctors look at the KOLs for the education. Talking about in state rheumatology societies, ACR, EULAR, where you communicate that, look, the treatment paradigm is changing. Stop using excessive steroids. Stop using DMARDs after DMARDs that are ineffective and you're losing time is muscle, and you're losing muscle in that timeframe. That education has to be communicated to the community doctor. Once they know that, it is very easy for them. They know how to get approval. They know how to get started with treatment. I'm not worried about that part. Only the education part, I think is the most important. I think I want to also touch upon increasing diagnostic tools is another area that the companies like argenx should focus on because there are a lot of misdiagnosis, there are a lot of delayed diagnosis, there are a lot of the patients who don't get diagnosed, old age. Once you give a person who comes with milder, maybe milder phenotype, you give them a wheelchair, do you think anybody's going to care about them? No. I think there is a lot of misdiagnosis and undiagnosed cases that diagnostic tools can really cover that ground. Very helpful. I'm going to close there, and I'm just going to say a profound thank you to the three of you for spending the afternoon with us. I think your insights are so valuable for everyone here. Thank you very much and appreciate it. Thank you. Thanks. At this point Thanks. Thank you. Now it's my pleasure to welcome Sandrine to the stage to talk about the commercial opportunity. Thank you. There you go. Thank you, Josh, and thank you to our panelists. I'll bring it home, bringing everything together from the biology and the science, the unmet need we heard about, and then VYVGART. Yes. I prepared this slide actually without knowing what our panelists will speak about because I wanted to anchor our discussion on the commercial opportunity on the unmet need. Actually, I think this is a pretty good summary of what we just heard. We heard from Larissa, my muscles are dying. I heard Dr. Aggarwal, you finished by saying, time is muscle. We heard patients who have IMNM within 3-6 months end up in a wheelchair. This notion of disability is very, very present, and this can impact the daily work, or this can impact them going climbing stairs, going to bed, et cetera. That's something where there is a huge, huge need. We also heard that the toolbox that is at physician disposal right now is far from being sufficient. Many patients need more. Many patients are going to live 10, 20, 30 years, and what is available today is not sufficient. We also heard that steroid tapering is going to be critical because long-term steroid use is not good for anyone. Actually, we saw in some studies that more than 85% of patients that suffer from myositis use steroids, and 60% of them are on those that are as high as 20 mg/day. This is not sustainable for the long run. You're adding to the disease beyond myositis. For all these reasons, there is a need for medicines that can bring what you have here on the slide. Rapid onset of an efficacy because time is muscle. Systemic efficacy, especially on the muscle, we heard for DM, 80% of the patients have both muscle and skin involvement. In IMNM, this is mostly muscle involvement. The safety, the long-term safety will be critical and have an established safety profile will be key that allows for steroid tapering. At the same time, we heard what Dr. LaChance finishing, convenience could also help. If you have a PFS, subQ or oral, much better than having had patient that have to come to the hospital for an infusion. That would be the perfect profile of medicines coming to the market to help these patients. What we know at argenx is that we have a playbook, something that we have been using to make our launch in MG and CIDP successful. This playbook is based on three pillars. High unmet need that I just described is one of these pillar. The other one is very clear biology, and Leentje here explained in details why we believe autoantibodies are really driving the disease and that the biology is very clear. The last key pillar is that this must be white space. Very little medicines and drugs available, little competition, little opportunities for patients to have actually tools in their toolbox that can make a difference. If you apply that to IMNM and DM, you see that actually we have a perfect argenx indication with these two subtypes. Let's summarize what we heard about IMNM. The biology, very clear. This is the strongest body of evidence we have of autoantibody-driven disease. We also conducted market research since many years, but the most recent one in this first quarter, I looked at it and there was one quote that stood out for me that one of our providers said. He said, stop the damage now. If we have to remember what is the unmet need is that we have to go fast, have a drug that act really fast with a rapid onset of efficacy. Sustained efficacy, especially on muscle. That's what we saw is the core need for IMNM. We heard in IMNM, there is nothing. Nothing has been approved. Drugs are being used off-label. The unmet need and the sense urgency is high. This is why when you ask physician in a market research, which has been blinded, we didn't share the names of the drug nor when we shared high-level profile of different drugs. Nine out of 10 rheumatologists who don't know VYVGART, nine out of 10 said that they would use VYVGART to treat IMNM should it be approved. If we move to DM, there the biology is clear as well, also driven by autoantibodies, but the spectrum of autoantibodies broader, which leads to more heterogeneity in