argenx SE (ARGX) Earnings Call Transcript & Summary

Please welcome Beth DelGiacco.

Hi and welcome to our Boston Innovation Hub. It's looking very transformed today. And 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. And the reality is, today, we know what drives myositis, which is our immune system. And so you're going to hear from us at autoimmune myositis. We're going to be making forward-looking statements, and the details of that are here. This is now -- we've held several of these topical focused events, and 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. And 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, so not today, but we will be able to add context around all the Phase II data we've shown and the path forward. And we have Sandrine Piret-Gerard, our Chief Commercialization Officer, who is going to talk about the evolving view of the commercial opportunity for autoimmune myositis. We have a great panel of external speakers today, and 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, and the opportunity for Vyvgart and much more. But what I wanted to flag as I introduce our external speakers is that we have 3 physicians with 3 different specialties. And actually, that is very reflective of myositis 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. And we have Dr. Rohit Aggarwal from the University of Pittsburgh, and he's a rheumatologist. And actually, if any of you who 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 like to just start with what you need to know right upfront. 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 very high unmet need in autoimmune myositis. In IMNM, there are no treatment options approved. In DM, there's been limited innovation. So 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. And 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 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 give 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. So today, we no longer see a path forward to approval in DM. So 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. So 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 shograns and future indications to come. I think all in all, for number five, we are well positioned to achieve our 2 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 1 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. And so that's really about that second goal, long-term leadership in autoimmune myositis. So with that, let's get the event started. We want to start where we always start, which is with the patient voice. So let's hear from Larissa. [Presentation]

Please welcome, Karen Massey.

Thank you, everyone. It's great to see you. And I've watched that video, obviously, a few times, but every time I watch it. I mean it's -- when you hear my muscles are dying. Can you imagine the feeling that you have and how she describes, my dreams went poof. And dreams of my husband went poof. Her whole life impacted by this disease. And 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 leave -- lead. And 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 to patients as quickly as possible. By the way, what's also really important to note is that myositis is deadly. Myositis has 3x the mortality rate of the general population. So this is not just about muscle weakness. This is not just about symptoms. This is also about a severe rare disease that is -- has a high mortality. So we have an urgency to act and what we want to share with you today is our clear path forward for autoimmune myositis. So 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. And I want to make sure that it's clear today and what you'll hear from Leentje is we are as -- 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. And 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. But what you'll also hear about today from our KOL panel is health care professionals are frustrated, treating myositis, they feel helpless. Sandrine will share some market research from neurologists, from hematologists 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 indications that are not treating the underlying disease. They feel frustrated when they're sitting across from the patient. So the opportunity is clear. We can help these patients and we can provide these tools targeted precision tools to health care professionals. As Beth said, we've prioritized 2 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 study data. You'll hear more from Luc on that as our path forward. So the opportunity is very clear. IMNM, roughly 20,000 patients, there are 0 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. So 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. But if we get positive data, we'll be moving as quickly as possible for a faster path -- fastest path to market for both IMNM and DM. Let's talk about the ALKIVIA trial that set us up for success in myositis. So 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. And to date, I think it's the only study to actively include IMNM patients. And the Phase II data are very convincing. So you're going to hear more from Luc in -- 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 efcatigamib 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 end points that patients and prescribers really care about, in particular, on the steroid tapering. So 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. So what are our goals and what does success look like for argenx and for patients in myositis. So 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. So we're focused on getting there fast and broadening access to reach more patients with Vyvgart got as quickly as possible. The reason that strategy is so powerful, is that this is our first step into rheumatology. Now 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 bought, 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 Sjogren's data reading out later next year. So that combination of first-in-class alongside that world-class team builds a moat that is hard for competitors to penetrate. But in true genic 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. So 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 2 strategies in parallel allow us to deliver both short-term leadership in myositis as well as long-term leadership in rheumatology. So 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. So 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. 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 old, when the first myositis-specific autoantibody, Mi2 was discovered. It was thought that autoantibodies were just by centers 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 a 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 IV 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 auto myositis subtypes are also associated with specific auto antibodies. And they can also lead to a whole spectrum of clinical symptoms. On the top left, you can see how antisynthetase syndrome auto antibodies, 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. But what my patients with IMNM, DM and anti-synthetase syndrome have in common? Is this a specific proximal muscle weakness as we also heard from Larissa. And this common feature actually allows to evaluate the therapeutic effect of novel treatments or muscle function across these different myositis subtypes, which we actually did in the ALKIVIA trial. But the biggest question in myositis was always are these auto antibodies just presence? Are they just markers of the disease? Or are they actually being pathogenic? And 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. But biometering research from the NIH has shown that the autoantibodies can actually enter muscle cells and skin cells in myositis patients. On top, you can see here the muscle biopsies of some patients, and 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 auto antibodies enter muscle cells, they combined to their target antigen and disrupt the normal function of this antigen. And this can, for instance, leads to interferon overproduction, lipid accumulation or disruption of transcription and translation, eventually leading to cellular damage and inflammation. So yes, autoantibodies are pathogenic. And autoantibodies, they can cause cellular damage in a dual way. As I just showed you, autoantibodies can have this intracellular effects, 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, access signaling and inflammatory cell recruitment. But one example of this, for instance, this pathway on top is the clear example of how in IMNM patients autoantibodies and 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 JAK inhibitors further confirm 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 then 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 auto antibody 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 B cells that the device develop necrosis, which is indicated by the black triangle. And this is also clearly reflecting what is seen in IMNM patients. Now when these mice are treated with efgartigimod starting on day 8, which is once the disease established in these mice, the mice show reduced muscle necrosis. And you see we saw this increased muscle generation present by the, I don't know, sorry, -- there is no point there. 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 lines compared to non-treated mice which are indicated in black and which keep on having a clear loss of muscle group strength. In a second model, when we immunized 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. So there are clear deposits of collagen, which actually disrupt the architecture and the function of the lungs in these mice. And 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. Now when these mice are treated with an efgartigimod mouse on the look, we saw that these mice had clearly improved lung fibrosis restoring the normal architecture of the lungs. So in the past 2 years, we have had the hypothesis that actually, by reducing the autoantibody levels, we could bring therapeutic benefit to patients. And what was just in 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 and muscle strength was paralleled by reductions in autoantibody levels. And in individual DM patients, we saw also reductions in interferon production and an 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 sentence 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, it's about new shoes, and I regret it. I want to back. Most of you were at our R&D Day in New York in '24, 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 speak are the drivers, not by standards and that days 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. And so we chose the primary endpoint, the test, which is a composite endpoint that encompasses 6 dimensions relevant to this disease, and I'll go in a bit more detail later, but the core feature is, of course, the muscle strength. As we already have said, at proximal muscle weakness is a core feature across the subtypes. But another very important aspect of these diseases is the high frequency of utilization of steroids. And Larissa, in fact, talks about this, which she said she gained 40 pounds under high steroid treatment. That is the least, I think, of the problem she encounters with this sort of treatment. So we also built in, in the program systematic approach as steroid tapering. Now where does the another part of the innovation line is that we said, and I said it 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 developments as time efficient as possible. And we developed an operationally seamless design. And I will show that more on the slides. And also as a first, and this was already indicated, but repetition is the mother of something. It's the first time that 3 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. So what does this look like? And this slide now, in '24, there were no numbers in there because, of course, this was ongoing. But here, you can see that in the 90 patients approximately that entered the 24-week Phase II study. And 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 and the adaptive aspect of this study was that we could stop a subtype should data warranted. 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 basically. But okay, we measure those and extramuscular activity. These patients in our Phase III trial, we have up to 175 patients we're 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 because the moment you do that, then you're basically in a convoy situation, where the slowest enrolling cohort determines the overall speed of the trial. And we didn't 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 already talked about was actually only executed in Phase II. Why is that relevant? Because the Phase II data I will show you are on top of standard of care, okay? The primary analysis, and this has already been talked about is that we are really going to look at the individual benefit in each subtype and the reasons why will come in the next slide. You've seen the slides and Leentje just showed it. But to me, it's still remarkable that over 24 weeks, we could see this solar effect on active. As already said, highly robustly significant. But a very simplified way to think about it is that TIS is an improvement score. And it's a derivation of percentages, and I can go in a very complicated explanation. But 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'm very excited about that data. Now where did those data come from? And here is the beginning of the story of the change, which is we didn't have a target enrollments, first come first serve. We saw that we very quickly enrolled IMNM patients to about 2/3 of the study. DM about 1/3, PM quite low. And during the panel, we can come back on some thoughts why that is. But 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 polymerize eyes. You can see steroid dose in Phase II. There was no tapering down age, et cetera. Yes. And then 85% had autoantibodies, 15% were seronegative. So the majority of this effect you see on the left side, logically was driven by the IMNM subset. And 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 of Vyvgart is speed of onset. And this shows you that on actually a responder analysis because if you take the continuous one, it actually starts separating earlier, but 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. And in this particular case, TIS over 40 to us is particularly encouraging. Now the TIS, as I said, is a composite. And here is just a message that each of the composite parts improved. Look at the muscle dimension. It improved significantly. And this is very rewarding for us because this is, again, biology at work. And this just shows you again the fast time it does it. And not only does this MMTA score, the patients feel it right very fast, right? Blue is efgartigimod. From early on, patients feel there's something different. Pretty exciting to see. What are the risks? By and large, the risks are, as we know very well, from our overall safety database. If you look at the event rates per 100 patient years, which is in each column, the first right, there is not really that much difference. We currently have 25,000 patient years of experience. But -- and I was sensitized to this by Dr. Aggarwal is that in these particular indications, infections and serious infections are, of course, always of interest. And there is on the more than Grade 3, 3 patients that had that in the whole study. I think that stands for the known safety profile. And we can discuss this further. But overall, in the context of 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. So what have we learned, what are we doing with it? And why does it matter? We have learned that M&M drove the Phase II results. DM showed a signal but due to 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. But 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 that we have an emerging strong data package in IMNM and the potential for the strong data package in DM. And so that positions us for, of course, either overall must be positive, but that we can file for at least one of these subtypes with urgency because thinking again about our principal speed to patients. And that's why it matters and the way we designed this program. So with that, I give the floor to Josh. Thank you.

