arGEN-X Aktie

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.

Good afternoon, everyone, and thank you for joining. My name is Rajan Sharma European pharma and biotech analyst here at Goldman Sachs. Very pleased to have argenx with us this afternoon for the last fireside of the day. And we've actually got 2 speakers. We're lucky to have two seekers because today, we've got Karl Gubitz, CFO will probably know and then we also have Arian Namen, who is Head of Corporate Development. Maybe just to kick off, Aryan, given that you probably someone that hasn't had as much time with investors, relative to call. Maybe if you could just give a brief introduction of your role yourself and how that's evolved over the years at Argenx.

Yes. No, happy to do so and happy to be here. So my role at Argenx is indeed that I had corporate development and strategy. I've been with the company since 2015. So I joined Argenx when it was just 30 people at the time with a responsibility on our business development deal making, I ultimately evolve my role in a broader corporate development responsibility in the sedan leadership team. So my team focuses on really everything related to third parties and dealmaking. So the business development, the partnerships, the alliances are sourcing with suppliers and corporate strategy as a whole.

So supporting the organization, which countries do we enter, which indications do we prioritize does the overall portfolio make sense? Which molecule do we take into what indication basically?

We'll definitely dive into some details that. But maybe just to start, maybe if we could just start on VYVGART commercials. You obviously had a very solid start to the year, 60% year-on-year growth in Q1. But competition in myasthenia in particular, is stepping up. We've had a couple of recent approvals and potentially 1 coming. Just in that context, how should we think about the growth outlook for firstly, in myasthenia gravis in the near to midterm?

Thank you, Rajan. Yes, MG still has a lot of growth ahead of it. We are now 17 quarters into the launch, but the growth is not slowing down. All the share of biologics, that's Webcor, all the other FcRns, C5s and so forth is only about 20% of a total market. 80% of the market is still on the orals, Mestinon steroids immune suppressants, there's a lot of growth into the earlier lines. And VYVGART is not only the biggest of innovators in that 20% share of biologics, it's also driving the growth because if you ask a doc 4 out of 5 docs will say, you start with Wipro -- and now, of course, we also have a CRO negative, which gives us the broadest possible and able to help with that growth, but at 11,000 patients to take the total addressable market, if you add 0 negative, moving into the earlier lines and also ocular, which we have a data, but not yet the approval to 60,000 patients. .

And one of our key growth drivers continues to be the PFS for self-injection because of a convenience of a 22-second injection, which none of our competitors can do of course, is also driving the growth. So a lot of growth looking forward in MG. And on CIDP, if I can quickly add -- we are in the early innings of a launch there. We still at the bottom of that patient funnel in about 12,000 patients, which are not adequately addressed with standard of care. Slowly over time, we can move earlier line. but both CIDP and MG continues to grow in all markets. So I think we're set for growth over the rest of the year.

And in terms of maybe just to double down on MG for a moment, you said 20% biologic penetration in the indication. Where do you think that can go? And are there any specific analogs that you look to as you think about how a biologic?

It's a great question. Of course, we also debated internally. And the short answer is I don't know what the share of biologics will be in a few years, but it should be multiples of 20%. And it is Webcor who's driving that biologic growth, as I said earlier, because of our efficacy, safety and tolerability and the patient convenience. So I think that we can look forward to expanding that biological growth numbers significantly .

And then just thinking about CRA negative, you're obviously clear that it adds a reasonably significant number of patients. But how should we think about the ramp there? I think at Q1, you talked about being ready to launch there, whereas in previous launches, you've talked to maybe 2 or 3 quarters to get reimbursement in place. Is it different to see your negative?

CRA negative is a little bit different. But typically, when you add a new indication, you have to go back to the payers to do a negotiation. Of course, this is not necessarily here because GMG is on the label, but the payers need to change the way formularies to say that the actually requirement to do a test and to send in the test but cannot be removed. But it's actually removing a bureaucracy or a process at the physician's office. And I think that, of course, is very helpful for them.

Remember that the triple negative -- the negative is 3 subsets and half of that patient population is the triple negatives, which has no options available today. So there are many patients waiting. But in terms of a trajectory of growth 17 quarters in, we continue to show growth quarter-after-quarter and to maintain that growth, you need new innovation. So this is the new innovation which is going to drive growth for this year in mg the 0 negative plus the PFS, which is continuing to drive growth.

Okay. And then obviously, we have the ocular potential as well we've seen that you've hit on the trial. Is that a seamless scenario where it could be a relatively quick uptake?

Yes. On ocular, is an important part of -- I already mentioned our strategy is to be the first-line biologic and to move earlier line. Ocular is earlier lines, if you like. 85% of ocular patients generalize into generalized myasthenia gravis. We think we're going to add around 7,000 patients there, and the unmet need is clear. At the recent medical conference at AAN when we presented the data, it was standing room only. And this is because the unmet need calls out for a new tool in the toolbox to treat these patients. .

And I think that we don't have approval yet from the FDA, of course. But what we're hoping is to change GMG into MG, and that will get you to the 60,000 total addressable market.

And I think the unmet need is very often underestimated in ocular. I think like this short hand has sometimes wrongly been that Ocular is less severe right, because you don't have these generalized symptoms yet. But just imagine how debilitating ocular on its own can still be, I mean, these patients with the double vision they have they cannot work on a computer. They cannot drive a car. It's hard to actually walk anywhere without falling, right? I mean -- so it's overall not a version that is less severe. It's just concentrated in the eye at that stage. And it is indeed typically earlier in the disease manifestation.

Okay. And then maybe just quickly touching on CIDP. Do you have a sense of where penetration is for VYVGART got right now? And you talked about kind of moving to earlier lines. And how do you actually not that do you need more clinical data? Or is it more of a case of physicians becoming more familiar with the product profile?

Yes. Moving earlier line, of course, is, let's call it, a little bit more aspirational. We're going to get there over time because where we are now is still early in the launch. If you just look at the patient numbers, 42,000 patients diagnosed in the U.S., 24,000 of them are treated, half of them not adequately treated with standard of care. What we continue to do is to educate the physicians and to activate the patients.

You'll see in the U.S. all the DTC, the television campaigns because what really helps to get the patient on VYVGART is if a patient go to the dock and ask a dock is VYVGART right for me. So we need to do a lot more work in terms of patient activation, physician education and then over time, we can increase the usage of it. But we're still early in the launch and the penetration is relatively low.

Maybe kind of moving to BD and then potentially M&A. Could you maybe just outline what sort of assets are potentially of interest to argenx. You probably -- I mean, you've done a few smaller deals, whether that's for technology platforms or formulation? And what was the rationale behind those?

I think partnership has really been in the DNA of Argenx right from the start. Actually, 1 of the cultural pillars of the company has been what we call co-creation. -- where we work together with our partners, either a technology partner or an academic partner, and that's how we've been able to create and design the molecules that we have in a differentiated way. And we actually consistently do that. So in our IIP, we do these business development licensing deals in close collaboration with the scientific team identifying the novel biology.

But there is actually not any program in Argenx that get started without some form of partnership at that from day 1. And we do, I think, a multitude of these deals per year. And you've seen if you track carefully the early-stage pipeline, we've systematically added to that early-stage pipeline building up, let's say, the innovation engine for the future. What I think has changed with the company turning profitable is the means to build on that playbook, but also apply it to later-stage opportunities. So what are we looking for? We're looking for opportunities that still fit the Argenx innovation playbook.

So we're looking for novel target biology, first-in-class opportunities. We're looking for opportunities where we can bring our pipeline in a product execution. And we're looking for that in context of neuromuscular and I&I. None of that, I think, by any means, is surprising. I think from a stage point of view, we're looking for opportunities that are IND minus 12 months or a preclinical asset or IND plus 12 months, maybe a Phase II asset -- it could be later if it's the right fit. I don't think that these rules are dogmatic in any way, but just to give you some color.

So at the beginning of the year, you saw us signed this option to acquire Ten Security, which is a Japanese biotech company. They have an antibody molecule against a novel target fn14 -- we believe that, that target biology has applications in multiple muscle wasting disorder. So we can apply our playbook there. It's an option deal. So we actually create a way for us to generate data together based on which argenix can decide to bring it in. And it's an incredibly strong antibody actually the tense -- for those of you that don't know, it's a spinout company out of Astellas. I mean that molecule was actually discovered in the Astellas discovery. So I'm just highlighting it because it's just a good example of what we've been doing. But there's other shapes and forms that potentially could fit.

Okay. And where do you think that you add value as a partner? Is it on the development? Because obviously, Visa's been pretty successful. It's been tested across multiple indications. You've been successful in most of them. Or is it as a commercial engine where, again, you've been pretty successful at commercializing the drug?

Yes. I think it can be both. So clearly, if it's something that fits our commercial organization, there's a way for us to add value. I think from a development execution pipeline in a product there, so there's a way to add value for the earlier stage program on the antibody engineering, there's a way to add value. I think 1 of the precoat is that we have to add value to the deal, right? We cannot only be a financial tool -- in that, we also need to bring capabilities, I think, to these assets that basically allow to either broaden or accelerate the opportunity that the biotech company otherwise would have been able to do.

Okay. And how do you think about capital allocation there? I mean not just from a balance sheet perspective, but then I guess, falls from a P&L perspective because if you're bringing things in, there's an R&D cost that comes with that, are you sort of holding back some of the internal spend in the anticipation that there'll be something external coming?

I think the strength of Webcor is it really is the type of company type of asset which builds companies. If you look at the scale of our revenue, even now and with a lot of growth, as I said, ahead of us, you already see the revenue falling through to profitability. That said, we have a unique opportunity to build the company for the longer run. We are going to invest in building durable growth now. Should give us that growth into the next decade. But after that, we're going to have a large base and to build durable revenues on top of that, you need to invest in innovation now.

And that is what Arion is doing now and what is the strategy of the company. I think that, as I said, we've got growth can afford, but we can do both. But the priority, number one, of course, is revenue growth, and that is where the dollars go first.

Okay. And maybe just on that point of sort of revenue growth dropping down through the P&L, how should we think about that on a forward basis? There's obviously some confusion within the market on the OpEx venture for '26. How do you think that going forward? And do you think the market is in the right place now?

Yes. I mean we were clear at the beginning of the year with the OpEx growth year-over-year and with this combined R&D and SG&A should be around 30%, that should get you to around $3.5 billion on a full year basis. So we wanted to put that market out there. At the end of Q1, we made a $400 million operating profit, which is an operating margin of 30%. We don't want to give targets out there in terms of operating margin because we don't want to box ourselves in. We want to chase the novel biology, as I said earlier on. But over time, of course, we think that we can provide operator -- and we will provide operating leverage. And so you can see that margin improving over time. .

Okay. And then maybe just 1 time, just moving on to pipeline readouts. It's obviously a relatively busy second half of the year. Lots of focus on my site. I'm conscious that you have the event in a couple of weeks. But could you just kind of walk us through the trial there, what population you're studying and how to think about the sort of respective commercial opportunities in those subtypes.

Every site study readout registrational study will be in Q3. In a couple of weeks, we have an R&D day on my side this. It will also be webcast, so please join us. It is a basket study across 3 subsets. dermo myositis, IMNM, immunonemediated myositis and also polymic -- in terms of -- I won't get into all the details here. I think the joint R&D Day. But there's a path to get all the subsets or 1 or 2 of these subsets, it really depends on the data and it depends on the FDA, of course.

The unmet need surely will also play a role. In terms of a commercial opportunity, let's start with IMNM because that's 20,000 patients, and it's a complete white space, but this is probably the best example in the myositis of being a prototype argenx indication, strong biology rationale and clear unmet need. If you take that 20,000 patients with no treatment options, I think we have an opportunity to very quickly transform the lives of those patients.

Very excited about that commercial opportunity. The bigger driver, if you like, is dermo myositis 40,000 patients. But of course, it's -- there will be more competition there. Ajacc2from Roivant, repo, will launch in September this year. It's an oral -- but of course, it's a JAK, which comes to a certain safety considerations. But at the end of the day, dermomystitis is a very heterogeneous disease. So I think over time, each innovator will find its place in that indication and VYVGART also be very excited there. So I think that more to come on the R&D Day. Another Phase III data in Q3, lots to be excited about.

Okay. And maybe just thinking on the OpEx point, it's kind of related here, just assuming that you kind of get the label in all 3 indications, how should we think about that incremental launch costs that come with that because there'll obviously be a new physician group that you'll be targeting?

Yes. So it is -- I mean, of course, argenx playbook is if we launch, we play to win. You've seen that from MG launch. You've seen that from the CIDP launch, and we will play to win. We will put in a field force for rheumatology. Part of my sites is prescribed by Neros, where we already have strong relationships and established capabilities, but we will need a rheumatology field force. We will look at what patient activation strategies which we will put in place.