the disease manifestations. You heard from Dr. LaChance, 80% of the patients have both skin and muscle involvement, and it goes even beyond that. If we have to summarize the unmet need here from this market research we conducted, actually the one I kept here was, help me manage for the long haul. This is the long-term management. Patients will live for long-term, and we need multiple options, and we need to make sure that the safety profile of these options is very strong, very established, and that we can use it for the very long term. VYVGART, 25,000 patient years experience. The profile of VYVGART is very strong from a safety perspective. In IVIG, there is already a treatment approved. IVIG already exists, highly burdensome for patient, as we know. We know that space quite well because in CIDP and MG, this is also drugs that are being used. We also know that in DM, you will need multiple mechanisms of action. Like you were saying, Dr. LaChance you need to layer one after the other just to make sure that it's fitting the different needs of the patients. When presented the blinded profile of VYVGART to rheumatologists, actually eight out of 10 say that they would use VYVGART to treat DM in case VYVGART would be approved for this disease. This shows that there is truly biology, unmet need, and white space, and it all boils together by a strong willingness to prescribe VYVGART, should it be prescribed for these two subtypes. Now the question I often get is, how big can it be? What we have been saying is that there are 20,000 IMNM patient diagnosed in the U.S. This is more than what often you see in literature. We triangulated this number using registry, using claims data, and physician information. We strongly believe that there are at least 20,000 patients diagnosed with IMNM in the U.S. This is more than the total addressable market that we had at MG when we launched MG in 2021, where we said 17,000 patients in the U.S. This is more than the CIDP total addressable market of 12,000 patients. This is a sizable opportunity. We know that there is a high sense of urgency to treat these patients, so the penetration will be fast and high. What we also know is the dosing for this patient is a CIDP dosing, so weekly use. If you combine all of that, IMNM on its own will be a multi-blockbuster opportunity. If you add to that DM. DM, bigger number of patients. Proxy, we estimate that 40,000 patients diagnosed with DM in the U.S. As we know, it is an heterogeneous disease. Multiple mechanisms of action can coexist and will be layered. There is room for multiple players, this is a broader market that we will share. This will be also significant opportunity. 20,000 plus 40,000 is 60,000 patients. This is actually the size for the people who have MG in mind. The total addressable market we have been speaking about is that MG now is a 60,000-patient total addressable market. This is the size of MG as we define it today. Then we have to add something else that our panelists mentioned at the end of day two, which is the biologic market expansion. This is often something we forget. Systematically, think about MS, when there was nothing and more treatments started to come on the market, more noise around optionality, more diagnosis, patients coming in, the market grew. Same for MG. We put MG on the map, now look at the number of players coming to the market, but also the number of patients being diagnosed and being put in the addressable market. Same for CIDP. We believe this will be the same case for autoimmune myositis, where the market itself, as it is defined today, is going to expand. If you bring that all together, this is an amazing opportunity to make a difference for patients. This is why we haven't been waiting for approval to start getting ready. What impressed me when I joined argenx six months ago was the commercialization engine. What argenx has been able to do since they launched and were approved in MG 4.5 years ago is unbelievable. There are a few strengths that this team has, the commercialization team has, and these strengths will be leveraged also for autoimmune myositis. The first one is our patient support programs. You are in rare disease. These patients need a wide global approach, and that we offer. That's what we offer, this is not going to change for autoimmune myositis. We are going to have this wide global approach for them as well. We also need extremely strong market access capabilities. For each of our indication, more than 90% of the lives in the U.S. cover VYVGART, we are going to leverage that same engine of market access also for autoimmune myositis. We also have an amazing team in the field. MSL or sales team. Actually, one provider mentioned to us, I don't only prescribe the molecule, I also prescribe the team behind the molecule. People who work at argenx are amazing, and we are going to use these people also to make sure that patients who need VYVGART, if approved in autoimmune myositis, will get it. Of course, we are going to augment this engine with some capabilities towards dermatologists and toward rheumatologists. This is important. That's what we have started to do, at least since a couple of years. We have engaged with autoimmune myositis patient advocacy groups working about education, how important it is to make noise around it. We have been proactively engaged with payers to educate them about the disease so that they are not taken by surprise when we come with a positive trial, if the data are positive. We have expanded our MSL team already since a while, and they've been engaged with 650 autoimmune myositis key opinion leaders across