Thank you, Luc, and good afternoon, everyone. So 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. And so today, we're really fortunate to have 3 leading experts across dermatology, neurology and rheumatology. It's come up here and talk to us about the landscape, the unmet need the treatment paradigms and what's exciting about innovation in the space. So with that, let's meet our panelists. Our first panelist is Dr. Avery LaChance, who is an Associate Professor of Dermatology at Harvard Medical School, and she is the Director of the connective tissue disorder clinic at that institution. We have Dr. Arjun Seth, who is an assistant professor of Neuromuscular Medicine in the Department of Neurology at Northwestern. Dr. Seth brings deep experience in neuromuscular disease, treating both MG CADP as well as autoimmune myositis and was a site in both Phase I and Phase II. And then we have Dr. Rohit Aggarwal, who joins us. He's a Professor of Medicine at University of Pittsburgh Medical Center, and he's the Co-Director of the UPMC Myositis Clinic. And he's been a key adviser, I think, as you heard earlier on this study and on this program. So we are absolutely delighted and privileged to have this expert panel. I would like to welcome the 3 of you up to join me. Thank you. Okay. Lovely. Well, so why don't we kick it off with Dr. Seth, and I think we're going to talk a little bit about the disease burden and the unmet need in the space. And I want to start by anchoring to the patient we heard from earlier Larissa, and specifically necrotizing myopathy patients. Can you talk to us a little bit about how these patients come into your clinic and present to you and some of the struggles they go through it.

Yes. 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 the weakness, they're not able to work out or do their normal activities of daily living, so getting up off a toilet, climbing stairs and they go to their primary care providers and explain that they're having symptoms, sort of 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 a rheumatologist to actually then do this testing to value for CK and then discovering that they actually have an immune-mediated necrotizing myopathy. So that story is very, very common.

Yes. And just a follow-up to that. We've been thinking about her disease course, but the course in IMNM in general, right, is we know it's very aggressive. So could you talk to us a little bit about how you think about the urgency to treat there?