But because the platform is already in place, I think the launch will be very profitable in terms of P&L. It will not be a drag in operating margin. It will actually support the operating margin. And just to put a sense of scale out there, we launched MG in the U.S. very successfully with 70 reps, 7 0. Just to give you an indication of a size you need for an orphan type of indication in the U.S.

That's super helpful. And then maybe just on the data itself. So we saw the Phase III data, it looked pretty encouraging. We don't know what the subtype split was in that. Is it fair to assume that there was a similar level of efficacy across all of these subtypes.

I mean we didn't provide all the detail, of course. But the only thing I will say is that at the end of Phase II, we had the option to not to continue in 1 or 2 of 3 subsets and we made the decision to continue with all 3. And we will, of course, now get the data in a few months of Phase III data. .

Okay. Perfect. And then maybe just switching to empathy probe as well, which I guess kind of fits with the extended innovation piece as well. How should we think about the commercial opportunity there in the initial indication of MMN?

Yes. MMN is I think it's the kind of indication where, first of all, like in CIDP with discard, there hasn't been innovation in that indication for decades, right? The only available option for those patients is IVIG. But what we've said is that there is about 12,500 patients in the core markets. We think about 6,000 of those in the United States. So that's, I think, the direction to think about. What is also important about -- to note about MMN and its unmet need is that we know that the MMN patients are actually the single highest consumers of IVIG. They tend to use a lot of IVIG, which I think is a testament to the level of need that exists in that patient population.

In terms of a broader context, if I can just add, the bare case on Argenx is that we are -- it's a single asset concentration risk and this is why IMPA and the MMN data, which we'll read out in Q4 is so important for us to show you what we're doing with VYVGART repeatable and scalable because an EMP is currently in 2 Phase IIIs and more indications to come. .

Okay. On that point, how much how much of important sort of readout is in passion in the sense that it de-risks put for you internally? And then is it a scenario similar to VYVGART once you have confidence in the profile that you then explore multiple indications.

Well, I think we're already executing that strategy, right? I think we designed a very strong molecule with Empire. It's highly differentiated in its molecular design. We think C2 is a great target to intervene in the complement system and the intersection of the classical and the lectin pathway. So it has this pipeline and a product potential. So MG and CIDP are leading the way. We've been there with DGF, but we're -- I think we're not done evaluating new indications for this biology.

And then eventually, is that something that you can foresee, again, kind of extending that they've got sort of playbook where you have multiple formulations.

Yes. I think the presentation playbook that we had for VYVGART would also apply to Empa but probably in an accelerated way relative to VYVGART.

Okay. Makes sense. And then you're also exploring the asset in -- how should we think about that coexisting with VYVGART? Is this a combination approach? Or is there a subset of patients that don't respond on VYVGART they need an alternative?

Yes. So we made a couple of important choices there. So first of all, we didn't subordinate our Empire development to VYVGART. So it's not fifthard failures in the EMPA trial. Actually, our strategy is to develop Empire for the broadest possible label, and we will let the data speak on how to think about that. We do know that there it's likely that these molecules target different biology to a certain extent.

In CIDP, it is characterized that IgMs also play a role IGM activates complement. VYVGART would -- biologically, it would not impact an IgM. So could you see that biology is part of the rationale of patients that don't respond on VYVGART it could be. And would these patients potentially have a right to respond to Empire, I think biologically, the answer would be yes. But we're putting that through the test. And basically, what we're doing on the co-positioning is we're generating then we will make a data-driven decision on what approach is based on the label, based on the data sets. We would be the only player in this market that has multiple modes of action. So we are, I think, in a strong position to continue to build out and generate a return on our investments in CIDP.

Makes sense. And then thinking a little bit deeper into the pipeline, you've obviously got a couple of next-generation SCRN assets. Maybe if you think with your sort of thinking about portfolio strategy and how did those exist? And is this the case of wait for the data to mature and then you make a decision on which you take forward?

Yes. I think portfolio is a very important work in that context. So I -- what we are trying to achieve on the next generation is to move our FcRn leadership with VYVGART into potentially a decade-long strategy. So we have -- from that, we created multiple next-generation molecules. And these have differentiated profiles. So we've been public on the profile of argenx 213 -- it's a longer-acting FcRn. It completed early-stage studies. It's ready for late-stage studies -- then we have argenx 124, where we have not been public on its design and its mode of action.

But what we can say is that it's not just another 213, right? It's a different molecule. It's a different profile. That is currently going through Phase I what does that optionality allow us to do, right? It allows us to think about life cycle for VYVGART in a way that still elevated, but it potentially also gives us the cation pipeline even beyond, let's say, the current set of indications. And we do know that there is more evidence being generated for anti-FcRn. There is a multitude of IgG-driven diseases in which we haven't explored yet. So we're creating this portfolio. And that's the second wave in this portfolio. I think at JPMorgan, and Tim also highlighted for the first time I think the third way is on how we think about that with a potential oral formulation in FcRn as well.

Okay. And in terms of time lines, you talked about 213, we know a little bit more about that. Is that potentially ready to go to Phase III? And can you be a bit more aggressive in terms of time lines, given you have the capital and you have the understanding of the mechanism.

I think that is exactly right. It's potentially ready to go to Phase III. It's really about what is the right plan. How to move that forward in the fastest possible way. In addition to that, the 124 data is not far out. We will see that in the second half of this year, and that will really, I think, give us the information to say which molecule is best positioned where, at what pace. So we're doing, let's say, all that scenario, strategic analysis as we speak.

Okay. And maybe just on the point of sort of there are more IgG-mediated diseases that you could target not just with VYVGART, but also with the next-generation assets -- how should we think about pricing? Because you've got Shogan coming next year, which is a potentially larger indication, you also exploring grades disease, which is a much larger indication. So can you maintain sort of orphan-like pricing as you expand into those indications?

Yes. If you think -- if you -- I mean, cogens a very big indication, more than 300,000 patients. But if you think about where the drug might work probably more in a moderate to severe subset of that, which gets you more to an MG like opportunity in terms of patient numbers. So I think, yes, you are right. As we add on more indications, pricing pressure will come surely, -- and maybe we need to adapt our price. But think of that as a very slow decline more than offset with incremental patients over time. .

Okay. Yes, I'm just kind of thinking about the strategy that Alexion or Astra had as they shifted from Soliris to Atomos and there was obviously a price incentive to do that. Is that something that may be rational?

That may be something -- yes, I think, as Aryan said, we want to have multiple next-gen FcRns. One will be life cycle management, and we can look at playbooks we or many successful playbooks out there. [indiscernible] is to automate surely is 1 of them, but then to have a second FCR at a different price point, possibly lower price point, maybe broader indications, we'll see. I think that will be all important aspects to consider. .

Okay. And just on 14 time line, should we expect an update there this year?

Well, we'll have the data this year, allowing us to make that portfolio level strategy decision-making -- to what extent we will communicate that this year. I'm looking at our IR.

We're going to be light and communication. .

I think that's exactly right. I mean there's -- I think in this very competitive environment, we will really want to maximize our position, and we will want to go as fast as we can and then do the communication in a very deliberate and strategic way.

Okay. Well, let's move on before you get in trouble. Maybe on systemic fluorites -- there's obviously a Phase II data readout coming second half of the year. What are you looking to learn from that? And how quickly could you then move to a registrational study? Or would this be 1 of those sort of seamless Phase II to Phase III that you've employed in the past?

I think scleroderma is an indication of a similar size as graphs where there's tremendous unmet need. There is really not that much that works the approved drugs are typically confined to the lung setting and more systemic settings or manifestations of the disease are really lacking treatment options. I think the autoantibodies are well characterized in this biology as a potential driver of the disease. That's really what we're putting to the test in Phase II. Can you intervene, can you see the kind of effect that justifies moving that forward? Can you intervene early enough to have a real benefit.

Okay. And then maybe in the last minute, I think there's building interest on the IGA sweeper. Can you maybe again just talk to the differentiation of that asset relative to everything else that's going on in that space? And maybe if I could ask about time lines there as well.

Yes. That molecule is -- it's a precision tool and it specifically targets IgA and what it does, it reduces IgA deep and fast -- so ultimately, we will roll out an indication development plan across multiple IgA driven diseases. We've communicated IgA nephropathy as the first indication. It's a pretty obvious one. It's also a competitive one. So we have to show, I think, those benefits in our clinical trial approach, where we have to show the benefit of the fast onset of action we have to show the benefit of the depth of the reduction because that's really, I think, what justifies the positioning of that molecule in this competitive treatment paradigm.

Okay. Perfect. I think we're just perfectly at time. So Ari and Karl, thank you so much.

Thank you, and thank you all for listening. Thank you.

Hello, and welcome back to the Bank of America Healthcare Conference. I'm Tazeen Ahmad. I'm one of the biotech analysts here at the bank. Our next presenting company is argenx. Sitting up here on stage with me is the new CEO, Karen Massey, congratulations, Karen, on the recent promotion. We're going to be spending time, I think, focused a little bit on the pipeline because there's a lot going on.

But maybe we can start off by talking about what your vision is for the company now that you're helming all the major decisions and how you think about strategy going forward?

Yes. Thank you so much. It's great to be here and a great conference. And I appreciate the opportunity. I mean I would say we have laid out our growth strategy for argenx, and that's Vision 2030. And so that gets us to 50,000 patients by the end of the decade, 10 labeled indications and 5 molecules in late-stage development. So we have -- I would say, we've had that plan in place, and we continue to execute on that plan. But as I think about my strategy and where we want to take argenx over the decade even beyond that. The vision for argenx has always been to be an immunology innovation company.

And so the first leg of that was building Vive VYVGART and establishing VYVGART. And we've -- and I think we've demonstrated the ability to do that. We want to continue that leadership in FcRn. So the first leg of the next part of the strategy is extending our FcRn leadership for decades to come. So we have 2 next-generation FcRns, and we're investing in an oral. So that's a big part of the vision for the company. But the second part is how do we also build a non-FcRn portfolio that is as meaningfully contributing to argenx as the FcRn portfolio. And that's really all about hopefully, what we can talk about today is the pipeline beyond VYVGART.

Okay. So since you mentioned them, let's maybe spend a couple of minutes on those next-generation assets that you're looking at for the gMG and CIDP indications as well as the oral FcRn. So -- until recently, you were heading up the commercial organization. So you can talk to this in real time. What do you think theoretically would be the benefit of, let's say, having an oral FcRn versus the various different methods that you have of delivery now, everything from IV to Hytrulo to prefilled syringe?

Yes. I mean, our strategy from the beginning with VYVGART and we'll continue with FcRn is that we want to transform these diseases that have significant unmet need. And with VYVGART, what we can -- we believe we can deliver in MG, what we're seeing we deliver also in CIDP is really strong efficacy, but importantly, safety across the broad indications. And then as you said, the convenience for patients. So we launched with the infusion, we brought subcutaneous and then prefilled syringe. Taking that playbook across all of the indications allows us to start to think about patients being treated earlier in their disease. So we're really expanding these indications, expanding these markets.

It's a big part of our strategy and will be a big part of our strategy for future indications. And the oral helps us to do that, so -- as well as our next gen. So 2 on 3, one of the next-gen FcRns moves to every 4-week dosing. So it's a step forward in convenience. And potentially with the oral, you can imagine that's another step forward in convenience, but still maintaining that efficacy and safety profile of FcRn. When you think about FcRn from an MOA, we know that there are many, many indications beyond what we already have approved in MG, CIDP and ITP.

And so we think by having multiple next-generation options, we have the opportunity, yes, to provide more convenience in the indications that will already be approved in, but we can also start to continue to push the boundaries of the biology of FcRn and even further expand those indications beyond.

Yes. So it seems though that you've done a good job of moving patients into front line. I remember, I think our first version of the model when the drug first launched had a much lower peak sales penetration. And I think part of the reason for the constant revision upward is that the company has been able to move higher in the lines of therapy. So as you think about in a world where, let's say, auto-injectors are much more commonly used because of, let's say, the GLP-1s, the company is developing an auto-injector pen. So as you think about the incremental benefit from moving to a prefilled syringe to an auto-injector to an oral, how much of a meaningful impact do you think you're going to be seeing with each of those iterations?

I mean I think for each of these innovations, we do see it as a step forward and driving the majority of our growth. I mean if you think about the step that we took going from subcutaneous to prefilled syringe. And as you said, they continually increasing the revenue and the projections, a lot of that's being driven by prefilled syringe because what you see is that we've been able to expand the prescriber base significantly beyond where we thought it would be when we launched VYVGART significantly expand the addressable market because of the simplicity of being able to use a prefilled syringe at home rather than having to go into -- for an infusion.

So it is a step forward. I think the auto-injector is less of a step change because the big shift was being going from HCP administered to patient administered with the prefilled syringe the auto-injector will still -- assuming approval and we get through the regulatory framework will still be patient administered. It helps because it's easier to handle. It helps because if patients are needle phobic, but it won't be as much as a step forward. But it is -- but it will continue to be a differentiator for us.