neurology, dermatology, and rheumatology. Actually, we like market research, so we did the market research to ask them, of all the MSL you engage with in the industry for autoimmune myositis, which one do you prefer? argenx came first. This is great. It means that the quality we have seen in neurology is also seen in rheumatology and in dermatology. We have also launched a disease education campaign, and we know how important this is because we want to make sure the market expands and that patients are aware that if they feel tired and weak muscle, maybe there is something, so that we trigger more diagnosis. Then we have planned a sales force expansion into rheumatology and dermatology once the data are positive. We are waiting for that. We can then press the button and make that happen. All in all, we are getting ready for a successful launch because patients really need it, and if we can avoid as many patients as possible ending up in a wheelchair, it would make me and all my colleagues at argenx so happy. With no further ado, I'm going to hand it over back to Karen, our CEO, to close, not the meeting because we still have Q&A, and I'm sure there will be questions knowing this audience, and to bring Karen back on stage. Thank you, Sandrine. That was great. Thank you. I want to close giving some of the key messages that you heard today, and just recap and then make a link to Vision 2030. What did we hear today? Number one, conviction in the biology. You heard from Leentje. It is clear that autoantibodies are driving this disease, and VYVGART is a targeted therapy that removes those autoantibodies. Number two, I think you heard clarity on the clinical data from Luc. In our phase II study, we had strong data, in particular statistical significance on the primary endpoint, the total population, statistical significance on IMNM and a clear trend or a clear signal in DM. Remember, there was less patients in DM. We have strong conviction as we go into phase III, phase III study is twice as big, twice as long. We have strong conviction in the potential for a positive outcome in the subtypes of IMNM and DM in the phase III study. You heard from Sandrine a very compelling commercial opportunity. We see both IMNM and DM individually as blockbuster, or as Sandrine said, multi-blockbuster indications. Conviction in the biology, clarity on the clinical data, and a compelling commercial opportunity. What's next for myositis? In Q3, we'll turn over the data card, and we'll see the outcome of the phase III data. What you heard today is that we have updated our strategy. In the U.S., we do not plan to analyze and file the data on the total population. The plan is to analyze IMNM on TIS and look at the data, and based on the strength of the data, have a path to filing in IMNM. We plan to separately analyze the DM population, based on the strength of the data, have a path to file for DM. PM, based on the fact that it enrolled in a similar way to phase II in phase III, we do not believe we will have sufficient data to be able to file. Hopefully that provides a clear path forward for myositis based on the compelling opportunity that we have in IMNM as well as DM. With that being said, how does this link to Vision 2030 and the future that we are creating with argenx? As you all know, Vision 2030 is our engine for growth and being able to deliver growth in the short, mid, and long term. Our goal is that we have 50,000 patients on VYVGART by the end of the decade. The majority of that will be delivered by MG and CIDP. Myositis, if approved, IMNM and/or DM will also contribute meaningfully to that 50,000 patients. In terms of 10 labeled indications, we have MG, we have CIDP, and ITP approved. With the data reading out in Q3, we have the potential to add two indications, IMNM and DM, to our goal of 10 labeled indications by the end of the decade. On our goal around five molecules in late-stage development by the end of the decade, we are well on track. At the end of this year, we have our first data readout for empasiprubart in MMN. That's our next molecule beyond efgartigimod. That's an exciting moment for the company to start building beyond FcRn. We have much more coming, and we're well on track to have five molecules in late-stage development by the end of the decade. Our goal as a company is not to be an FcRn company. It's to be an immunology innovator and a disruptor in the space. We're building the portfolio with the breadth and the depth to be able to deliver VYVGART, FcRn leadership over the long term with our next-generation molecules, as well as a broad and deep portfolio beyond FcRn. With that, I'm going to close the presentation part of the meeting and bring to stage Beth, Sandrine, Luc, and someone you haven't heard from yet today, Peter Ulrichts, our Chief Scientific Officer. Come to the stage. The good news is we are right on track for Q&A, we have about 30 minutes to go through Q&A, there's also time afterwards. We have a reception, and so please come and find us. Hello. Thank you. Yatin Suneja from Guggenheim. Thank you for taking my question and putting this wonderful presentation. Two for me. The first one is, could you maybe talk about how well does IVIG work in IMNM and DM? What is the hypothesis that you would see a bit of a differentiation or differential effect in these two subtypes, especially for FcRn mechanism, which tends to be a little bit more cleaner and more narrower? The second is more on the regulatory front. Any feedback or buy-in from the FDA on these two separate paths that you are highlighting, and what would be the split of these two subtypes in the phase