So immune-mediated necrotizing myopathy, in particular, can be quite aggressive as an dermato, but immune-mediated necrotizing myopathy, typically patients progress quite quickly over the first 3 to 6 months and are initially able to just noticed some site difficulty with, let's say, running or getting up out of bed and then over 6 months are really in sort of kind of end up being wheelchairs. And so those are the -- 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. And so that's the sort of burden.

And these patients have a privilege of getting to in a very specialized sort of tertiary center, but I would imagine that could be somewhat disparate depending on where you are and your access to care.

Absolutely. And so most patients actually end up coming into the hospital. So their first admission is actually into the hospital where they end up seeing a specialist then get diagnosed and then initiated on treatment on a hospital.

Excellent. So shifting gears, we'll go to you, Dr. LaChance, and I want to ask specifically a bit about DM. So 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. So I think for dermatomyositis, we've really been anchoring and hearing a lot about the impact of muscle on patients we can see a similar thing in dermatomyositis as well, where patients have difficulty walking, getting upstairs, et cetera. But as the dermatologists in the room like the Lorex the trees, I also speak for the skin and say that actually in dermatomyositis, dermato skin, myo muscle, that inflammation in the stim in the muscle is a really big thing to know about in dermatomyositis. And in fact, a lot of our patients, the burn pain, discomfort can keep them up at night and prevent them from sleeping team can have just a bit as big, if not bigger impact for those patients as well. So 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 in only disease, so amyopathic. And then layered on top of this, this can also be a multisystem disease where we have to think about interstitial lung disease and other internal disease manifestations as well. So this is not really just impacting the muscles but really is a multisystem inflammatory disease state.

Thank you. And Dr. Aggarwal, shifting over to you, 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 wall that can limit the use of steroids. So I think we do not have a treatment that encompasses all 3, 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. So there is a huge unit. The reason that you see a lot more IMNM in your trial is because that's what they're telling you that is -- that's the subset has the highest unmet need. So 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. And 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 auto antibodies, distinguishing subtypes over time. But I guess how has it evolved from your perspective and you think about pacing in the space?

So in the last 20, 25 years, what has happened is mostly put by the slides that how the DM and PM was combined and then they took a part and how the journey of the myocyte is diagnostically. So all of that has been influenced heavily by autoantibodies to begin with diagnosis and classification has been heavily influenced. We know auto antibodies define a unique clinical phenotype. So we know that for sure. And then lately, we have been using autoantibodies to drive our management itself. But what has happened in the last about 5 to 10 years, we have seen increasing data about pathogenic role of autoantibodies. Largely to multiple scientists across the world, but 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. So now we really have these direct proofs. So lowering these autoantibodies should get to the improvement even in 10 years ago, when we did studies where the antibody level will go down, disease get better, antibody get -- levels go up, disease get worse. We knew their clinical association. But having a direct pathogenic experimental proof was not there. And I'm really happy to see that coming through now.

Dr. Seth, I want to sort of ask you a similar question, and I guess thinking about how you've seen it evolve and also around auto antibodies in your experience?

I think the auto antibodies, you're absolutely right. It really does help guide sort of 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, there sort of clinical course and can actually change our treatment strategy based on that. There's also a whole subset. These -- the HMG antibody was only discovered 16 years ago. And so there's a lot of these other novel types of immune-mediated necrotizing myopathy , what we call seronegative without known antibodies that probably exists and they present very similarly. So we do send other labs to look for actually different types of novel antibodies that will present in the same way.

And Dr. LaChance, I want to ask you a very similar question in dermato, which we know that auto antibodies depending on your phenotype have found impact on your comorbidity risk and other things. So I'd love to hear your thoughts. .

Yes. I think a couple of 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. So historically, if you look back at a number of the different studies that have come out, some say X number of patients were -- 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 curious and experts for a long time have really thought actually those autoantibodies are there, we just need better assays to detect them. So I think that's one thing that's important to nail Home. And secondly, in dermato, although you don't need those auto antibodies 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. So some patients their autoantibodies, MDA5, you're going to be very worried about rapidly progressive interstitial lung disease. Their patients may have very NXP2 mild skin disease, very aggressive muscle involvement. And so auto antibodies seeing that they play a role really in driving these heterogenous disease state and the different things that we see in terms of how they present clinically helps us also understand the role of these autoantibodies as truly pathogenic.

Excellent. So 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. And obviously, I know the 3 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, and maybe Dr. Aggarwal will start with you.

Yes. So I think we have been using the toolkit that was prescribed to us from rheumatology per se, which is DMARDs, methotrexate, meclofenamate [indiscernible] these are -- none of these are really proven, and none of them really works on its own. They're all sort of steroid -- they need steroid help in -- steroid plus these modulators would work. But then 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 to the next step. But that said, that's all we have. So 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 3 months, this patient is going to be wheelchair bound and have nothing to really push the treatment forward other than keep bombarding them with steroid, next immunosuppressive agent, next immunosuppressive agent and nothing else. So I think that's a really significant unmet need that we feel that needs to be fulfilled by hopefully the drugs like FCR and receptor blockers.

Dr. Seth, I don't know anything to add.

That's a great answer. I think I totally agree. I think there has been huge unmet need, no FDA-approved drugs for M&M I think that's where the space and this trial actually fills that space.

So Dr. LaChance, I want to skew slightly differently, right? So these patients are going to be chronically immune suppressed for a long time. So 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?

Yes. I think for a really long time, exactly as Dr. Piira mentioned that we've been having to rely on our DMA, so methotrexate, mycophenylate mofetylin and you imagine coming into your doctor and saying, "I can't walk or I have this burning rash and we say, okay, I've got a drug for you, but it's going to take 3 to 6 months to kick in. And then the eyes get wide and you say, okay, but that's going to have -- while that's ramping up, we're going to turn this off really quickly with a fire hose. And 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. And those steroids, we have to remember, have a really big impact for our patients as well. So there are a lot of risks associated with long-term high-dose steroids. And especially when we're talking about the myositis space, there can be muscle impacts and loss of muscle from those long-term steroids as well. And then over time, you're saying, am I dealing with the steroid myopathy? Are we still having ongoing inflammation? There are these really important things that we need to know that the steroids can do. And so for a while, we've had to layer therapies on, and it's a really exciting time to now have some more targeted quicker-acting agents that we can bring into this space, and 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, give them tons of steroid, make them -- make me feel better that their myositis is better. I show the numbers, the seek is going down, but I'm exchanging a big long-term disease with them, which includes diabetes, cardiovascular disease, bone health, muscle health, kidney. So 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. 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. And so how do you see the role for multiple MOAs in the DM space in the future?