And then you can imagine the oral, as you say, I mean, we'll see how it plays out with the GLP-1s. But I think you can imagine that going from an injectable to an oral opens up a different pool of patients for whichever indication you're looking at.

Okay. So maybe let's talk about a couple of the near-term data catalysts that you have upcoming late stage. Let's start with myositis. So just remind us when is that Phase III reading out? And you were looking at 3 different subtypes. I think there's been some questions about what the company thinks is going to be the biggest value drivers. So maybe talk to us about those items.

Thank you. It's exciting. We have the data reading out in Q3. And yes, so we see myositis as our next growth frontier, our next growth opportunity. And we see the addressable market as around 70,000 patients. So to put that in context, that's similar to where we see the MG market addressable market right now. So you can think of it as an MG-like opportunity from that perspective.

There we designed a clinical trial that allows us to explore 3 of the different subtypes. So we have IMNM; we have DM, dermatomyositis; and then PM. And from my perspective, each of the subtypes has a clear biology rationale, and we can go through what that is. I would say we're very disciplined at argenx at always starting with the biology and the science. So we have a clear biology rationale for each.

And we designed a clinical trial that is very thoughtful and that it allows us to look at the overall population, but also the subsets so that we can really explore and we have multiple paths to success depending on data that we see. In terms of the value driver from my perspective, and certainly, as a commercial person, I'm really excited about M&M, and that's what we've been talking about as we've been doing our homework to really understand the commercial opportunity, what you see in IMNM, there's nothing else approved.

This is a completely white space indication. We see there's around 20,000 patients. So that's bigger than the TAM for CIDP. It's bigger than the addressable market when we launched MG and you'll remember that with myositis, it's weekly dosing, so CIDP-like dosing. So being able to go to a space where there is a huge unmet need there is no competition, including the competition on the horizon. And there's also quite a bit of overlap in IMNM. It's -- if you think about the treatment -- the treating physicians, it's more neurology and rheumatology. And obviously, we have strength in rheumatology. So the overall opportunity is a big value driver for us. We have a lot of belief in the biology for all of the different subtypes. But if you had to ask me to prioritize and where I'm most excited about, because of the patient unmet need, I think IMNM is going to be really exciting.

Okay. And to say that you're most excited about is not the same thing as less bullish about DM. Correct?

That's exactly right. I would not say that. I mean I think in DM, it's just a different dynamic. I'm also -- I'm excited about the overall myositis opportunity. In DM, we have a strong biology rationale. The difference from a commercial perspective is just is the dynamics. It's more heterogeneous. So we know that there's more at play in driving the disease and there is more competition, but it's a larger patient population.

We think that that's a 40,000 TAM. So look, I think that's also an exciting opportunity. It's another one where it's bigger than the CIDP TAM at launch. So yes, it's certainly a big value driver. There's a good biology rationale. And I look forward to seeing that actually the data play out for each of the different subtypes because I think they all -- each have their own unique opportunity.

So when you -- when it comes time to showing the data in the press release, like give us a sense of what level of granularity we're expected to see?

Yes I mean at argenx and the style that we have is that we like to be transparent, and we want to share as much data as possible. This is our first entry into rheumatology and some of the medical congresses and conferences with rheumatology are a little more strict. And we want to make sure that we have the opportunity for -- to make a big splash with this data because when it reads out. So we'll definitely share the top line and as much detail on the subtypes as we can. But we'll just have to -- once we see the data, we'll have to determine what the right path forward is there. But we like to be able to give transparency, and we'll be able to give a good sense of where we think we're going with this indication.

Okay. Now because of the different prevalences of the 3 different subtypes, how should we be thinking about the balance of each of the subtypes that finally enrolled into the study?

Yes. So the way that we designed the study, if we maybe just take a step back, it's a seamless Phase II, Phase III. And when -- and we did not cap any of the subtypes. So we let the enrollment run both for Phase II and then also for Phase III. So you can imagine that it's not an equal distribution across all of the different subtypes, but it enrolled based on, I would say, unmet need and as well as the disease characteristics. So we haven't shared the underlying sort of the number of patients across subtypes, but we'll be able to do that, I would say, at top line.

Okay. But there isn't a concern internally that you enrolled too few people in one of the subtypes and therefore, it wouldn't be like strong enough to support an application?

No. I mean the trial -- it's a basket design. So we're able to look at from a statistical analysis plan perspective, the total population as well as the subtypes.

Okay. And one other common question we're getting lately is what are your discussions with the FDA on the subtypes? Like is there flexibility to look at the data and then decide if you want to apply for a full label for all 3 or a subset of them?

Yes. I mean, as always, we're engaged very closely with the FDA on -- especially on such an important study. And as always, it will come down to let the data speak and then it will be a review decision. But I think we have multiple paths forward.

Okay. And then in terms of commercial organization, assuming that you move forward in some capacity with this indication, what changes would you need to make, if any, to the field force?

Yes. So this is our -- potentially our first step into rheumatology. And so we -- with this step and then, of course, we have on the horizon, Sjogren's, another exciting potential rheumatology indication. So we do start to think about expansion so that we can cover more of the rheumatology. It's a different footprint, also potentially different support services for patients so that you can compete in rheumatology versus neurology. So we can leverage a lot of the commercial infrastructure that we have with, let's say, some expansion so that we can make sure to have the reach that is needed to succeed.

Okay. So if this becomes, let's say, another potential vertical for the company, you just mentioned Sjogren's. So maybe let's talk about that. You've got a study underway, which I believe reads out in sometime in 2027. So you wouldn't be alone in looking at Sjogren's. So maybe mechanistically, can you just talk us through why it made sense to invest the money and the time into looking into this?

Certainly. I mean I think one sort of takeaway that I think about with Sjogren's is and some of these rheumatology indications is there was always -- the auto antibodies were generally known. But it was always thought that they were more of a bystander or an outcome of the disease. And I think what the real shift has been is like is that no, in these rheumatology indications, actually, these IgGs could be driving the disease. And I think that's what we've seen in Sjogren's.

So the way we went about Sjogren's is the same sort of disciplined approach that we go about to choose any indication, look at the biology, and that's what we can look at and look at the development path and then what is the unmet need. The way our development plan, I think, was quite innovative and agile and reflects the argenx way.

Our competitor did a big Phase II study. So we were able to leverage the data from that competitor in FcRn that really demonstrated that the biology rationale was there. And what we did was small, very focused Phase II study where we went deep to really understand the drivers of the disease and really understand how to run a clinical trial so that we were able to execute, and I'd say, leapfrog ahead.

And as you say, we have data coming out next year. And it's certainly an exciting indication. In terms of the third category that we always look at Sjogren's, I mean, it's a big patient population, 300,000 patients. But what we see is especially in the sort of around 100,000 more severe patients, there's a real serious unmet need and patient need. It goes beyond just dry eyes, the systemic manifestations of the disease, and that's where we think we'll have the biggest benefit.

Okay. And the investments that you would theoretically be making now into rheumatology would be for all indications. That's right.

That's right.

And with the targeted physicians, we've talked about the overlapping, let's say, of neurologists who treat CIDP and gMG. So when you make the decision into moving into various rheumatology indications, is it too simplistic to say that any rheumatology indication would be something that a community physician of community rheumatologist would be treating? Or are there specializations within that?

I think it will -- we still need to do the work up, but it will be -- I would say it's more -- it will be more specialized than that. Even when you look at neurology, we have over 5,000 neurologists that are writing VYVGART. And so there are a lot of breadth. That's not all of neurology. There are some neurologists that mostly treat migraine. So as an example, so we're not targeting them. It will be the same in rheumatology. And so what we'll be able to do once we have the data and once we -- as part of our launch preparation is really target what's the -- where do we need to focus our energy to get the best return on investment.

Okay. Let's maybe move on to MNM, which is another pivotal study that's going to read out in the fourth quarter, I believe. And it's going to be your first foray of a late-stage study that's not efgartigimod. It's going to be with empa. So maybe talk to us about the excitement that you guys have internally about this particular program because it could open the door to many other indications for this different drug.

Yes, absolutely. We're very excited about empasiprubart. When I talked earlier about the long-term strategy for the company, it is to become a leader in immunology. And so this is our next medicine C2 as the target and MMN as the first indication. And when you look at MMN, I think it's a very argenx-like indication.

It's very clear biology rationale for C2 with MMN a really strong development path that we can unpack a little bit more in terms of a head-to-head versus IVIg based on very strong Phase II data and importantly, a very high unmet need. I mean it's another place that there hasn't been innovation for decades and in MMN. It's a progressive disease.

IVIg is the only option and patients continue to progress even with very high doses of IVIg. So this is a great first indication. But empasiprubart is a pipeline in a product. So we see more indications coming. And one of them that we've announced is obviously CIDP, but there's even more beyond that.

Can you maybe just talk to us about the trial design for MMN and what we should be looking at in particular?

Yes, absolutely. So the trial design is a head-to-head versus IVIg. And the reason for that is because we have such confidence based on the Phase II data that we can design a Phase II study -- sorry, a Phase III study, non-inferiority versus IVIg. The primary -- it's a 24-week endpoint and the primary endpoint is actually is on grip strength. And that's important because what we've learned in CIDP is that grip strength is a really meaningful endpoint to prescribers and to patients, mostly because it's very easy to understand.

I mean if you're losing the ability -- losing nerve function and you can't pick up your coffee cup in the morning, if you can understand as a patient, as a lay person, oh my grip strength is improving. And what we actually saw in the Phase II study is grip strength was able to improve over time, not just slowing the decline. So it's an important endpoint that's meaningful to doctors, understandable to patients and I think really shows functional improvement potential for empasiprubart.

And then what about quality of life? Like maybe talk to -- tell us about what patients feel they need to have that they don't have right now?

Yes. I mean this is another indication where at the very simplest level, a patient's immune system is attacking their nervous system. So they lose the ability to use their hands to walk to -- they lose strength. So from a quality of life perspective, group strength is a good -- is one of the -- is a good endpoint. We also have an endpoint MMN-RODS, which is more holistically looking at various quality of life measures to be able to assess the impact on the disease.

One of the most important data points from Phase II that we saw was when you ask patients to compare how they felt on empasiprubart versus at their peak on IVIg, 9 out of 10 patients said they felt better in empasiprubart. So there's a lot of secondary endpoints also of those qualitative quality of life outcomes.

And what are -- which of those quality of life measures are you looking at? Or will you be looking at?

We have a very long list of secondary endpoints that look at physician-rated quality of life, patient-rated quality of life in MMN-RODS, as I say so. So it's a deep study.

Okay. And then maybe just one more question on mechanism, C2 versus, let's say, C1. On the complement cascade, some might think of are those really that different from each other. But the work that argenx has done, maybe explain why C2 might make more sense?

Yes, absolutely. I mean whenever we look at and identify targets for argenx, we always like to work with world-leading experts to really understand what are the -- what's the best target from an efficacy and safety perspective that's going to be able to open up this pipeline in a product. And for us, C2 is that in the complement cascade. And why is that?

First of all, it's at the intersection between the classic and the lectin pathway. So you're able to capture indications that are driven by both of those pathways while leaving the alternate pathway free, if you will, which has an important safety benefit. You can still mount an immune response to a bacterial infection. But there's also -- the other reason is for C2 in addition to having the indications opened up for the classic and lectin pathway is that we think that it's the safest place to intervene in that complement cascade. And we've seen that with the strong safety and the data that we've generated in Phase II as well.

Yes. So you've focused in on safety, which was going to be my next question. I guess, in particular, is there any reason to think baseline assumption that any kind of black box warning would be part of what a label could theoretically look like?

Yes. I mean, with complement inhibitors, obviously, there's always the consideration of a black box warning around vaccinations and considerations. So in our clinical trials, yes, we do run the clinical trials with vaccination, but we're also working very hard in developing data packages alongside that to demonstrate that you can still mount that immune response and -- so that we can start to work towards. And I think we're relatively confident that we should be able to get to a good place in terms of the vaccination requirement.

Okay. And then same question as before, what to expect at the top line level disclosure?

Yes. I mean here, again, we will be as transparent as we can, and we'll balance that need for making sure that we can -- especially in this indication, I mean, we are first-in-class in this indication, first innovation in decades. You can imagine how much excitement there will be in the medical community. And so we want to make sure that we get a good -- are able to have a good presence at Congress as well as share the top line results when we get them. So we'll be as transparent as we can.

Okay. And what is the specialty that treats MMN?

It's neurology. So it's also a strong overlap with our current footprint.

Okay. So maybe in a couple of minutes we have left, I did want to touch upon IgAN because you will be beginning a program for 121. And I think some people find it interesting that the company wants to invest time and money into this, just considering the view that it's becoming a quickly crowded space given the April and April BAFFs that have launched, will be launching. So just quickly, mechanistically, why do you think there is still room for a new entrant like this?