II study? Thanks. I suggest actually, Peter, do you want to talk about the IVIG and IMNM and DM, also, Sandrine, you can layer in, and Luc, of course, to hear from the filing strategy. Yeah, I think it's clear that IVIG does have an effect in dermatomyositis as it's approved there. IMNM, as the panelist will confirm also, is showing benefit in IMNM. On what the mechanism of action of IVIG is in these subsets, it's a bit unknown whether it's linked to autoantibody reduction or complement inhibition or something else. I think in IMNM, based on the phase II data which we have, I think we saw a very strong signal, which is definitely competitive as compared to what we see with IVIG in these patients. For DM, I think what we need to understand, not only for IVIG but also for the JAK-TYK inhibitors, is how they will work in that spectrum of autoantibody present in DM. What we do know is that these treatments are working. What we don't know yet is how good they're working for the individual subtypes in terms of autoantibody. I think that is something which we will learn in the future, and our data from ALKIVIA will help understanding that and will help also positioning the different mode of actions or maybe even show that there's room for combination treatments. Luc, the second one was on the regulatory front, feedback or buy-in on the strategy. This, as we said, we went with our phase II data set to the agency discussing the potential Breakthrough Designation. They looked at the data package. They picked up the IMNM results as being quite significant. Also, where the white space is in terms of available treatments, they selected that one for Breakthrough Designation. Of course, we discussed the whole package, and it is clear from that and also from our sample size that we talked to. phase II, you saw the proportion. We see similar proportions in phase III. The inherent probability to hit on IMNM is just higher. They are very interested in the risk-benefit assessment of that. If the data card is turned over and DM makes it, we evidently will also include that in our filing. Maybe just to add on the question of the engagements with the FDA and related to the subtypes. Yes, obviously, we're engaging with FDA on an ongoing basis, but there is a path to approval for the subtypes based on the analysis. Hey. Andy Chen from Wolfe Research. Just a question on the difference between IMNM and DM. Obviously, empirically, it looks like your data is better in IMNM. We also learned earlier from the experts today that IMNM is a more aggressive disease, and doesn't that just make it harder to treat? Why is it that efficacy is now worse or is now better in DM? Is it just because of the sample size is smaller, so you saw maybe an unfavorable swing in the data? Is it possible with the phase III we're going to see better data on DM just because it might be an easier-to-treat population? I don't know, Karen, if you want to start and then Luc. Yeah. Vice versa. Yeah. Go ahead, Luc. Yeah. I know. I think, in fact, the speed of enrollment shows that the IMNM, as was already said, a very high unmet need, and patients came in at times we could still affect the disease. That to us, very rewarding to see that us opening that door and it actually allowing them to create such a benefit. From my point of view, it's not an inherent more likely to or not between IMNM and DM. It just we got a much higher influx allowing us to have a better assay sensitivity, if you will, of the trial. Now, indeed in the phase III, as was said, double the length, double the size. Even if it's at 30%, it's again going to be a significant sample size on its own. There is a reasonable likelihood that DM can come from a clear signal to a significant signal. It's just lower than IMNM inherently. Great. Alex Thompson from Stifel. Thanks for all the updates here. I guess, again, on the primary endpoints and thinking about the bar for the subsets, I think in the prepared remarks, you talked about a clear path for IMNM and sort of looking at the primary analysis on total TIS. For DM, is there as clear of a path there as you think about it? Is it total TIS? Are there the totality of the data? What is the role of the phase II dataset when you're thinking about filing in DM? Thanks. For dermatomyositis, we also took the CDASI. They are multiple readouts we have. The TIS isn't less weighted towards dermatomyositis, if you will, because the derm is only in the extra. Extramuscular Extramuscular, yeah, thank you, domains. For me, the foundation of the path is the strength of the delta in the sample, and that is dependent on what's the variability in the phase III that allows, is it lower or higher than in phase II? We will really only know that once we turn the data card. That's why we say in at least one it's clear, because 60% or 2/3 of the sample in phase III from IMNM, we feel that has a very robust chance of repeating what we saw in phase II. Yeah, maybe just to add, if this helps, because I think this is an important point. There's no difference in the analysis strategy for IMNM versus DM nor the filing strategy. The only difference is there's more patients in the IMNM group than the DM group. That's the simplest way that I think about it. Let's see. Where's the mic? I have it. Okay. Thanks. Tazeen Ahmad from Bank of America. First of all, thanks for hosting. Second, maybe this is for Karen. Since there's a lot of focus on DM, you've provided us a lot of color, and also I think the physician panel was helpful. I think Dr. LaChance said that 80% of DM patients have muscle involvement. Do you have a sense of the type of patients that