Yes. I think as a dermatomyositis doctor, it's a very exciting time to be caring for these patients. But 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, and there are multiple pathogenic drivers of disease. And actually, to date, we've been using JAK inhibitors off-label. We've been using IVIg. We've been using our DMARDs. And it's really not uncommon for us to need to layer different therapies together. And 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 gut, 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. And it's not uncommon for us to see to layer therapies for patients. And so actually having multiple MOAs, multiple targeted agents, all in the name of getting patients off of steroids is very important, very exciting. And I think we will be using these therapies in combination moving forward.

And so to keep up with that same theme of the last answer we heard from you, Dr. Aggarwal, the way you answer -- finished your answer, Dr. LaChance. Let's talk about the steroid taper in Phase III and sort of how you think about that? What is that going to accomplish? Why could that be meaningful when we see the data?

Yes. 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. So we said if we do steroid tapering, it may jeopardize the treatment outcome. But now the thinking has evolved. What we are seeing is studies after studying long-term effects of these steroids, specifically in myositis coming out. So doctors are now worried about giving long-term steroids. So I think that's one of the reasons. The clinical reason is so huge because doctors are seeing burden of these long-term steroid when they follow these patients 5 to 10 years down the lane, the myositis might be better by now, but now there's a lot of other problems. So that's the clinical reason. But also from the regulatory standpoint also, the FDA has learned through various of the 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 until now. Now they want neurodrum, novel therapeutics or targeted therapies to be effective on their own, not requiring steroid help and now the steroid has done this much job. Let's move it to here. No, we need that the whole thing has to be travel by that drug so that the steroid can be tapered off to a large extent.

And how do you see FcR inhibition fitting in to that potential?

So I think I expect -- so 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, and having subjects enrolled. And 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 it plays -- we know that these are IgG sort of -- we think that their IgG mediated disorders, we have good evidence to say that, I think depleting the IgG and those pathogenic immunoglobulin has -- does play a role. We've seen that in myasthenia quite robustly and also shown steroid-sparing effect, so it reduced the amount of steroids that patients needed CIDP similarly have shown benefit in that. I think the same thing will happen in -- with this study as well. I have 2 patients enrolled in the Phase II, and 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 in. It's not -- this is an autoimmune disease. The median age is 50 years. They're going to live another, let's say, 30 years. It's a 30 years of drugs. So a single drug will not going to cut it. We need -- even in DM, I would say we need at least 3 or 4 or 5 drugs to really be able to serve about 90% of our patients. So I think the fact that one drug is approved them, this is a second drug is a wrong understanding. This is not a second or this is an option for the patients that could be even the first line in the future.

Yes. And 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 and I still struggle with some of my RA patients. These are lifelong diseases, that one drug may work for 1 year, 2 year, maybe 10 years, but it may fail because autoimmune disease evolve and overcome that mechanism of action and you may need a second mechanism of action to counter the disease. So I think this is an autoimmune space is a chronic disease space where these drugs are going to be used for long term.

Very helpful. Okay. So 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. And 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 multicomponent score, there's a lot to unpack. So could you tell us a little bit more about how you think about sort of the 6 core attributes and why they're meaningful?

So 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. And the reason that rheumatology has been revolutionized by the RA field because of these clinical trials that use composite response criteria called ACR 2050 70, some of you may be familiar. So rheumatologists are very familiar with composite response criteria. Why? Because in rheumatology, it's not a single disease is not a single organ, a straight manifestation. It's a complex disease, a heterogenous disease. So we need composite response criteria so that we can hit multiple aspects of our heterogeneous disease. Same in myositis. We need to know how is 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 is the function is doing. Then you get a better overall picture. If you 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 over the lung, some over the muscle. So it's -- so that's the power of the total improvement score encompasses 6 outcome measure that looks holistically the patient. And then because of that improvement, then you're able to see, overall, we feel patient improved. Now there is efficiencies 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, then you have to look at the core set measure improvement to see what exactly improved that the patient had an overall improvement.

And just to further ask some questions about total improvement score. So I think one thing we've seen across trials is that there can be a very notable placebo rate. So I was wondering if you could give some insight on that than anyone else spoken away as well.

So the placebo rates are not truly placebo rates. So think about this. These are patients on 1, 2 or 3 drugs on the background immunosuppression. So the background immune suppression is going to improve the patient. So 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 the 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. So there is a second aspect, which is also not placebo, which is fully treatment. And then the third aspect, which is true placebo, which is the bias that comes in because of the hope of being in a truck. So I think the overall placebo effect would be wrong to say it's about 40%, 45%. It's about 10% to 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. So -- and this is not the only study where we have seen this hypo placebo response. Almost all myositis studies, we have seen significant high rates of placebo response. And that also speaks to the extent that if you have a positive study, despite high placebo response, that means that treatment is working really, really well to overcome that placebo response is not an easy. So I think from that standpoint, I believe that this delta of 15 mean this and a delta of 20% to 30% is hugely meaningful.

And I also think added on top of that, 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 at 4 weeks, I think, is very important because that doesn't mean we're going to have to wait 6 months to start to take for those steroids.

So 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. But I do think we saw moderate and major improvement marks there, right, [indiscernible] I was wondering if we could maybe hear across the panel sort of what is that meaningful impact for the patients you see that's representative of that. So Dr. Seth, I don't know...