Yes. Absolutely. So two things. One, when we look at MG, whenever it was, and I remember I was -- when others looked at MG, they also felt like it was a competitive space and there wasn't enough room and look how much that's transformed. And so I think there's plenty of space in IgAN. If we do the same thing as we have in MG, which is provide transformative outcomes. And I think we have the opportunity to do that because our IgA sweeper, what -- it's differentiated because it drops IgAs -- it targets only IgA and it drops them rapidly and sustained. And if you think of kind of this idea of time is nephron, then we think we can provide more rapid efficacy, and that's going to be important for these patients.

And what about on safety? There are some questions about risk of infection for the April BAFFs. And just theoretically, what do you think that profile could look like for 121?

Yes. I mean we'll have to see it play out. But I mean you have people that are walking around and from a genetic perspective, don't have IgA and there's no risk infection. So we think actually targeting IgA is going to actually produce a good safety profile and will allow us to compete there.

Okay. What is the status of the program? It's enrolling?

It's -- no, we're starting the program shortly.

Okay. So not necessarily data this year then?

No data this year. Yes.

Okay. Great. So with that, we're just about out of time. So I'll say thank you for making the trip all the way to Las Vegas. I know you travel a lot. So I'm not even sure where you might have traveled once again here, but thank you. And thanks, everybody, for sitting and listening to the session.

Thank you.

Good morning. My name is David, and I'll be your conference operator today. I would like to welcome everyone to the call. [Operator Instructions] I'd like to introduce Beth DelGiacco, Vice President of Corporate Affairs. You may now begin your call.

Thank you. A press release was issued earlier today with our first quarter 2026 financial results and business update. This can be found on our website along with the presentation for today's webcast.

Before we begin on Slide 2, I'd like to remind you that forward-looking statements may be presented during this call. These may include statements about our future expectations, clinical development, regulatory time lines, the potential success of our product candidates, financial projections and upcoming milestones. Actual results may differ materially from those indicated by these statements. Argenx is not under any obligation to update statements regarding the future or to conform those statements in relation to actual results unless required by law.

I'm very excited to be joined on the call today by Karen Massey, our new Chief Executive Officer. Today is her first official day on the job, marking a very important milestone in the story of argenx. We're also joined by Karl Gubitz, Chief Financial Officer; and Sandrine Piret-Gerard, Chief Commercialization Officer. I will now turn the call over to Karen.

Thanks, Beth, and welcome, everyone. I'll begin on Slide 3.

I want to start by saying what a privilege it is to step into the CEO role at this point in argenx journey. I joined the company 3 years ago for the culture, the science and the opportunity to help build a different kind of immunology innovation company alongside an exceptional team, one that scales innovation through collaboration, delivers meaningful impact for patients and creates lasting value for all stakeholders.

I'm excited to carry forward Vision 2030, our road map for growth and value creation at a moment when we have so much opportunity across the near, medium and long term. Near term, we see continued growth with VYVGART across both MG and CIDP. While we see the typical effect of seasonality, the underlying demand trends remain very strong and continue to point to a business that is both growing and expanding. I'm particularly encouraged by our new patient demand. Q1 was amongst our highest quarters ever.

Our leadership in neuromuscular was on display at AAN last month, where consistently strong efficacy and safety data reinforced why physicians should treat broadly and earlier with VYVGART in both MG and CIDP. Importantly, that growing confidence amongst neurologists positions VYVGART well for the next phase of growth with potential expansion into seronegative, ocular and pediatric MG population based on the strength of ADAPT SERON, OCULUS and Jr.

When I consider the growth over the medium term, we see strong runway of launches ahead, reflecting the scale of our ambition and the depth of opportunity across our pipeline. We're advancing into rheumatology with readouts in autoimmune myositis and Sjogren's. And we expect the first readout and potential launch of our second medicine, empasiprubart in MMN.

Lastly, we're investing in our future. We're building a pipeline by sourcing novel biology relevant in diseases of high unmet need, positioning us to sustain long-term growth and reach thousands more patients.

Slide 4. Our strategy is ambitious, but it's one we know how to execute. Vision 2030 is built on a proven immunology innovation model that has already delivered a strong foundation. Today, we have 5 clinical stage molecules that follow our model, first-in-class against a novel immune target and collectively addressing more than 15 distinct diseases. Empasiprubart is positioned to be the second medicine we bring to patients. Like VYVGART, we built this molecule very intentionally to target C2, leveraging novel biology insights from leading experts in complement biology.

Through empasiprubart's development, we've also unraveled critical insights into MMN biology that position us to fully transform the treatment paradigm. The Phase III readout is expected in 4Q, bringing us closer to launching our second medicine. In MMN, we see a familiar opportunity, build and lead the category, much as we did with VYVGART and MG, transforming the entire disease space. In CIDP, we have the same ambition. We continue to grow our market share with VYVGART and are generating extensive real-world insights as patient experience increases. And now by advancing a second targeted approach with empasiprubart, we will deepen our understanding of the underlying biology, helping us learn which patients benefit most from which treatment and positioning us to secure leadership in CIDP.

Slide 5. Across VYVGART and empasiprubart, we're solidifying our leadership in neuromuscular diseases and amongst the physician and patient communities. One of the most critical therapeutic area expansion for argenx is into rheumatology, and this starts with an important Phase III readout in autoimmune myositis in the third quarter. This is a disease with significant unmet need, defined by progressive muscle weakness that makes basic daily activities really challenging, if not impossible. There are no approved treatments in necrotizing myositis. And in dermatomyositis, where serious symptoms can emerge in the muscle, in the skin and in other organ systems, the complexity of the disease means more innovation is needed.

VYVGART has the potential to be the first truly targeted therapy in this indication, targeting autoantibodies against proteins that are highly expressed in the muscle. In the case of positive data, we plan to take an approach similar to what we've done with MG and CIDP because the myositis opportunity has similar attributes overlapping physician community, long established conventional treatment patterns and our goal to transform patient outcomes and become the #1 prescribed biology.

Slide 6. We've significantly broadened the number of clinical candidates across our pipeline in the last 12 months, and you can expect to see this cadence continue. Adimanebart is in Phase III in CMS. ARGX-121 is in Phase II development in IgAN with more indications to follow. And our long-term FcRn portfolio is taking shape with ARGX-213 ready for Phase III and ARGX-124 to follow.

To expand our pipeline at a cadence that will sustain our long-term trajectory, we need to deliberately expand the ecosystem from which we source novel biology. We'll double down on collaborations and licensing agreements with academic institutions and biopharma companies alongside acquisitions and strategic investments, giving us the flexibility to engage in whatever form accelerates innovation into our pipeline. The establishment of our China entity supports this strategy, building on the clinical and commercial strength of our partnership with Zai Lab and embedding us into the local ecosystem to effectively access emerging innovation, accelerate evidence generation as part of our pipeline and product strategy and ultimately expand our impact in this region.

As I step into this new role, I'm reminded of our purpose as a company, our patients. When we launched VYVGART 5 years ago, we made a commitment to continue raising the standard of care for people living with myasthenia gravis. Today, with 17 consecutive quarters of growth, we continue to see that commitment translate into real-world impact in MG, in CIDP and in ITP. This is what gives me confidence in the opportunity ahead. We're deeply committed to our purpose, we're disciplined in our execution, and we'll be flexible in how we source innovation. With that, I'll turn the call over to Karl to walk through our financial performance and outlook.

Thank you, Karen. Slide 7. Product net sales for the first quarter were $1.3 billion, representing 63% year-over-year growth. By region, we generated $1.1 billion in the U.S., $67 million in Japan, $112 million in the rest of the world and $12 million in product supplied to Zai Lab in China. The 1% quarter-over-quarter growth reflects the impact of Q1 seasonality in the U.S. and is aligned with our expectations. Gross to net adjustments and net pricing in the U.S. remained consistent with the prior quarter.

Next slide, Slide 8. Total operating expenses in the first quarter were $919 million, representing a decrease of $36 million compared to the fourth quarter of last year. Research and development expenses increased by $68 million quarter-over-quarter, principally driven by CMC investments to support the expected launch of a VYVGART subcu auto-injector in 2027, continued development of efgartigimod across several indications and advancing our pipeline assets. These strategic investments will deliver long-term growth through innovation in providing transformational outcomes to patients.

SG&A decreased 17% quarter-over-quarter, reflecting higher discretionary expenses in the fourth quarter of last year. We delivered an operating profit of $394 million in the first quarter and operating margin of 30%, representing 183% year-over-year growth. With revenue growth exceeding operating expense growth, we are on a clear path of continued margin expansion, demonstrating the operating leverage we are building as VYVGART scales and we advance our pipeline.

Tax for the quarter is in line with expectations at 14% of profit before tax. We ended the quarter with a cash balance of $4.9 billion, including cash, cash equivalents and current financial assets, an increase of more than $400 million from the beginning of the year. This strong financial position gives us significant flexibility as we deploy capital to fuel long-term growth. Our capital allocation priorities are clear: maximizing the VYVGART commercial opportunity, advancing our pipeline, strengthening our supply chain and pursuing business development opportunities to source the novel biology that will fuel our long-term growth. With our profitability profile, we are investing from a position of strength to deliver on Vision 2030.

I will now turn the call over to Sandrine, who will provide details on the commercial front.

Thank you, Karl. I'll begin on Slide 9. Over the past several months, I have spent a lot of time with our field teams and meeting with physicians and patients. What stood out to me is how argenx translates differentiated science into execution in the market, from securing access to building physician confidence in VYVGART in MG, CIDP as well as in ITP in Japan and to delivering white glove patient support designed to help patients start and stay on therapy. This level of disciplined execution and building trust among our core stakeholders will be critical as we approach several important growth catalysts. Today, I'll focus on what's driving our performance and where we see the most meaningful opportunities to build from here under Vision 2030.

Slide 10. We continue to deliver on our long-term growth strategy in 2026 with strong momentum across all indications and all regions. Our fundamentals are incredibly strong. Now 4 years into MG and 2 years into CIDP launch, we see no signs of demand slowing. In the first quarter, new patient starts were amongst the highest since launch, and we continue to have an expanding prescriber base, reflecting increasing confidence in VYVGART. We now have over 5,000 neurologists prescribing VYVGART in the U.S.

Since launching in CIDP, we have effectively doubled our prescriber base and each incremental physician meaningfully expands the number of patients we can reach. We are also seeing a change in prescribing behavior. Across both MG and CIDP, we are seeing a clear shift towards earlier use of VYVGART as physicians gain confidence with what it can offer patients. In the U.S., our market research now shows that 4 out of 5 HCPs prefer to start with VYVGART as the first targeted biologic in gMG.

New patient demand continues to build across both indications, driving consistent quarter-over-quarter patient growth. The prefilled syringe has materially changed the demand of VYVGART. By giving patients and physicians more flexibility, it continues to drive earlier adoption across MG and CIDP with 68% of PFS patients being new to VYVGART since launch.

Slide 11. VYVGART is the #1 prescribed biologic in gMG, a market that continues to grow. We still believe the biggest opportunity is ahead of us, particularly given the nearly 80% of MG patients who are not yet on a biologic. We know the VYVGART profile is resonating with physicians in this population and more than 70% of patients starting VYVGART today come directly from oral therapies. This continues to be the focus of our strategy to extend our leadership by reaching patients earlier in their treatment journey and expanding our reach to broader MG populations.

The data we presented at AAN served as an important driver of this strategy, and we were excited by the positive response from neurologists. VYVGART is delivering fast, deep and sustained efficacy and safety across MG patients. This supports our ambition for VYVGART to be the targeted treatment of choice, simplifying decision-making for the HCP and underscoring VYVGART's growth potential. I want to share one patient story that underscores why this matters.

Pam first presented with blurred vision and muscle weakness around her eye, but her ocular symptoms were not taken seriously, and she was unable to access appropriate treatment. As her disease progressed, she ultimately generalized, suffered a serious fall and was hospitalized. When Pam later started VYVGART, the impact was meaningful, helping us regain both mobility and independence. Our experience is a powerful reminder that ocular MG is not an eye disease. It can be profoundly debilitating and disrupt independence in ways that are often underestimated. Our positive ocular MG data, which demonstrated consistent improvements in both total and double vision, bring us closer to extending innovation for these patients.

We are now 3 days away from our May 10 PDUFA date for seronegative. So we are limited in what we can say at this point. A potential approval represents a meaningful opportunity to reach patients without detectable acetylcholine receptor antibodies up to 11,000 additional patients in the U.S. Many of them have been left out of studies or lack access to targeted innovation, and this commitment is what drives us every day.

Slide 12. Turning to CIDP. We continue to see consistently strong patient adds quarter-over-quarter with nearly 80% of new starts coming from direct switches from IVIg. As neurologists gain real-world experience and digest emerging data, they are becoming more thoughtful about when to introduce a targeted therapy like VYVGART and are increasingly considering earlier use. Physicians are citing VYVGART's functional outcomes as a key differentiator, particularly our grip strength data.