got enrolled that were DM that have that? Do you think that they match that 80% of patients who have the muscle involvement, and does that increase, as a result, the chance of the DM portion of the study working? Again, assuming that it's a smaller N of patients relative to IMNM, but do you think that as long as that portion holds, does that have a good chance of allowing that portion of the study to work? Yeah. Yeah, there's two. Oh, yeah. Maybe I'll jump in and then Luc add as the expert. Two things that give me confidence on that front. One is that if you look at the baseline characteristics, the commonality across IMNM and DM in the inclusion criteria, what you'll see in the baseline characteristics is the score of 120, which is the average severity of muscle weakness. So we have patients from the DM patient cohort. They have that muscle weakness, so we should be able to see that. Yeah. Oh, sorry. Go ahead. No, I think to answer directly your question, there's an inclusion criteria, which is demanding for a certain amount of muscle weakness, so I think it will be even more than the 80%. Actually, it will be 100%. The other important point, just to add to that, there's the inclusion criteria. What's important that Luc pointed out is the significance of demonstrating impact on MMT8, which is the muscle component of the TIS score, and we saw that in phase II. That's important because there is muscle weakness present in dermatomyositis. It's not just skin manifestations. Seeing that significance of that clinical endpoint of MMT8, I think is a good signal for DM. This is David Nierengarten, Wedbush. I was curious on background with steroid use. Is there any differences in general patient benefit for steroids, patients who have dermatomyositis versus IMNM, and therefore, would the steroid taper affect those populations differently in the phase III? Maybe one of the KOLs wants to talk about the difference from a clinical perspective? From a clinical perspective, I think what happens is because IMNM is more refractory, you see how many patients were included, they tend to have higher steroid use as compared with dermatomyositis. These patients are entering in the trial, that means they are definitely refractory, they would also have a significant steroid. There may be a small difference between the two, but overall, I think the median steroid dose was 10 mg, and that's the same median steroid dose we saw in IVIG study, which was only dermatomyositis. I think there may be minor differences and perhaps a little bit more in IMNM or a little less in DM, but pretty much both would require steroid because these are refractory patients entering clinical trials. Specifically linked to the trial, I think we have, of course, set specific rules in terms of steroid use, stableness, and the tapering, which is identical between the subtypes. I don't think it's a factor there. Hi, Sam Semenko. Thanks for the question. Two questions from me. For the IMNM and DM subgroups in the phase III, given we know that they're the same, roughly, enrollment as phase II, just to put a finer question on it, could you maybe speak to the powering that we have in each of these subgroups? Then layering on top of that, for the placebo arm, now that we have the steroid taper in the phase III, does this give you more confidence that the DM subset could be positive? Thank you. Yeah. We're not going to actually discuss what the actual power is. We just are confident that it's robust enough to be able to complete the mission, which is bring VYVGART to IMNM patients based on what we learned from the phase II. Remember, this is still an open database. We cannot give answers that might bias even in this late-stage data outcome. Yeah. Maybe I can just add something. We saw a clear signal in DM, and what you saw here of the percentage, that was a relatively small population, and this is a heterogeneous disease. To see a clear signal is meaningful, and now we have a bigger study. I do think that you have to think about that, and where we'll have the power of the phase II and the phase III to make a compelling case with the FDA once we see the data. Peter. No, I was just going to say, Peter, maybe you want to talk about the steroid tapering. Yeah, on the steroid taper, I think we have some precedents with recent trials in DM as well. I don't think it's a factor to the plus or the con for the placebo and the powering. Oh, okay. Sorry, can't follow all the Hi, team. Thank you so much for the really helpful presentation. This is Sarah on for Yaron at TD Cowen. Two quick questions from us. Can you share maybe how the TIS subcomponents effects are different between IMNM and DM? Was the overall TIS improvement similar for both subtypes? Secondly, is there any known autoantibody involvement in skin similar to what you've been able to show in muscle, specifically for the MDA5 or NXP2 autoantibodies? Thank you. Yeah. First of all, it's a relevant and logical question, for the same reason that I spoke about, we're not giving further details on the subtypes thus far. You see the total population. You saw the movement across all six domains, which is encouraging, we have not nor will we share subtype data at this moment. On your question on the TIS, it's exactly the same metric in IMNM as well as DM. On your question on skin involvement, in our DM subset in phase II, we did recruit different types of patients having different types of autoantibody, also including MDA5. When we turn the phase III data card, that will be a sub-analysis, of course, we will look into specific benefits in all of these different autoantibody patients. Thank