Sure. I think some of the big things are functional functionality. So getting up off a toilet, climbing stairs. I ask patients that or simple things like rolling in bed. So 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. So those sort of simple things are having to sit up. So these patients when they do come in, they're really weak. And so those are the big questions I initially asked them and then swallowing. So if their swallowing is impacted, they tend to lose a lot of weight because they're not able to keep up with nutrition. And so they tend to lose around like 30 to 40 pounds as they're going through this whole process. So if that's stabilized their weight has stabilized and they're able to swallow. So those are big things in terms of functionality that I look at.

Yes. From my standpoint, what I look at is because we have done studies where sure if you hit this 40, that means your pain is improved, your function is significantly improved, fatigue has improved. If the skin involvement and skin is part of this, then in your skin has improved, so overall, their activity function, pain, fatigue, all the disability part has improved. So 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 improves. So for me, TIS 40 is my gold standard that what I evaluate the drug on.

And 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 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 and when patients are improving, they say, I feel comfortable in my skin again. And that's really kind of what patients are saying to say, is not just the look and the appearance of the rash, it's how they feel in their skin.

Excellent. And so I want to change direction for sort of 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. And so 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 sort of being seen with these diseases. So Dr. Seth, why don't we start with you?

I think you'll -- so the myasthenia work has been outstanding, okay? Honestly, with the odds and everything on TV, patients come out of the work 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 and with more awareness, they will actually look for and care I think one of the things that we've been doing at least at my institution is like we are 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. And so we've done a lot of work on that aspect, at least in Chicago.

Avery?

Yes. I think absolutely the same thing we've seen is 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 rheumatologist, but actually, one of the benefits of a subcu therapy in oral therapies is there's an ease of prescribing that's not there with an infusion-based treatment. And actually, we have a lot of our community dermatologists feel very comfortable prescribing a whole multitude of targeted therapeutics and psoriasis atopic dermatitis. So with a clean safety label that's on the dire side, what everyone is always looking for and subcu injectable dosing, those are 2 things that people are getting much more comfortable prescribing. And 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.

Yes. I agree. I think the education is key because community doctors look at the KOLs for the education, so talking about in state rheumatology societies, ACR, EULAR where you kind of 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 you're losing muscle in that time frame. 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 on treatment. So I'm not worried about that, but only the education part I think, is the most important. But I think I want to also touch upon increasing diagnostic tools. Also 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 parts who comes with milder milder phenotype, you give them a wheelchair you think anybody is going to care about them? No. So I think there is a lot of best diagnosis and undiagnosed cases that diagnostic tools can really cover that growth.

Very helpful. Well, I'm going to close there, and I'm just going to say a profound thank you, 3 of you for spending the afternoon with us. I think your insights are so valuable for everyone here. So thank you very much, and appreciate it.

Thank you.

Thank you.

Thanks.

And now it's my pleasure to welcome Sandrine to the stage to talk about the commercial opportunity. Thank you.

Thank you, Josh, and thank you to our panelists. So I'll bring it home, bringing everything together from the biology and the sand, the unmet need we heard about and then Vyvgart. So yes. So 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. And actively, I think this is a pretty good summary of what we just heard. We heard from Larissa, my muscle are dying. I heard Dr. Aggrawal, you finished by saying time is muscle. We heard patients who have IMNM within 3 to 6 months end up in a wheelchair. So 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. So that's something where there is a huge, huge need. We also heard that the toolbox that is physician disposal right now is far from being sufficient. Many patients need more. Many patients are going to leave 10, 20, 30 years and what is available today is not sufficient. We also heard steroid tapering is going to be critical because long-term steroid good is not good for anyone. And 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-milligram per day. So 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. System 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 and the long-term safety will be critical and have an established safety profile will be key that allows for steroid tapering. And at the same time, we heard Dr. LaChance finishing convenience could also help. If you have a PFS subcu or oral much better than having had patients that have to come to the hospital for an infusion. So that will be the perfect profile of medicines coming to market to help these patients. So 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. And this playbook is based on 3 pillars. High unmet need that I've just described is one of these pillar. The other 1 is very clear biology, and LaChance explain in detail why we believe autoantibodies are really driving the disease and that the biology is very clear. And 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 actively tools in the toolbox that can make a difference. And if you apply that to IMNM and DM, you see that actively with a perfect argenx indication with these 2 subtypes. Let's summarize what we heard about IMNM. So the biology very clear. This is the strongest body of evidence we have of autoantibody-driven disease. We also conducted much 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 is that stop the damage now. So 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. And we heard in, there is nothing. Nothing has been approved. Drugs are being used of label, the unmet need and the sense of urgency is high. So this is why when you ask physicians in a market research, which has been blinded. We didn't share the names of the drug and we shared a high-level profile of different drugs, 9 out of 10 rheumatologists who don't know Vyvgart, 9 out of them said that they would use Vyvgart to treat IMNM should it be approved. So if we move to DM. There, the biology is clear as well, also driven by 2 antibodies, but the spectrum of autoantibody is 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 with, help me manage for the long haul. So this is a 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. And you know Vyvgart, 25,000 patient years' experience. So 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 patients. As we know, we know that space quite well because in CIDP and MG, this is also drugs that are being used. But we also know that in DM, you will need multiple mechanisms of action, like you were seeing the outlets, you need to layer one after the other, just to make sure that it's fitting the different needs of the patients. So when presented the blinded profile of Vyvgart to rheumatologists, actually 8 out of 10 say that they would use Vyvgart to treat DM in case Vyvgart would be approved for this disease. So this shows that there is truly biology, unmet need and white space, and it all boys together by a strong willingness to prescribe Vyvgart prescribed for these 2 subtypes. So now the question I often get is how big can it be? So what we have been saying is that there are 20,000 IMNM patients diagnosed in the U.S. This is more than what often you see in literature. But we triangulated this a 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 added 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. So this is a sizable opportunity. Now 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. So if you combine all of that, IMNM its own will be a multi-blockbuster opportunity. Now 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. But as we know, it is a heterogeneous disease, multiple mechanism of action can coexist and will be layered. So there is room for multiple players. And so this is a broader market that we would share. But this will be also a significant opportunity. So 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 and patients total addressable market. So this is the size of MG as we define it today. And then we have to add something else that our panelists mentioned at the end of day 2, which is the biologic market expansion. And this is often something we forget, but systematically, think about MS when there was nothing and more treatment started to come into the market, more noise around optionality, more diagnosed patients coming in, the market grew Same for MG. We put MG on the map and 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 -- we believe this will be the same game for autoimmune myositis where the market itself additives defined today is going to expand. So if you bring that all together, this is an amazing opportunity to make a difference for patients. And this is why we haven't been waiting for approval to start getting ready. What impressed me when I joined argenx 6 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. And there are a few strengths that this team has the commercialization team has. And this strength 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 glove approach. And that's we offer. That's what we offer, and this is not going to change for autoimmune myositis. We are going to have this wide growth approach for them as well. We also need extremely strong market access capabilities. For each of our indications, more than 90% of the lives in the U.S. cover Vyvgart, and 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, our sales team, actively one provider mentioned to us, I don't only prescribe the molecule. I also prescribe the team behind the molecule. So people who work at argenx are amazing, and we are going to lose these people also to make sure that patients who need Vyvgart, if approved in autoimmune myositis will get it. So of course, we are going to augment this engine with some capabilities towards dermatologists and toward hematologies. This is important. So -- and 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. And actually, we like market research. So we did a market research to ask them. So of all the MSL you engage within the industry, for auto myositis, which one do you prefer? Argenx came first. So 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 that we trigger more diagnosis. And then we have planned the 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. So 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 it in a wheelchair, it would make me and all my colleagues at argenx so happy. So 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. Okay. So I want to close giving some of the key messages that you heard today and just recap and then make it link to Vision 2030. So what do we hear today? Number one, conviction in the biology. So 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 Clari on the clinical data from Luc. So we're now Phase II data. We had -- in our Phase II study, I should say, we have -- 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. So we have strong conviction as we go into Phase III. Phase III study is twice as big, twice as long. So we have strong conviction in the potential for a positive outcome in the subtypes of IMNM and DM in the Phase III study. And 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. So conviction in the biology clarity on the clinical data and a compelling commercial opportunity. So what's next for myositis. So 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. So 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 test 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 have sufficient -- we will have sufficient data to be able to file. So hopefully, that provides a clear path forward for iris based on the -- and the compelling opportunity that we have in M&M as well as DM. So 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 what 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, but 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 2 indications: IMNM and DM to our goal of 10 labeled indications by the end of the decade. And on our goal around 5 molecules in late-stage development by the end of the decade, we are well on track. So at the end of this year, we have our first data readout for Impasapprubat in MMN. That's our next molecule but beyond efgartigimod. That's an exciting moment for the company to start building beyond FcRn. But we have much more coming, and we're well on track to have 5 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. And so we're building the portfolio with the breadth and the depth to be able to deliver. They've got leadership over the long term with our next-generation molecules as well as a broad and deep portfolio beyond FcRn. So with that, I'm going to close the presentation part of the meeting and bring to stage Beth, Sandrine, Luc and someone who haven't heard from yet today. Peter Ulrichts, our Chief Scientific Officer, come to the stage.