When CIDP patients were followed from ADHERE to the open-label extension, mean grip strength continued to improve with weekly treatment up to 96 weeks. While neurologists shared that it is rare to see patients regain function after deterioration, which makes an observed recovery in grip strength especially compelling. We remain focused on understanding how best to serve the broader CIDP population and how we can shape the market for earlier use of VYVGART. We are steadily expanding within our initial 12,000 patient addressable market and are seeing our strategy to work increasingly beyond this. At AAN, we presented the post-hoc analysis of the ADHERE study showing 87.5% response among treatment-naive patients, which continue to support this effort.

As we look ahead, our focus is on repeating what has already proven successful. The commercialization playbook we built in MG and CIDP is repeatable, combining a patient-first access strategy, deep prescriber engagement and disciplined execution. This positions us well as VYVGART expands into new indications and our future medicines, including efgartigimod, move closer to launch. With that, I will now turn the call back over to Karen.

Thank you, Sandrine. Slide 13. Putting patients first is how we define success at argenx. I'm incredibly proud of what this team has accomplished, and I'm energized by what lies ahead. I'm grateful for the trust of our patients, our partners and our shareholders as we continue this journey together. Thank you. And with that, operator, we'll open the call up to questions.

[Operator Instructions]

Your first question comes from the line of Yatin Suneja from Guggenheim Partners.

First, congratulations to Karen on the CFO confirmation. Perhaps 2 questions for me. So I would love to hear -- Karen, would love to hear your perspective on the outlook of argenx as you see it. Once you are fully settled in the role, do you anticipate or should we think about any sort of changes to the company's strategic direction? So that's one.

And then the second one is more around VYVGART. You do have 2 significant label expansion opportunities ahead of you. You probably will have the broadest label for MG across various subsets. How does this change the growth outlook as we head into second half? And how do you expect this differentiation to play out from a competition standpoint?

I appreciate the congratulations on the new role. I'm really excited to be taking on this role at this time for the company. We're in such a position of strength with a really strong quarter and strong momentum, and there's so much opportunity and momentum ahead.

So in terms of the question around strategic priorities, as I step into the role, my priorities are very clear. I mean, I was very much involved with Vision 2030, and there won't be a change in that strategy. For us, Vision 2030 is not just an aspiration, but it's a growth strategy. And so when you look at what we've laid out for that strategy, by the end of the decade, we want to have 2.5 more times patients -- 2.5x patients on VYVGART. We want to have 3x more indications approved and 5 molecules in late-stage development. And those 5 molecules in late-stage development really set us up for the next decade of growth. So there's no change to the strategy, and I'm incredibly optimistic about our future.

In terms of your second question on label expansion, we've laid out a strategy in MG for continued growth by bringing continued innovation to the market. So we have our PDUFA date for seronegative in 3 days. Beyond that, we have ocular MG that we'll be filing quickly, and we're also looking at an expansion into the pediatric population in the future. So as you say, with this, we should in MG have the potential to have the broadest label and be able to reach the broader set of patients. And we see this as a huge differentiator in the market.

What we're already seeing today is that physicians are choosing VYVGART 4 out of 5 times for their early line patients as their first biologic. So we see really strong momentum already and that growth strategy of expanding our label should continue that momentum through this year, but also into the future. Thanks for your questions.

Your next question comes from the line of Tazeen Ahmed from Bank of America.

Okay. So Karen, there's a big second half of the year upcoming for the company with several data readouts. I did want to focus my question on myositis in particular. Can you clarify your view of the likelihood for success for each of the 3 subtypes that you're studying? In particular, do you feel like anyone is more likely to work than the others? I think some people recently have interpreted comments you've made to indicate that you might be less bullish on DM?

Thank you so much, Tazeen, and I appreciate the pipeline question early on in the earnings call. So yes, as you said, the second half of the year is exciting. Myositis is our entry into rheumatology. And we should remember this is a first-in-class opportunity. This is a white space opportunity. And we have a very thoughtfully designed trial that really lets us explore and understand across 3 different subtypes. Each of those subtypes is grounded in a very strong biology rationale. And you'll recall that we had Phase II data in these same 3 subtypes, and we did move forward into Phase III.

So what we see as a win is a positive study in meaning statistical significance on the primary endpoint. More broadly, I think what's important in myositis is that there's significant unmet need across myositis broadly. And we've been talking about IMNM quite a bit recently because we've had some learnings around IMNM. Specifically, as we've been learning about IMNM leading up to the readout and looking into the data in more detail, what you see is that because IMNM is -- those patients have no treatments available, it is severely underdiagnosed and undertreated. So we see that the TAM opportunity in IMNM is bigger than we previously thought. It's around 20,000 patients. That's more similar in size to a CIDP opportunity and with similar dosing.

So that's why we've been focused on IMNM. But of course, the other subtypes, for example, DM also have significant unmet need and with limited treatment options. IVIg is the only treatment option available there. DM is a little bit more heterogeneous, but we still think that there's plenty of room for multiple mechanisms of action, and we think that VYVGART has a good value proposition in DM. So we're looking forward to the data readout in Q3.

Your next question comes from the line of Derek Archila from Wells Fargo.

Let me add my congrats, Karen, to stepping into the CEO role. Just 2 quick questions. So first, just on 2Q '26 VYVGART step-up. Like in the last 2 years, we kind of see that move from 1Q growth to 2Q growth, and we see kind of a nice magnitude of step-up. So I guess, can you characterize what we should expect this year? And then just a follow-up to Tazeen's question on myositis. So my understanding is that it's not powered for the individual subtypes, but will you give any qualitative information on how the subtypes performed in the Phase III?

Thanks, Derek. Yes, let me hand it over first to Karl so that he can give you some comments on the momentum that we have heading into Q2. And then maybe, Beth, you can comment on the primary endpoint and communications.

Thank you, Derek. Nice to hear from you. Every quarter has its different dynamics, of course. I think we need to focus on the underlying dynamics, which, as Karen already said and as we said earlier in the prepared remarks, which are very strong at the moment. Our full year expectations are unchanged. And the shape can look -- and you can look at the shape of the curve, which will be consistent with prior years. Thank you for the question, Derek.

Derek, on the question about what we're going to share on the myositis readout, I think at this point, you know the style on which we communicate. Our plan is, of course, to give the outcome of the primary endpoint. The primary endpoint of the study is the mean TIS score, and that is taken at week 52. But we also understand the importance of contextualizing that subtype performance. How we do that and what that looks like will still to be seen. I think it's important to remember that because this is a new therapeutic space that we're entering, we will need to preserve some of that data for an upcoming medical meeting so that we can inform and generate enthusiasm among the rheumatology community.

Your next question comes from the line of James Gordon of Barclays.

James Gordon of Barclays. I had a question on competition in MG. So I've had some questions from investors about competitors in the U.S., such as Amgen who have been talking about UPLIZNA, so CD19. They're talking about strong uptake in both bio-naive and switch patients even without step through. So are you seeing UPLIZNA being used much in MG? And is it displacing in any patients that could use VYVGART? And also, I think that Amgen has said they're taking into a CIDP trials. So could that be a threat in addition to potentially C1s coming along? And then also from the competitive point of view, Regeneron, they've got cemdisiran, so also hitting C5, but also a potential MG approval later this year in Q4. Do you think that could impact VYVGART in MG?

Yes. Thanks for the question, James. There's a lot in there. I'm actually going to hand it over to Sandrine. She's been spending a lot of time out in the field with customers and at AAN, and I think has probably recent experience to talk from.

Yes. Thank you. Thank you, Karen. Thank you, James. So indeed, competition has come. We have put MG on the map. So there are more and more players in there, and we see that as a good sign. It means there is a lot of potential in that market, but also more option and innovation for patients, which drives the size of the biologic market, which benefits all of us and especially VYVGART as 4 out of 5 providers really prefer VYVGART as the first biologic.

Now going to your question specifically on some more recent entrants. So what is interesting to see is that most of the recent launches are really positioned towards the later lines. So more for refractory patients and after VYVGART. So we see some use but not really directly competing with us. Because what we are trying to do is to go in earlier lines because we know that 80% of the MG market is still not in the hands of biologics. And this is where we see a really big opportunity, and that's our strategy. So some use indeed, but more in later lines and refractory.

So you also mentioned a recent competitor in CIDP. I mean, CIDP, as you know, we have been in the field for now 2 years. We have another product in development, empasiprubart in development. So what we believe is that CIDP is a progressive disease, but very heterogeneous and there is space for multiple mechanism of action. And so with the current profile of VYVGART, we believe we have a very strong value proposition between the PFS, the efficacy, the safety, recent grip strength data where we showed sustained efficacy up to 96 weeks and then we just presented the data at AAN on earlier use where we did a post-hoc analysis. I don't know if you saw that one, where we showed that naive patients had 87.5% clinical efficacy. So we are really trying to extend here the overall market for VYVGART, and this is very great for CIDP patients.

So now for the C5 question, I think Karen wanted to say something. So I'll hand it over back to Karen.

Thank you, Sandrine. I think that's great. And I think you're exactly on point. As we see new competitors coming into the market, C5s and others, they're mostly being used in the refractory space. So thanks for the question.

Your next question comes from the line of Alex Thompson from Stifel.

Congrats to Karen here. I was wondering sort of, to talk at a high level about your appetite for later-stage business development than what you've done historically? And maybe in the context of that, how you're thinking about your Forte equity investment?

Yes. Thanks for the question. Yes, maybe to take a step back, we talked about our ambition earlier with Vision 2030. And over the long term, we want to become a leader in immunology. And what that means is that we're focused very much on building our pipeline. In the past, we've been focused on building our pipeline through partnerships with academic institutions. You all know our Immunology Innovation Program where we've sought novel biology that can provide transformative outcomes for patients through those partnerships with academic institutions.

As we've been developing a stronger cash balance and financial strength, what that allows us to do is broaden our lens a little bit and also look for other opportunities to source novel biology and where we can provide transformative outcomes. So your example that you're calling out of Forte is one example of that where we made a strategic investment in something that we see is novel biology and similar to what you also saw with Tensegrity earlier this year, where we're investing in options in novel biology. So you can expect to see more of this from us as we continue to build our pipeline and continue to leverage our balance sheet. We want to invest in our internal innovation pipeline and source novel biology from wherever we can find it. Thanks for the question.

Your next question comes from the line of Rajan Sharma from Goldman Sachs.

Maybe just on the topic of competition. We saw that J&J are running a head-to-head trial of ImAAVY versus VYVGART in myasthenia gravis, which could read out next year. I was just wondering if you could provide your perspectives on the trial design and expectations here. To what extent is that a risk to VYVGART or not conscious of the different formulation? And then a very quick follow-up for Karl. I heard your comments on operating leverage. Should we expect to see this incrementally quarter-on-quarter as well as on an annual basis?

Yes. Thank you. I'll take your question on competition, and then I'll hand over to Karl for the question on operating leverage. Yes, look, I think Sandrine said it best, we put MG on the map and many competitors are following us, especially as a first-in-class FcRn. And I think what you see is that we've set the standard for efficacy in terms of MSE in MG and have the stronger safety profile and we have all of these innovations. We started with IV, we launched subcutaneous and then we most recently brought PFS to market. And in fact, PFS is driving the majority of our growth at the moment.

And so when you think about that, I think the question to ask about some of these studies and these other competitors is what problem are they trying to solve? And I think what we're really focused on is how do we bring more value to more patients where there is unmet need. And for us, that's focusing on PFS, which is unmatched as well as focusing on that strategy we were talking about earlier, which is broadening the population through seronegative, through ocular and in the future through pediatrics. So with that being said on competition, maybe, Karl, you can talk about our operating margin.

Thank you. Thank you, Rajan, for the question. Yes, I want to start off by reminding we are on an innovation mission. The patient is your North Star. We have a unique opportunity now to invest in innovation and set the company up for the long run to build a long-term sustainable company. That is the capital allocation priorities of the company.

But that said, yes, you are right. The very successful launch allows us to build a P&L where we already have a very good margin structure. Our gross margin is around 90%. Our operating margin is around 30%. We added $400 million of cash this quarter, getting us to $4.9 billion. So yes, you can expect going forward to see margin expansion every quarter year-over-year, and we're going to continue to build on that. But that, of course, is not the objective at the moment, but I think we can do both. Thank you for the question.

Your next question comes from the line of Allison Bratzel from Piper Sandler.

This is Ashleigh, on for Allison Bratzel. Congrats on the quarter and all the progress. So just from us, -- just curious to learn more about the go and no-go decision on the Phase II VARVARA trial in delayed graft function, which is expected midyear. What specific clinical or biomarker signals are you looking to see to justify advancing clinical development? And just more broadly speaking, how are you viewing the commercial opportunity in delayed graft function?