you for taking my question. Xian from UBS. Two, please. Just wondering, the first question, you mentioned your enrollment in phase II also reflects the unmet need. Just wondering, how much do you think that might also have the impact that you are the only one running the trials in IMNM versus there are multiple other companies running trials on DM? Just wondering whether that has any impact on how reliable is, or do you think maybe for DM, you might not be able to detect the true power of VYVGART just because of the competition of the enrollment, et cetera? That's the first question. Second one is, just wondering, is it fair to say another major difference between phase II to phase III, other than longer, bigger, is also the introduction of steroid tapering. Just wondering, how do you think that might affect the placebo arm? Just wondering, do you think the placebo arm with all the concomitant medications and steroid tapering, is that generally quite stable? Thank you very much. On the first one, I think there's actually two questions there. It's like, why do we think that there was a discrepancy in the enrollment, I think the powering one we've kind of discussed already. Maybe we want to talk about what we think contributed to the speed at which IMNM enrolled, right? There's different factors there. Yeah. In my mind, it was more about we had a fixed sample size, the slots filled up much faster. The room for DM to come in was just so and the PM even less. I know Dr. Aggarwal has a hypothesis around that. It was just that, we think. I think the other. I would. Oh yeah, go ahead. I was going to say, I do think to keep it in perspective, though, IMNM enrolled very quickly. DM enrolled quickly. I don't think we should take away from this that the DM was slow enrolling. Yes, PM was quite slow in enrolling, but also we've been seeing that that's a shrinking part of the population. I'm actually really pleased. If you look at the speed of how fast we were able to enroll IMNM and actually how fast we were able to enroll DM. I think we have a good opportunity in both. The other thing I would just add is unmet need, right? There's nothing available, as you said. There's nothing available in IMNM, and there is innovation available in DM. Of course, still a lot of room for improvement there. The second is also the fact that there are neurologists who may be more frequently treating IMNM, and they would know VYVGART well. Thank you, Danielle Brill from Truist. I have two questions as well. Understanding that you're not breaking out subgroup-specific data, maybe broadly speaking, can you just help us understand what our expectation should be around efgartigimod's ability to improve skin manifestations of DM? I believe IVIG clears rash. Any reason why we shouldn't expect an impact there? It sounds like you didn't enroll enough polymyositis patients to meet the regulatory threshold for approval by that subgroup. What is the minimum number of patients that you need to enroll in each subgroup for approval? Thank you. Luc, why don't you take the second one, and then I was thinking that Dr. LaChance, maybe you could answer the first one on the skin manifestations. IVIG works very beautifully for the skin in a lot of patients and has been very helpful for patients with refractory disease. Again, sometimes the skin can be more treatment refractory even than muscle, it's not uncommon for us to need to layer therapies, but IVIG we do use quite a bit for skin manifestations. As was alluded to earlier, the role of autoantibodies in driving different manifestations of disease, including the skin, is thought to be very high. Pathomechanistically, it would make sense that we'll see the hopeful response in VYVGART as well. I just want to also add, if you see the extramuscular component improved significantly, and in dermatomyositis, the extramuscular component by and large comes from skin. I think I would say overall it looks like the skin would improve. With respect to PM, there is not a fixed sample size or percent. It's about they need to be able to figure out what is the actual risk benefit, and that depends on effect size, a major effect in a small number of patients can be enough, and the safety profile. Now, in that particular case, safety, we know with VYVGART is not an issue, but it's about can we reliably measure the benefit? Yeah. Good afternoon. Sophia Graeff Buhl-Nielsen from JPMorgan. I had a question on do you have any estimates in terms of the prevalence of seronegative IMNM patients? Did you see any differential response in phase II amongst this subgroup? If so, is that similar in phase III in terms of proportion of enrollment? Also on ASyS, just to clarify, are you enrolling ASyS patients across the three subgroups in phase II? Was this concentrated in PM? Did you see a differential response across ASyS patients in the phase II study? Peter, do you want to talk about these two? Yeah. I think on your seronegativity, approximately 20% is seronegative. In the trial, it was a little bit less. It's a bit the same story as in myasthenia, where there is a fraction of seronegative patients, and we discussed it before in the panel, whether it's an assay thing or an identified autoantibody that remains to be seen. I think the data sets in seronegative IMNM from phase II is relatively small, but we did see these responses there as well. On ASyS, I think there, that was predominantly in the PM bucket. Again, data set is a bit too small to give a good answer to your question there. You can just talk into it. Sorry. This is Cassie for Luca Issi from RBC Capital Markets. Thanks so much for