So the good news is we are right on track for Q&A. So we'll be about 30 minutes to go through Q&A, but there's also time afterwards, we have a reception, and so please come and find us.

Yatin Suneja from Guggenheim. And putting this wonderful presentation. So 2 for me. So 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 2 subtype, especially for FcRn mechanism, which tends to be a little bit more cleaner and more narrower. And then the second is more on the regulatory front. Any feedback or buy-in from the FDA on these 2 separate path that you are highlighting? And what would be the split of these to subtype in the Phase II study in the Phase III study?

So I suggest, actually, Peter, do you want to talk about the IVIg and IMNM and DM and also Sandrine, you can layer it in Luc, of course, to hear from the filing strategy? .

Yes. I think it's clear that IVIg does have an effect in dermatomyositis as it's approved there. IMNM as the panelists 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. So I think in IMNM, based on the Phase II data, which we have, I think we saw a very strong single 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 JAKTC inhibitors is how they will work in that spectrum of autoantibody present in DM. What we do know is that these statements are working. What we don't know yet is how good they're working for the individual subtypes in terms of [indiscernible]. 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.

And Luc, the second one was on the regulatory front, feedback or buy-in on the strategy.

Yes. I mean, so this, as we said, we went through our Phase II data set to the agency, discussing the potential to break to 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 and so they selected that one for break to designation. But of course, we discuss the whole package. And it is clear from that, that. And also from our sample size that we talked to has -- you saw the proportion. We see similar proportions in Phase III. So the inherent probability to IMNM is just higher. And they are very interested in the risk-benefit assessment of that. But if the data card is turned over and DM makes it, we evidently will also include that in our filing.

Yes. And maybe just to add, on the question of the engagements with the FDA and related to the subtypes. So yes, obviously, we're engaging with FDA on an ongoing basis, but we -- there is a path to approval for the subtypes based on the analysis.

Andy Chen from Wolfe Research. Just a question on the difference between IMNM and DM. So obviously, empirically, it looks like your data is better in M&M. But is it just -- but we also heard earlier from the experts today that IMNM is a more aggressive disease and doesn't that just make it harder to treat. So why is it that efficacy is now worse or is not 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 a Phase III, we're going to see better data on DM just because it might be an easier to treat population.

Yes. I don't know, Karen, if you want to start and then Luc or vice versa.

So I think, in fact, it shows when 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. And that's, to us, very rewarding to see that us opening that door and actually allowing them to create such a benefit. So from my point of view, it's not an inherent more likely to or not between IMNM and DM. It's just we got a much higher influx allowing us to have a better assay sensitivity, if you will, of the trial. Now in the Phase III as was said, double the length, double the size. So 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 just lower than IMNM inherently.

Alex Thompson from Stifel. I guess again, on the primary endpoints and sort of 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 sort of the itality of the data? And what is the role of the Phase II data set when you're thinking about filing in DM?

For dermatomyositis, we also took the CDs. So there are multiple readouts we have that this isn't less weighted towards dermatomyositis, if you will, because the derm is only in the assessment of the extramuscular, yes, thank you, domains. So 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 -- so is it lower or higher than in Phase II. And we will really only know that once we turn the data card. And that's why you say 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.

Yes. And 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.