Yes. Thanks for the question on DGF. As I said earlier, it's great to hear these questions on our pipeline. So DGF is an important indication for us for our second molecule, empasiprubart. And we're able to pursue DGF as an indication because of empasiprubart being a C2, so involved in both the classic and the lectin pathways in complement. So that's a differentiator for us.

In terms of the study, it is a Phase II study. So think about it as an exploratory study. And what we wanted to do was see the readout of the data for longer term. So we're following this data out to 52 weeks because in this patient population and what we hear from both patients as well as health care systems and providers is what they care about is the long-term outcomes. So as soon as we have that data, we'll be able to analyze it, and we'll have a go/no-go decision for Phase III. Thanks for the question.

Your next question comes from the line of Daniel Brill from Truist Securities.

This is Alex, on for Daniel. Congrats on the quarter. Another question on myositis. On the placebo response, just curious if you could talk a little bit about what factors are known to drive the placebo response? And do you expect any difference in the 3 subgroups? And then alternatively on the steroid taper, just curious what effects of the steroid tapering you're anticipating in the placebo response? And also, do you have any thoughts on why Roivant steroid tapering did not yield any decrease in the overall TIS endpoint in its placebo arm in its DM trial?

Yes. Thanks for the question. So let me take them one by one. So first, when you think about placebo response, whether across immunology, you see this pretty consistently. We've seen it in MG, in CIDP, you see it in Sjogren's studies and similar in myositis. So I think this is a pretty common phenomenon. And when you're developing an immunology like we are, then you start to get sort of good learnings around how to make sure you're minimizing that placebo response in the trial. And that can include things like training the sites to make sure that they understand how best to use the tools and the measures for the primary endpoint and that type of thing. So in this case, as you said, it's TIS. So I don't think there's anything special across the different subtypes or in myositis there.

In terms of the steroid taper, we think this is actually a benefit of the design of our study because what we've been able to do is build it in late enough in the trial so that you have a systemic steroid tapering, which should actually unmask any placebo response and help us to show a clear benefit on active disease. So we see that -- the way that we've designed it is very elegant, and it should actually help us to uncover the benefit of VYVGART. In terms of Roivant, I would encourage you to ask them. I'm not sure about the details on their steroid taper. Thanks for the question.

Your next question comes from the line of Yaron Werber from TD Cowen.

Congrats, Karen, again. A couple of sort of interrelated questions. One, can you just give us a little bit of a sense? We're kind of thinking that CIDP is around 40% of sales right now, maybe kind of 37%. I don't know if I'm in the right ballpark. And then secondly, for the seronegative study, it was a very wide study with a p-value of 0.1 across all patients, which you hit successfully. And it looks like it was driven by the MuSK and LRP positive patients. In the seronegatives, technically, the endpoint wasn't met, but because just it came together literally at the end, there was a benefit throughout the period. Just trying to get your conviction that you can get a broad approval and not just in the autoantibody positive?

Yes. Thanks for the questions. I'm going to hand it over to Karl to talk about CIDP and how the mix of business is evolving. And then I'll turn it over to Sandrine to talk about seronegative. I want to just make a point that's really important, though, related to the specific question you asked. We're 3 days from our PDUFA date. And so we have to be very careful in how we talk about this. So we're going to keep the discussion very general. And what I want Sandrine to talk about is, in general, how you see the seronegative opportunity in the case of approval so that we don't go into those details. But maybe we can talk about CIDP first.

Yaron, thank you for the question. Yes, both CIDP and MG continue to be growth drivers for us. And of course, CIDP is mainly in the U.S. now, but also in Japan and Germany, other markets we still have to launch. In terms of a percentage breakdown, I don't want to get into that, but I will say that MG is still the majority of our revenues and of course, the majority of our patients, but both still have a lot of growth in them. Thank you for the question. I'm handing over to Sandrine.

So thank you for the question on seronegative. So like Karen said, I will stay very general because we are only 3 days away from the PDUFA date. So if approved in seronegative, as you mentioned, I mean, there is a pool of patients, which we assess at 11,000 patients that would cover potentially these 3 subtypes. And so as we are only 3 days away from PDUFA date, we are obviously ready to launch. I mean the good news is that we are already embedded into MG. There is a big overlap of the prescriber base with more than 80% of the target we already did it that are actually -- that we cover seronegative patients. So we don't need to add any field force.

The prescribers know extremely well VYVGART and the trust, their experience of VYVGART and its efficacy that is deep, fast and sustained. And then we had a good presentation at AAN with lots of questions. So it shows that there is an interest really and that physicians and providers are really waiting for that. So I won't be able to go more into the details, but we should hear in the next few days.

Your next question comes from the line of Thomas Smith of Leerink Partners.

Let me add my congrats to Karen on stepping into the CEO role here. It sounds like the VYVGART auto-injector continues to advance and you're guiding to launch in '27. Can you just provide an update on where you are with this formulation? What are the outstanding gating factors for bringing this to market? And how are you thinking about potential uptake in this form versus the prefilled syringe?

And then if I could, just a clinical follow-up on efgartigimod in Graves' disease. We saw the Phase III design that you recently posted on clinicaltrials.gov. And I was wondering if you could comment on some of the design considerations for this multipart study? How are the patients being handled between Part A and Part B? And how are the background ATDs being managed? And maybe just higher level, like what are your expectations with respect to the primary endpoint registrational path?

Yes. Let me start with the auto-injector question. We're moving into manufacturing stage at the moment, as you say, to get ready for auto-injector launch in 2027. The key ungating factors are really just moving through those different gates of making sure that we're ready for production and approval. In terms of the opportunity that we see with auto-injector, what we saw with prefilled syringe is that it opened up a significantly larger patient population. And actually, and we said earlier, prefilled syringe is driving the majority of the growth for us today.

And so with auto-injector, I don't think it will be as much of a step forward as prefilled syringe. You'll recall that in the U.S., prefilled syringe moved us out of health care administration into at-home administration. But the auto-injector will be a step forward in terms of patient convenience and ease. So I think that's an important consideration for how we compete in MG.

In terms of Graves' disease, clinicaltrials.gov covers all of the details that we want to disclose publicly. But I'm going to hand over to Beth to talk about some of the additional details.

Yes. So we designed the Graves' study, taking into account, of course, precedent studies, and that was aligned with what the regulators wanted. So it's actually going to be 2 studies. You're going to see some kind of similar attributes of this study where we're actually dosing on top of antithyroid drugs. We're looking at patients at the end of the study who are euthyroid off antithyroids. So you're going to see kind of a tapering off that. I think beyond that, we'll get into more details at a later date. But we're really excited about kicking this off. We're focused on moving enrollment along as quickly as possible. And yes, more to come at a later date.

Your next question comes from the line of Akash Tewari from Jefferies.

Karen, congrats on the new role. Very well deserved. Just on your Phase III myositis trial design, will the FDA allow you to file on full data? Or does each subset need to be statistically significant for broad approval? And additionally, can you go over the rationale of your ADAPT Forward trials that look at VYVGART and empa in combination in gMG? What type of signal would you want to see to move that forward in larger studies?

Yes. Thanks for the question. So in terms of myositis, look, the label that we get, that will be a review decision, and we'll have to see how the data unfolds and let the data speak in each of the subtypes. So we look forward to that data in Q3. I'm glad you asked about ADAPT Forward because it's a key part of our combination strategy that I think we're uniquely positioned as argenx to pursue in MG and also in some other of our indications like CIDP.

So ADAPT Forward is a platform study. And what we're looking at is can we dramatically increase the efficacy and outcomes for patients in MG. So what we're looking at is VYVGART as the backbone of therapy and then looking at different combinations, for example, empasiprubart on top of VYVGART and can we increase the number of patients reaching MSE. Over time, we want to -- it's a platform trial. So we will be adding different arms to the trial to explore different combinations of -- that we have in our pipeline so that we can explore which we would want to move forward in Phase III. Thanks for the question.

Your next question comes from the line of Sean Laaman from Morgan Stanley.

Two questions. The first one is your recent data presented at AAN for VYVGART in treatment-naive CIDP patients. How do you see that evolving? Do you see VYVGART potentially moving up into the front line? I think there's a lot of focus on just the cost of drug, but considering you've got just a short injection with VYVGART versus all the [ plough ] that goes on with Ig administration, just to give your view there. And Second question is just on the IMNM opportunity. And I think, Karen, you mentioned a CIDP-like opportunity. But just give us a bit more color on the accessibility of that patient base. Are they readily diagnosed? What do you have to do there to get into that market?

Yes. Thanks for the question. I'm going to hand over to Sandrine to talk about the CIDP data. She was at AAN, and then I'll come back to the question on IMNM.

Yes. So great question. And indeed, in my prepared remarks, I mentioned that post-hoc analysis because I think it's data what we have never presented before, showing that VYVGART can indeed have an impact -- a sustainable impact and fast impact and efficacy on naive patients, truly naive patients. So we are very excited by this data. A few analysts picked that up, and I think this is going to expand the possibilities for VYVGART because if you look at our label in the U.S., we actually could be used first line. So there is actually theoretically no barriers to using.

And so in practice, we see 2 barriers for broader usage in first line. The first one is indeed getting physicians comfortable using it when patients are doing okay. And for that, it's very important to come with convincing data like the one in the post-hoc analysis, but also data like we are showing with the grip strength, where we show really very good efficacy on a sustained basis at 96 weeks. And the second barrier we are seeing is indeed payers, and you mentioned that in your question. So having data like the one we had in the post-hoc analysis allows us to go back to payers and a discussion because ultimately, this is better for patients. So we believe this kind of data will help us move the needle step by step into broadening the market in first line for VYVGART. So I'll hand it back to Karen for your other question.

Thank you, Sandrine. Yes. And in relation to your question on IMNM being a CIDP-like opportunity, so the way that we see it is we size the addressable market as around 20,000 patients. But when you first look at the treated population of IMNM in claims data, it looks more like it's around 6,000 to 7,000 patients. So we think that those are quite easily accessible because there's no treatment options available at the moment.

Beyond that, what we will need to invest in, in the case of positive data is really disease state education to increase awareness and increase diagnosis of this patient population. But what the opportunity that we have is that IMNM is frequently treated by neurologists, and there's quite a lot of overlap with those neurologists with our MG and our CIDP prescribers. So we see the opportunity to build this market in the same way that we've built the CIDP market, we've built the MG market. And I think we'll see, assuming positive data, the same outcome in IMNM. Thanks for your question.

[Operator Instructions]

Your next question comes from the line of Gavin Clark-Gartner of Evercore.

This is [ Yi Zhang ], on for Gavin. Congrats on the strong quarter. So one question about the next-generation molecule 213. We saw now it's become Phase I ready. Just wondering, can you share more details on the time line and how you are thinking about the indication selection? And also for the Phase III, will it be a noninferiority study head-to-head against VYVGART or it's going to be a stand-alone placebo-controlled study?

Yes. Thanks for the question. The strategy that we're laying out for FcRn is to continue our leadership for decades to come. And so as you mentioned, we have ARGX-213, which moves dosing to every 4 weeks and we also have ARGX-124, another next-generation asset in the FcRn space as well as our program focused on developing an oral FcRn.

So we have a portfolio of options here for how we'll continue to build the FcRn space, explore the FcRn biology and deliver value to patients. So we aren't public on our clinical development plan for 213 yet, but it is Phase III ready and we'll be moving quickly. And we see a few different opportunities. One is to advance patient outcomes in the indications we already have approval for with a more convenient -- with 213 being a more convenient option. And we have the opportunity to expand the indications that we have FcRn approval in. So continuing to expand the boundaries, if you will, of FcRn biology. So we're really excited about our full FcRn portfolio, and we think that it will be able to deliver growth for many years to come. Thanks for the question.

Your next question comes from the line of Samantha Semenkow from Citi.

Your next question comes from the line of Jacob Mekhael from KBC Securities.

I have one maybe further down the line on the oral FcRn and your collaboration with UMP. Maybe if you can share a bit more on how that's evolving. And a follow-up on that, we see other disease areas that if you introduce an oral, that could expand the market. So I'm keen to hear your view on the potential impact of an oral FcRn on the overall biologics market in MG and CIDP. Could this lead to further market expansion? Or do you see it more as a tool to prevent the competition from taking existing share?

Yes. Thanks for the question on the oral. Our partnership with UMP is progressing incredibly well. They are great partners. And we've -- we're partnering with them on a number of targets and FcRn being the first one. And exactly, as you said, our strategy here is that we believe an oral FcRn can expand the market. You can imagine there are patients earlier in disease that would prefer to have an oral option rather than an injectable even if it is a PFS that we have with VYVGART. So the strategy here across all of our indications, and as I mentioned on the prior question, even potentially in new indications is that we'll be able to bring more convenient options to patients that continue to deliver the same efficacy and safety standard that we've seen with VYVGART. Thanks for the question.