taking our question. Luc, can I ask you to talk about stats again? You mentioned that the primary analysis is now updated to evaluate each subtype. Can you expand on that? I appreciate not much you can comment today on powering, but are you splitting the alpha between IMNM and DM? If so, should we assume that you're splitting the alpha equally between the two subtypes, meaning that you need to hit P < 0.025 in order for the trial to be successful? Any color very much appreciated. Quickly related to that, is the stat analysis hierarchical, meaning that you have to formally successful trial in DM first before you can hit on IMNM or reverse, et cetera? Thanks so much. Thank you for posing it to me, there is somebody much more qualified to talk about. So it's An Vandebosch, our Head of Development. I'm formally a statistician, I think that's why they bring it to me. We usually do not disclose that much detail on the statistical analysis plan up front. As Karen and Luc and Beth already explained, we have, based on an ongoing dialogue, and on the learnings, set up a path separately for IMNM and DM for success. We have evaluated what matters for each population, how we evaluate hierarchically the different endpoints, taking into account the heterogeneity of the disease, for example, that skin matters, speed of onset matters, the muscle component in setting up our strategy. Yeah. Hi. Akash at Jefferies. I just want to make sure I understand this. This is my read. You would not want to split the trial separately if you had your way with the FDA. Because I can't help but think, you look at the standard error assumptions, I'm assuming it's probably high teens TIS on IMNM. DM is let's say 10 or 11. It would make more sense for you to actually have the study combined, and from a powering perspective, it seems it was more at the FDA's behest f or you to actually look at this study separately. Is that the right assumption here? I just want to make sure I'm interpreting that correctly. That's why I wanted to bring us back to where we started originally with the basket study, where we bring three indications in, and the sample size was indeed powered on TIS over the overall. That was on the assumption we would about equally enroll. Remember, there was a question, would you have 38% of each during that? It turns out that wasn't the case. It was two-thirds basically, well, 60%, 30%, 10%. That's the data we had in hand. When we went to the agency with the data package and asked for Breakthrough Designation, given all the unmet need, et cetera, they focused in on IMNM and said, this is where we think you could make the biggest difference. This is why we assign Breakthrough Designation to this. We then take that with where our phase III is, then we start to say, our fastest, surest path to bring to these IMNM patients, VYVGART is to focus and indeed split that study up where IMNM becomes, and it's not first because then I know what you're going to ask. It becomes its own study within the study, and DM becomes its own part. If you have 60% versus 30% a priori, our ability to get a positive outcome is going to be higher in IMNM. It was an outcome of the dialogue, our own insights, and then saying, okay, how do we match this up with speed to patient? Yeah. I think that final point is really important. If we take a step back, think about what we heard from patients. It was compelling, actually, that we heard in IMNM, within three months, these patients are in wheelchairs. Time is muscle. There is nothing approved. When we looked at the data, and of course, when we engage with the regulatory agencies, the focus is we have this data set on IMNM. We have this opportunity. How can we move as fast as possible to turn over the data card and get this therapy to patients? I think what we've been able to do is define a strategy that achieves that, leaves a good path forward for DM based on the clinical data that we saw in phase II, and allows us over time, in the same way that we have in MG, to be able to build and transform this market. I think the team has done actually an incredible job of being able to maximize speed as well as breadth, and so that we can have leadership in the market. Okay. That makes sense. By the way, my read on that is actually, it seemed like the FDA wanted that more than you did, which I would argue is a bullish thing for DM, not a bearish thing, but two cents. Okay. Going to the seronegative example, and Karen, you alluded to this before, how can you take, let's say you generate somewhat of a robust, maybe it's barely statistically significant, or it misses in DM. Can you combine that data set with another trial in DM? What would the timelines be if, let's say, there's a borderline result in that population given we already do have a precedent with seronegative? Yep. Do we want to let An to answer again? Yeah. We will look at the data. First of all, we have strong conviction in our phase II data, we will look at the phase III data, what the data will tell us in that regard. We are a company that makes decisions based on data and based on the science. We will indeed look at how can we set up the best possible trial design, indeed learning from the data, and how can we leverage that data in that trial design in the path forward. How that exactly will look will depend at that moment in time and if and when we ever have to do that in that scenario. Yes, if we are in that scenario, we will incorporate a strategy that leverages innovative trial design and the data. Yep. Prioritizing speed. Yeah, that's fair. On a separate topic, sorry. Peter, we were talking about this. I wanted to