Tazeen Ahmad from Bank of America. First of all, for hosting. Second, maybe this is for Karen. So since there's a lot of focus on you provided us a lot of color and also, I think the physician panel was helpful. So I think Dr. LaChance said that 80% of DM patients have muscle involvement. So 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 of the chance of the portion of the study working, again, assuming that it's a smaller end of patients relative to IMNM, but do you think that as long as that portion of holes does not have a good chance of allowing the study that portion of the study to work?

This too -- so maybe I'll jump in and then Luc at a 2 things that give me confidence on that front. One is that the -- 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. And so we have patients from the patient cohort, they have that muscle weakness. So we should be able to see that. And -- sorry, go ahead.

No, I think to answer direct to 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, so 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 that was -- and we saw that in Phase II. That's important because there is muscle weakness present in dermatomyositis. It's not just skin manifestations. And so seeing that significance of that clinical endpoint of MMT8, I think, is a good signal for DM.

David Nierengarten, Wedbush. I was curious on background with steroid use. Is there any differences in general patient benefit for steroids who -- patients with dermatomyositis versus IMNM and therefore, with the steroid taper effect as populations differently in the Phase III?

Maybe the want to talk about the difference in -- from a clinical perspective?

I think what happens is because IMNM is more refractory and you see how many patients were included they tend to have higher steroid use as compared to dermatomyositis, but these patients are entering in the trial, that means they are definitely refractory. So they would also have a significant steroid. There may be a small difference between the 2 -- but overall, I think the median steroid dose was 10 milligrams. And that's the same steroid median steroid dose we saw in IVIg study, which was only dermatomyositis. So I think there may be minor differences and perhaps a little bit more in IMNM or a little bit less in DM, but pretty much both would require steroid because these are refractory patients entering clinical trials.

And specifically linked to the trial, I think we have, of course, set of specific rules in terms of steroid use, stableness and then the tapering, which is identical between the subtypes. So I don't think it's affected there.

Sam Semenkow. So 2 questions for me. So for the M&M 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 and 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 subject could be positive?

Yes. So 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. So I would like everybody to we cannot give answers that might buy us even in this late-stage data outcome. So...

And maybe I can just add something. We saw clear Signal and DM, and what you saw here of the percentage, I mean that was a relatively small population, and this is a heterogeneities. So to see a clear signal is meaningful. And now we have a bigger study, so I do think that you have to kind of think about that and where we'll have the power of the Phase II and the Phase III to kind of make that -- make a compelling case with the FDA once we see the data. Peter, do you -- no, I was going to say, Peter, maybe you want to talk about the steroid tapering.

Yes. On the state of paper, I think we have some precedent with recent trials in DM as well. I don't think it's a factor to the plaza the con for placebo and the powering.

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? And was the overall TIS improvement similar for both subtypes? And then 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 auto antibodies?

Yes. So as well -- so relevant and logical question. But for the same reason that I spoke about, we are not giving further details on the subtypes that are. So you see the total population, you saw the movement across all 6 domains, which is encouraging, but we have not -- or nor will we share subtype data at at this moment.

On your question on this is exactly the same metric in IMNM as well as DM. And 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. And of course, we will look into specific benefits in all of these different autoantibody patients.

Xian From UBS. Two, please. So just wondering the first question. So you mentioned your enrollment in Phase II also reflects the unmet need. But just wondering how much do you think that might also have the impact that you are the only 1 running the trial in IMNM versus on multiple other companies running trials on I'm just wondering whether that has any impact on how reliable or do you think maybe for DM is you might not be able to detect the true power of Vyvgart just because of the competition of enrollment and et cetera, et cetera. So that's the first question. And second one is, just wondering, is it fair to say that another major difference between Phase II, Phase III is the introduction -- other than a longer, bigger is also the introduction of steroid tapering. So just wondering how do you think that might affect the placebo arm. So just wondering, do you think the placebo arm with all the concomitant medications and start tapering, is that generally quite stable.

And on the first one, I mean, I think there's actually 2 questions there, it's like why do we think that there was a discrepancy in the enrollment. And then I think the powering one we've kind of discussed already, but maybe we want to talk about kind of what we think contributed to the speed at which IMNM enrolled, right, because there's different factors there.

Yes. In my mind, it was more about -- we had a fixed sample size and the file up much faster. And so the room for DM to come in was just so and even less, but I know Dr. Aggarwal as a hypothesis around that. It was just that we think yes, go ahead. I was going to say, I do think to keep it a 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 enrolling, but also we've been seeing that that's a shrinking part of the population. So 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, so 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 on IMNM, and there is innovation available and DM, of course, still a lot of room for improvement there. And then the second is also the fact that there are neurologists who may be more frequently treating menu, and they would know Vyvgart well. .

Danielle Bongero from Truist. I have 2 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 Vyvgart's ability to improve skin manifestations of DM. I believe IVIg clears rash any reason why we shouldn't expect an impact there? And then 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 this subgroup for approval?

So Luc, why don't you take the second one? And then I was thinking about Dr. LaChance, maybe you could answer the first one on the skin manifestations. IVIg works very briefly for the skin in a lot of patients, and it has been very helpful for patients with refractory disease, again, sometimes the skin can be more treatment refractory even than muscle. So it's not uncommon for us need to layer therapies. But IVIg, we do use quite a bit for skin manifestations. And as was alluded to earlier, the role of autoantibodies in driving different manifestations of disease, including the skin is thought to be very high. So patho mechanistically, there -- it would make sense that we'll see the response that we're hopeful response to 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, come from skin. So I think I would say, overall, it looks like the skin would improve.

With respect to PM, I mean, 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 the 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.

[indiscernible] JP Morgan. I had a question on -- do you have any estimates in terms of the prevalence of negative IMNM patients? And did you see any differential response in Phase II amongst this subgroup? And if so, is that similar in Phase III in terms of proportion of enrollment. Also on ASIS, just to clarify, are you enrolling ASIS patients across the 3 subgroups in Phase II? Was this concentrated in PM? And did you see a differential response across ASIS patients in the Phase II study?

Peter, do you want to talk about these 2?