Your next question comes from the line of Victor Floch from BNP Paribas.

Maybe just a quick follow-up on 213. And I mean, I was looking at the initiation of the Graves' disease Phase III. And I was just wondering how should we think in terms of additional VYVGART Phase III studies in new indication moving forward? Basically, should we assume that the Graves' disease program will be VYVGART's final Phase III for new indication and that any promising signal from the ongoing proof-of-concept studies will instead be pursued with the ARGX-213 due to IP consideration. So any comments on the life cycle management there would be helpful. And maybe if I can just squeeze one on the on CDP. You've mentioned that the penetration of biologics in MG was around 20%. Can you share the same metrics for CDP? And can you discuss like the drivers that you have to further penetrate the market there?

Yes. Let me take the first question, and I'll hand over the question on CIDP to Sandrine. So for Graves' disease, it's -- we're pursuing Graves as an indication for VYVGART. And I wouldn't assume that future indications that we name all are going to 213 or 124 or any of our future pipeline. We still see that we have a lot of runway with VYVGART and a strong development program with VYVGART. So we continue to invest and we'll continue to grow VYVGART. And in parallel, we'll be developing 213, 124 and the oral as well. As I mentioned earlier, we see those molecules as a real expansion opportunity for FcRn. But let me hand it over to Sandrine to talk about the CIDP opportunity and market growth opportunity.

Yes. And I like that you picked that up on the 80% in MG being still among orals, where there is a huge market opportunity. We see something similar with CIDP. So the total number of diagnosed patients for CIDP in the U.S. is 42,000 patients and 24,000 of these patients are treated. That means the remaining are not right now. They have been diagnosed, but they are not treated. Out of these 24,000 patients, 12,000 of them are on IVIg, but are not optimally treated. And these are the one we have been focusing on when we started launching because these are the ones that have a reason to switch to something better and that's why we feel that VYVGART is the answer.

The other 12,000 that are treated and feel optimally treated with IVIg could also potentially switch to VYVGART because could benefit from efficacy like the grip strength data that we -- where we showed strong efficacy. So if you have to compare the 80:20 split of MG with what we see here in CIDP. I would say out of the 42,000, only 24 dozen are treated. The others are not. So there is room there. And then 12,000 feel optimally treated, but there is an opportunity for us to expand the market beyond what we already see today. So still a big potential beyond what we have focused on until now.

Your next question comes from the line of Myles Minte from William Blair.

This is John, on for Myles. Wondering if you could talk a little bit about how you're viewing the evolving CIDP complement development landscape, especially as some of the early [ C1 ] inhibitor data has suggested a potentially best-in-class profile there? And as a follow-up, maybe if you could just talk a little bit about your views on knocking down both the lectin and classical pathway with C2 versus just knocking down the classical pathway?

Yes. Thanks for the question on empasiprubart. It's exciting to be bringing our second medicine potentially to market with our readout -- our first Phase III readout at the end of this year. Certainly, from my perspective, on the competitor data, I see this as a real confidence booster for why we're pursuing empasiprubart in CIDP. It demonstrates that they're in CIDP. IgM is part of the driver of the disease and complement is at play. And so that reinforces why we think empasiprubart could have best-in-class potential in CIDP.

And I think from a company perspective, argenx is very well positioned in CIDP. There hasn't been innovation in CIDP in 30 years. The first innovation was VYVGART. And now as we develop that market, we also, in parallel, are developing empasiprubart. So I think what you'll see is that we have the opportunity between VYVGART and empasiprubart to really shape that market and transform the market. And I think it will look very different in the future from where it looks today as we really raise expectations of patients of what they can get from their medicine. So we're excited for that.

In terms of the classic and the lectin pathway, the reason we chose C2 was very specific. And one of the reasons for that is because there are indications where lectin plays an important -- the lectin pathway plays an important role. I was talking about DGF earlier. And so we think that it gives us better pipeline and a product opportunity by targeting C2 to be able to get the efficacy benefit there, but also the safety benefit of leaving the alternate pathway intact. Thanks for the question.

Your next question comes from the line of Samantha Semenkow from Citi.

Apologies for the technical difficulties. Just wanted to follow up on a couple of the previous questions on combination strategy for both CIDP and MG. How do you think about the market evolving? It seems combo therapies is a growing theme within I&I. And as you start to see some of that data in the platform trials that you talked about, Karen, how do you see the market evolving there and your opportunity to continue being a leader in both indications?

Yes. Thanks for the question, and we had some technical difficulties earlier today as well. So no problem. In terms of our combination strategy, as you see -- as you said, you can see that this is emerging in I&I in a way that it's similar to how it did in oncology as well. So we're at the forefront of that, and we're driving innovation. And I think we're very clear on what we want to achieve. The value proposition for combination therapy has to be that it substantially raises efficacy outcomes for patients. I think that's the bar that we need to see in combination therapy. And you have to be able to deliver that efficacy benefit without a safety trade-off.

So that's what we'll be looking for in the platform studies with the different approaches, the different combinations that we'll be testing. And as I said earlier, the reason we did a platform study is that, that will allow us to test these quite quickly. And then when we see a signal, we'll be able to move quickly into Phase III with the goal that we always have as a company of elevating outcomes for patients. Thanks for the question.

That's all the questions we have time for. I'd like to hand the call back over to Karen Massey for closing remarks.

Thank you, everyone, for the questions and the great discussion, and we'll see you next quarter.

That does conclude our conference for today. Thank you for participating. You may now all disconnect.

Good morning. My name is Rob, and I will be your conference operator today. I would like to welcome everyone to the call. [Operator Instructions]

I'd now like to introduce Beth DelGiacco, Vice President of Corporate Affairs. You may now begin your conference.

Thank you. Two press releases were issued earlier today, one sharing the positive results from our Phase III ADAPT OCULUS study and the other, which outlines our fourth quarter and full year 2025 financial results and business update. These can be found on our website along with the presentation for today's webcast.

Before we begin on Slide 2, I'd like to remind you that forward-looking statements may be presented during this call. These may include statements about our future expectations, clinical developments, regulatory time lines, the potential success of our product candidates, financial projections and upcoming milestones.

Actual results may differ materially from those indicated by these statements. argenx is not under any obligation to update statements regarding the future or to conform those statements in relation to actual results unless required by law.

I'm joined on the call today by Karen Massey, Chief Operating Officer; Karl Gubitz, Chief Financial Officer; Luc Truyen, Chief Medical Officer; Sandrine Piret-Gerard, Chief Commercialization Officer; and Tim Van Hauwermeiren, Chief Executive Officer.

I'll now turn the call over to Karen.

Thank you, Beth, and welcome, everyone. I'll begin on Slide 3. 2025 was an incredible year of execution for argenx. We reached 19,000 patients globally, driven in part by the successful launch of our prefilled syringe for self-injection. We also continue to advance our deep and differentiated immunology pipeline, including 4 new molecules from our IIP, positioning us for sustained long-term growth. This progress is grounded in our commitment to patients to innovate in ways that don't just improve care, but meaningfully change what patients can expect from their treatment.

I'm speaking to you today from our U.S. national team meeting, where hearing directly from patients is a powerful reminder of why our work matters. One moment in particular, stayed with me. We recently received a handwritten note from a patient, thanking the team for the impact VYVGART has had on her life. We later learned that before starting treatment, she had been living with very severe MG symptoms that significantly limited her day-to-day activities. Today, at the meeting, we saw a video of the patient about a year into treatment with VYVGART Hytrulo, sharing an update from a hype she was on. She is thriving. It's one individual story, but it reinforces the real-world difference VYVGART can make.

Slide 4. At the start of the year, we outlined our strategic priorities for 2026 that will guide our next chapter of growth towards Vision 2030. We want to impact more patients globally with VYVGART through broader patient adoption and label expansion. We're shaping the future of FcRn medicines with next-generation molecules, delivery modalities and combination approaches and delivering the next wave of immunology innovation, supported by a strong late-stage portfolio and a goal of at least one new pipeline candidate per year.

Slide 5. VYVGART is leading the growth of biologics in both MG and CIDP, and we're confident that we have the right strategies and milestones ahead to sustain this momentum. Today marks an exciting moment for ocular MG patients with the positive ADAPT OCULUS results, which Luc will discuss shortly. Together with our progress in seronegative MG, we see a meaningful opportunity to broaden VYVGART's reach to patients who have historically had limited or no targeted treatment options. What's guided us here is a long-standing commitment to the MG community and to advancing our understanding of the underlying biology of the diseases we treat. Across MG populations, our data confirm that disease is driven by pathogenic IgGs regardless of antibody status.

In seronegative MG, we demonstrated a clinically meaningful improvement in MG-ADL in the overall population with responses becoming more pronounced with subsequent treatment cycles across all subtypes. In ocular MG, we're seeing that same biology extend to another patient population with VYVGART meeting its primary endpoint and driving clear improvements in ptosis and diplopia.

Our seronegative PDUFA date is May 10. And based on today's results, we see a clear path to expanding our label into ocular MG as well, positioning VYVGART to have the broadest MG label and to reach our target addressable population of approximately 60,000 patients in the U.S.

In CIDP, we're also having a meaningful impact on patients with clinical data showing functional improvement and these benefits increasingly reflected in real-world experience. VYVGART is driving a paradigm shift in CIDP. While there remains significant opportunity within the initial 12,000 addressable patient population, we're also beginning to see expansion beyond that population, a core focus as we build leadership in CIDP. Sandrine will speak more to this later in the call.

Slide 6. Over the next 12 to 18 months, we have multiple avenues for expansion beyond MG and CIDP, including autoimmune myositis and Sjogren's disease, which broaden VYVGART's footprint into rheumatology. In particular, our work in IMNM highlights a significant unmet need with an estimated 20,000 patients and no approved treatment options today. Meanwhile, our upcoming Q4 readout for empasiprubart in MMN marks an important milestone, positioning us to advance a second medicine to patients and extending our neurology footprint with a first-in-class C2 inhibitor. We have an opportunity to address a clear unmet need in MMN with IVIg as the only approved treatment and symptom progression in 60% of patients.

Slide 7. Lastly, we continue to strengthen the pipeline that will shape our long-term future. VYVGART is just the beginning of FcRn leadership that we aim to establish for decades to come. As part of this, we're advancing 2 next-generation assets, ARGX-213 and ARGX-124. We're investing in efgartigimod anchored combination approaches and new delivery modalities like the auto-injector and oral peptide capabilities.

At the same time, we're seeing real momentum across our broader innovation platform, progressing first-in-class molecules like ARGX-121 targeting IgA and ARGX-118 targeting Galectin-10. We are deliberately source agnostic in how we identify new biology drawing from both leading academic research and opportunities emerging within biopharma.

In 2026, we expect to progress 3 Phase I programs, including a program from our Tensegrity collaboration, reinforcing our ability to bring forward high-quality science wherever it originates.

We have an exciting year ahead of us with a strong foundation in place and exciting progress across the pipeline. Let's turn to the data that's shaping our next steps. Luc?

Thank you, Karen. I'm excited to share the positive outcome of our Phase III ADAPT OCULUS study. Our second MG expansion milestone to hit just months after we shared positive seronegative data.

Let's turn to Slide 8. Together with leading global experts, our team designed the first registrational study in ocular myasthenia gravis, filling a long-standing gap for the patient population that has historically been excluded from clinical trials. We leveraged the screening period to ensure patients had a confirmed diagnosis of ocular MG, defined as MGFA Class I, meaning patients had meaningful measurable eye symptoms without evidence of generalized disease.

Patients were also required to be on stable background therapy. 141 patients were randomized 1:1 to VYVGART Hytrulo versus placebo. And in Part A, they received 4 weekly injections. In Part B, participants received multiple cycles of VYVGART Hytrulo. The primary endpoint of the study was a change in MGII patient-reported ocular score from baseline to day 29, a measure focused on the key ocular symptoms of myasthenia gravis, diplopia and ptosis.

Slide 9. The study met its primary endpoints. Treatment with VYVGART Hytrulo led to a statistically significant improvement in MGII patient-reported ocular score at week 4 compared to placebo with a p-value of 0.012. VYVGART-treated patients experienced a mean 4.04 point improvement compared to a 1.99 point improvement on placebo, including clear improvements on diplopia and ptosis. VYVGART was well tolerated, upholding its consistently strong safety profile with no new safety signals. We will present a broader data set at an upcoming medical meeting.

This is a big day for patients. Ocular MG strips people of independence. Many suffer from headaches and the persistent double vision and drooping eyelids don't just affect eyesight, they can take away the ability to drive, work and confidently engage in daily life, often with a heavy psychological burden and stigma. And today, too many patients are still relying on chronic steroids and symptomatic therapy, which comes with an unacceptable treatment burden over time.