hit on it. When we look at the Roivant study with brepo and the steroid protocol for people who deviate from the protocol, there's a certain imputation penalty that occurs, which actually helped them if you look at their trial. Can you comment about your protocol, and how do you deal with patients who actually deviate from your steroid tapering? What have you seen from a blinded basis about adherence to your steroid tapering protocol in phase II/III? I think it's a similar penalty, and the adherence is good. Obviously, it's an element which we're controlling or at least looking into very tightly. Yes. Hi. Thanks for taking the question. It's Rajan Sharma from Goldman Sachs. Just on DM, and not to labor the point, but just for clarity, if you show a comparable efficacy signal in the phase III that you showed in phase II, is that enough to hit stat sigs, or is it enough for a regulatory pathway? Secondly, on IMNM, can you just maybe talk about what you think current diagnosis rates are there and where you think that can go? I think one of the doctors talked about the job that you've done in myasthenia in terms of growing diagnosis and patient awareness. Thank you. An, do you want to answer the first one about the benefit, and then maybe actually Dr. Seth, you could answer the one on diagnosis, and if there's anything, Sandrine, you want to layer in on market expansion? On the first one, actually, as Luc pointed out, we're still in the process of preparing for a data readout and not disclosing what the data in phase II look like. At this moment, actually, because of where we are in the trial design, it will be significant or not. We will have to look at what the data tell us, and then based on that, determine what the appropriate next steps will be. Also maybe reiterating also the point on the innovative trial design. We would not be here today to actually have this conversation if we didn't start based on the biology and with speed as a mission in that regard. Concluding on that, I would say we have a very strong conviction in our phase II trial data. We had statistically significant on IMNM, we had a clear signal on DM, and we will now prepare for a database lock in a rigorous manner and then wait what the data will tell us, what appropriate next steps will be, and then execute with speed. That was a great question regarding the diagnosis for myositis and immune-mediated necrotizing myopathy. I think one of the things has been a lot of education around this. In myasthenia, at my center, I did not expect to see so much myasthenia. Really, after the VYVGART trial results came out, patients started showing up. The same thing I think has happened with IMNM. To a certain extent, we set up a myositis center at Northwestern, and patients have been coming. I tend to see one to two at least news every two-ish weeks to three weeks of immune-mediated necrotizing myopathy. There are a lot of primary care providers that are now referring because of education. Yeah. That's why we believe the market expansion is not something that will just happen. We see it happening when you have trials, when you make noise around it, and that's why in our launch preparation, we already spent time developing disease state education. It's not about a brand, it's about what is IMNM, what is DM, and if you start feeling muscle weakness, what does it mean? Working with patient advocacy group started two years ago. We just don't come and then leave. We are there to stay until we can really make a difference for patients. We are in together to shape the market and expand the market in terms of number of patients who can benefit from a treatment. Yeah. I think we have time for one more question. Hi, thanks for taking my question. This is Tracy on for Leland at Oppenheimer. A couple of questions from us. First, given that TIS incorporates multiple core measures, are there any individual components that you're most focused on for phase III? Would any of those drive your label strategy if TIS were positive but heterogeneous? Two, for IMNM, given the time is muscle message, how do you expect prescribers to position VYVGART relative to IVIG, primarily as a switch option for those who are dependent or in earlier line settings? Yeah. Maybe I can take the first one, then Sandrine, if you want to touch on that. From my perspective, the TIS is a composite measure. I mentioned earlier, one really important component is the MMT8, because that's the component that focuses on muscle, and it's called myositis. Muscle weakness is the hallmark feature across all of the different subtypes. You heard from our KOLs here that that's often what patients present with. For me, I think focusing, of course, on the total, but MMT8 is going to be a really important one to watch out for. Then in terms of how you think? Yeah. In IMNM, basically, IVIG is actually not approved for IMNM. When you look at market research, you have heard that I have been looking at quite a lot. You can discuss with your providers here during the drink. Most of the providers said if the data reflects what we have seen in the phase II, they would be ready to really start as a first line after using some more steroids, et cetera, directly with VYVGART. We will have to see the data, and every prescriber is different. For short, this will be the first and only approved treatment available. Yeah. Thank you. That's all the time we have for Q&A, but we will be around, and so please come find us with additional questions. Our excellent KOLs, thank you. They'll also be available during the Q&A if you want to continue to get their perspectives. Thank you. Thank you.