Yes. I think on your set of negativity, approximately 20% is seronegative. In the trial, it was a little bit less. We -- and 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 asset or an identified autoantibody that remains to be seen. I think the data sets in seronegative IMNM in Phase II is relatively small, but we did see these responses there as well. And then on ASIS, 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.

If you can just come on that.

Sorry. This is Cassie for Luca Issi from RBC Capital Markets. Luc, can I ask you to talk about that 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 offer between IMNM and DM? If so, should we assume that you're splitting the alpha equally between the 2 subtypes, meaning that you need to hit p smaller than 0.025 in order for the trial to be successful. Any color very much appreciated. And then quickly related to that, is this analysis hierarchical, meaning that you have to formally successful trial in DM first before we can hit IMNM or reverse, et cetera?

Thanks for posing it to me, but they are somebody much more qualified to talk about as [indiscernible], Head of Development.

Formally statistician. So I think that's what brings it to me, sir. We usually do not disclose that much detail on the statistical analysis plan of home. But as Karen and Luc and Beth already explained, we have based on an ongoing dialogue and on the learnings, set up a bat separately for IMNM and DM for success. And we have evaluated what matters for each population, how we evaluate hierarchically the different end points, taking into account the heterogeneity of the disease. And for example, that skin matters, speed of onset matters, the muscle component in setting up our strategy.

Akash at Jefferies. So I just want to make sure I understand this. Like did you want to make -- this is kind of 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, like you look at the standard error assumptions, I'm assuming it's probably high teens TIS on IMNM. Probably DM is probably like, let's say, 10, 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, the hest for 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?

So -- and that's why I wanted to bring us back to where we started originally with the basket study, where we bring 3 indications in and the sample size was indeed powered on this over the overall. Then -- but 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. So it was 2/3 basically 60 30, 10. And so that's the data we had in hand. So when we went to the agency with the data package and as to break through designation given all the unmet need, et cetera, they focused on IMNM and said, this is where we think you could make the biggest difference. This is why we assign brick designation to this. If 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. But if you have 60% versus 30% a priori, our ability to get a positive outcome is going to be higher in M&M. So it was an outcome of the dialogue our own insights and then saying, okay, how do we match this up with speed to patients?

Yes. And I think that final point is really important. If we take a step back, think about what we heard from patients. I mean it was compelling actually that we heard in IMNM, within 3 months, these patients are in wheelchairs. I mean, time is muscle. There is nothing approved. So 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 get -- to turn over the data card and get this therapy to patients. And 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 and allows us over time in the same way to have an MG to be able to build and transform this market. So 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. And by the way, my read on that is actually, it seemed like the FDA wanted that more than you did, which I would argue as a bullish thing for DM, not a bear thing, but two cents. Okay. So then 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 stat sig or it misses in DM. How can you combine that data set with another trial in DM? Like what would the timelines be if, let's say, there's a border line result in that population, given we already do have a precedent with seronegative.

Do we want to let -- to answer again.

So we will look at the data. First of all, we have strong conviction in the Phase II data, and 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. So 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. But yes, if we are in that scenario, we will incorporate a strategy that leverages innovative trial design and the data.

Yes. Prioritizing speed.

On a separate topic, sorry. Peter, we were talking about the on it. Like when we look at the ROYVAN study with BEPO and the steroid protocol for people who don't -- who deviate from the protocol, there's a certain imputation penalty that occurs, which actually help 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 stereo tapering? And then -- what have you seen from a blinded basis about adherence to your steroid tapering protocol in Phase III?

I think it's a similar penalty and the deans is good. So obviously, it's an element which we're controlling or at least look into very, very tightly.

It's Rajan Sharma from Goldman Sachs. Just on DM and not to kind of labor the point, but just a clarity, if you show comparable efficacy signal in the Phase III that you showed in Phase II. Is that enough to hit stat sig? Or is it enough for a regulatory pathway? And then 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.

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 on a market expansion?

Yes. So 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, right? So we will have to look at what the data tell us. And then based on that determine what the appropriate next steps will be. And also maybe reiterating also the point on the innovative trial design, right? 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. So concluding on that, I would say we have a very strong conviction in our Phase II trial data. We had start on IMNM. We had a clear signal on DM, and we will now prepare for database lock in a record center and then wait what the data will tell us what appropriate next steps will be and then execute with speed.

And that was a great question regarding the diagnosis for myositis and immune metacritizing myopathy. I think one of the things there has been a lot of education around this. in myasthenia, I did not -- at my center, we -- I did not expect to see so much myasthenia, and they really after the Vyvgart trial results came out, patients started showing up. And the same thing, I think, has happened with IMNM. And to a certain extent, we set up a myocyte center at Northwestern and patients have been coming. And so I tend to see like 1 to 2 at least news every 2-ish weeks to 3 weeks of immune-mediated necrotizing myopathy. And so there are a lot of primary care providers that are now preferring because of education.

And 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 2 years ago. We just don't come and then leave. We are there to stay until we can really make a difference for patients. So we are in together to shape the market and expand the market in terms of number of patients who can benefit from a treatment.

So I think we have time for one more 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. And would any of those drive your label strategy if TIS were positive, but heterogeneous. And two, for IMNM, given the time of muscle message, how do you expect prescribers to position Efgart-relative to IVIg primarily as a option for those who are dependent or in earlier-line settings.

Yes. Maybe I can take the first one and then Sandrine, if you want to touch on that. So from my perspective, I mean, 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. And you've heard from our KOLs here, but that's often what patients present with. So for me, I think focusing, of course, on the total, but MMT8 is going to be a really important one to watch out for. And then in terms of how you think...

Yes, in IMNM, basically, IVIg is actually not approved for IMNM. So when you look at market research, you've heard that I have been looking at quite a lot. And 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, I mean, they would be ready to really start as of first line after using some more series, et cetera, directly with Vyvgart. We will have to see the data, and every prescriber is different. But for sure, this will be the first and only approved treatment available.

Thank you. That's all the time we have for Q&A. But we will be around, and so please find us with additional questions. And our excellent KOLs, thank you. They will also be available during the Q&A if you want to continue to get their perspective. Thank you.