For the first time, we are bringing forward a therapy that specifically addresses the underlying pathological mechanism of ocular MG, and that is something we should all be excited about. Based on these results, we plan to file an sBLA with the FDA.

Now before I turn the call over to Karl, I want to sincerely thank the investigator site teams and most importantly, the patients and families who made this study possible. Karl?

Thank you, Luc. Slide 10. The fourth quarter and full year 2025 financial results are detailed in this morning's press release. Product net sales are consistent with our preannouncement in January at $1.3 billion for the fourth quarter and $4.2 billion for the full year, which represents a year-over-year growth of 90%.

Regional breakdown of product revenue in Q4 2025 reflects $1.1 billion in the U.S., $63 million in Japan, $110 million in the rest of the world and $26 million in product supplied to Zai Lab in China. The product net sales in the U.S. grew by 68% from the fourth quarter of the prior year, reflecting solid patient demand and prescriber confidence driven by PFS. The gross to net adjustments and the net pricing in the U.S. are in line with the prior quarter.

Next slide, Slide 11. Total operating expenses in the fourth quarter are $955 million, representing an increase of $149 million compared to the third quarter. Cost of sales for the quarter is $150 million as our year-to-date gross margin remains consistent at 11%.

The combined R&D and SG&A expenses totaled $2.7 billion for the full year, which is in line with our financial guidance for 2025 discussed in our most recent earnings call.

Looking ahead into 2026, operating expenses will continue to grow at a similar percentage as in prior years. SG&A growth will support the significant revenue growth in our current markets as well as expansion into new patient populations. R&D expenses will increase due to our continued commitment to execute on our pipeline.

Our operating profit for the quarter is $367 million and $1.1 billion for the year, which marks our first year of annual operating profitability. Tax for the quarter and full year reflects a net benefit. This is largely due to nonrecurring tax items and favorable foreign exchange movements. Going forward, you should continue to expect an effective tax rate in the low to mid-teens. This brings us to the profit for the fourth quarter of $533 million and $1.3 billion for the full year, respectively.

Our cash balance represented by cash, cash equivalents and current financial assets is $4.4 billion at the end of the fourth quarter, which represents a more than $1 billion increase over the year. The strength of our balance sheet allows us to invest with confidence in growing our commercial business as well as our pipeline.

I will now turn the call over to Sandrine, who will provide details on the commercial front.

Thank you, Karl. Slide 12. I'm thrilled to be joining argenx at such a pivotal moment. What excites me most is the combination of bold science and a deeply patient-driven mission, what I often describe as science with purpose.

I've spent time in the field already, met clinicians and seen firsthand the real impact our science is having on patients' lives. With Vision 2030 as a road map, we have a clear path to meaningfully improve the lives of more than 50,000 patients.

Slide 13. Echoing Karen, we entered 2026 from a position of strength following a year of phenomenal execution. We closed 2025 with approximately 19,000 patients on treatment globally, reflecting consistent growth across all regions and all indications.

We successfully launched the prefilled syringe, which has proven to be a key driver in increased overall VYVGART demand. At the end of the fourth quarter, we had more than 4,700 prescribers, including dozen new prescribers since the PFS launch. This momentum underscores the execution strength of our field teams, the added convenience the PFS brings to patients and the growing confidence in VYVGART among clinicians.

As we highlighted at the start of the year, our next chapter is about applying a proven indication expansion playbook to reach even more patients. MG and CIDP remain the cornerstone of our commercial strength, and we are well positioned to build on that foundation as we scale.

Slide 14. We entered the MG market with strong biology and a first-in-class therapy. Since then, we have redefined what patients and clinicians can expect with the highest MSE and a favorable safety and tolerability profile. As a result, VYVGART is the fastest-growing and #1 prescribed biologics in MG with continued momentum driven by earlier line adoption. 6 out of 10 MG patients starting on biologic start with VYVGART. 70% of VYVGART patients are already coming from orals, and we believe the PFS will continue to help drive near-term growth.

We are now on track to reach 18,000 additional patients through 2 label expanding opportunities, seronegative and ocular MG. Seronegative MG alone has the potential to move us towards the broadest possible MG label with our May PDUFA just around the corner. And ocular MG gives us a chance to be the first to market in a patient group that has had no precision treatment options. What gives us confidence here is that these expansions build on strong relationships we have already established with neurologists, many of whom are confident in VYVGART through experience treating generalized MG.

Slide 15. We are earlier in the CIDP launch trajectory, but are delivering on the same disciplined approach that has led to our successful market expansion in MG. Significant opportunity remains within the 12 dozen patients who are not well managed on current treatment, and our focus today is on continued evidence generation, patient activation and new prescriber adoption.

Clinicians continue to respond to the meaningful functional benefit data and well-characterized safety shown in the ADHERE trial. The prefilled syringe is further driving uptake by reducing the administration burden and offering more flexibility to patients.

Worth noting, we secured an important access win for PFS in Q4 with UnitedHealthcare, broadening our covered lives to over 90%.

CIDP is a highly heterogeneous disease, and we are committed to advancing the science to expand our reach to broader set of patients. Our biomarker program is designed to better define responders and unlock earlier and broader use, and we are advancing empasiprubart in a head-to-head study against IVIg to further explore the bounds of efficacy. Together, these efforts position us to expand the CIDP population we can serve and continue shaping this market over the long term.

Slide 16. Our clinical pipeline continues to broaden and deepen, providing a multiyear runway for commercial growth. I'm excited to join the company at this pivotal moment to help scale the organization thoughtfully and translate this pipeline into even greater patient impact.

With that, I'll now turn the call over to Tim.

Thank you, Sandrine. Reflecting on where we stand, argenx has never been better positioned, and our leadership transition comes at the right moment as we enter our next phase of growth. Karen is the right leader to take this forward. She understands our innovation playbook, leads with patients at the center of every decision and brings the operational discipline needed to continue executing against Vision 2030 and beyond. I have complete confidence that she will nurture what has always made argenx special while driving the next chapter of growth for the company.

My dedication to argenx and to our mission remains as strong as ever. I look forward to supporting Karen and the entire leadership team as we continue to advance meaningful innovation and deliver for patients and shareholders alike.

With that, operator, we will open the call up to questions.

[Operator Instructions] Your first question today comes from the line of Tazeen Ahmad from Bank of America.

First off, Karen, congratulations on the new role. We're looking forward to continuing to work with you. And Tim, what else can I say, but thank you. You've set the example for everyone to follow, and we wish you the best in your new upcoming role as well.

So my first question is going to be on the addition of both seronegative as well as based on today's results, assuming ocular MG to the revenue stream for VYVGART. How should we think about, number one, what the average price would be for each of these subindications? And can you talk to us about what proportion -- you talked to us about how many patients there are. But have you done any market data research to indicate what proportion of those patients are more likely to seek this type of treatment?

Well, thank you, Tazeen, for your comments and also for your question. It's a really exciting day for ocular MG patients and certainly for argenx, as you call out. It's important to think about the fact that we are now the first and only -- or VYVGART is the first and only to have positive data for patients with ocular MG. So a really exciting day for patients.

And as you called out, that, combined with the seronegative data that just read out a few months ago, and we have the PDUFA date in May, really positions us well for continued sustained growth in MG and I think an expansion even further of our leadership position in MG. So we're very excited to share that data today.

I'll let Karl talk to the price in a moment. But just on the second part of your question around the addressable market, we obviously have done quite a bit of market research, and we'll continue to do so to prepare for how best to go to market. But the best numbers to look at are those that we've provided with the seronegative expanding the addressable market by 11,000 patients and ocular by 7,000 patients that we've provided before. That 7,000 patients in ocular MG, that's not the total ocular MG patient population. That's actually the portion that when we've done the research before, we thought would be eligible for VYVGART. So that's the number that I would stick with. And obviously, as we get closer to -- as we unpack the data more, as we get closer to submission and hopefully approval, we'll be able to provide more color on that.

And then maybe, Karl, you could comment on the price.

Thank you, Karen and Tazeen, thank you for the question. Yes, we still have to have the discussions with the players, of course. But I do want to mention that we have a strong capability and market access. It is an enabler of our launch, not a hurdle, and the value proposition of VYVGART is well understood and appreciated by all stakeholders.

At this stage, I will say that we would expect to have broad access also for seronegative and ocular, and we can assume a similar price as MG, i.e., $225,000 the net benefit or a net price to argenx. Thank you for the question.

Your next question comes from the line of Danielle Brill from Truist Securities.

I think I'll ask a question on the CIDP opportunity. Karen, you mentioned in your prepared remarks that you're beginning to see expansion beyond the initial 12,000 patients that you were targeting. Can you elaborate a bit? Are you seeing a step-up in frontline use? And then I think you also mentioned that you secured additional coverage, broadening coverage for PFS to over 90% of covered lives. What impact do you expect this to have on adoption rates in the setting going forward?

Thanks, Danielle, for the question and the interest in CIDP, we're really pleased with the continued growth in CIDP. So, yes, we laid out that the strategy was first to focus on that 12,000 patients that are treated -- that are already treated, but continue to have symptoms. And that is -- continues to be where we see the majority of our patients and the majority of our growth. But you'll recall that our label does allow us to be used in a broader patient population. And there are some payer policies actually that also allow that. So we are starting to see some use of VYVGART beyond just the switch from IVIg.

In general, it's still about at 85% of our patients are being switched from IVIg, but there are some that are coming directly. I think as prescribers and neurologists get more experience with VYVGART and see the impact in the real world, then over time, we'll start to see that expansion even more.

And as you said, continuing to expand access with the recent UnitedHealthcare decision and having 90% coverage, that also helps to contribute to our growth. So I would say what to expect in CIDP is that continued steady momentum. We're still early in the launch. And so I think we still have some quite a bit of growth ahead of us.

Your next question comes from the line of Derek Archila from Wells Fargo.

Congrats on the progress in the Phase III win today. So I had a question on, do you think approval in ocular MG will drive more utilization in the less advanced MG patients? And I guess, is there anything in the data set that you'll present in the future that could demonstrate prevention of progression to more generalized disease?

Yes. Thanks for the question, Derek. I'll comment on the first and then maybe, Luc, I can hand it to you for the data. So certainly, I think that our hypothesis, I mean, we know that in MG, the majority of patients first do present with ocular symptoms and then the majority of those ocular MG patients do transition into gMG. So a big part of our strategy is expanding the use of biologics to earlier line uses of MG.

We are already seeing that. Biologic use is growing in generalized MG. We are driving -- we get 6 out of 10 of those patients that are first use biologics. So we're driving a lot of that earlier use and a lot of that growth. As you say, I think the ocular MG data will help us with that strategy and will provide a halo to that strategy. And then maybe, Luc, you could comment on the data and progression.

Yes. Thanks, Karen, and thanks, Derek, for the question, which is close to my heart. So with the data in hand, we show that we can meaningfully impact the current symptomatology of ocular MG, which is not MG like. It's a significantly debilitating state to be in. But of course, the excitement of continuing to collect long-term data as we are planning to do and compare that to what is known with the natural progression, which, as Karen said, is a high percentage up to 80% will allow us to make some statements on do we delay progression to generalized MG. So I would say stay tuned.

Your next question comes from the line of Yatin Suneja from Guggenheim.

Just with regard to the Q1 dynamics, could you point to us if there are any particular consideration that we should have for Q1 in particular?

Yes. Thanks for the question. And it's important as we're in Q1. So obviously, across the industry, we can see the pattern that there always are Q1 dynamics around reverifications and winter storms, of which we've had quite a few in the last couple of weeks. So argenx and VYVGART are, of course, privy to the same, those same seasonal dynamics. And we saw that last year as well. If you recall, we did have a slowdown in Q1. And then in the end of the year, we delivered 90% full year growth. So I think you can recognize the pattern and expect that. But maybe, Sandrine, you could comment on the underlying dynamics that we're seeing since you've joined.

Yes. Thank you, Karen. And this is something that I looked at before joining argenx, what is the growth we are seeing. And year-after-year, we have been delivering consistent growth, and this is a pattern you can expect this year, full year because the underlying dynamic are very healthy.

I mean when you look at the new patient starts, the provider and the prescriber expansion. When you look at our access, we just mentioned that, but also how strong we are and VYVGART is in leading the growth of the overall biologic market. These are all amazing underlying factors that will help us continue that growth.

And then you have the PFS that was launched less than a year ago that drove a lot of momentum last year, plus the expansion of the labels that we are expecting both for seronegative and later for ocular. So all are good underlying factors that will help us continue that growth, as Karen mentioned.

Your next question comes from the line of James Gordon from Barclays.

James Gordon from Barclays. The question was on VYVGART for myositis. And my question was, what is the efficacy bar you're looking to exceed in the Phase III in myositis in Q3? What's a good result? Is there hope to be more efficacious than [ brepo ] or JAK/TYK and what they did in the VALOR trial? Or is it more -- a good result would be if you had a similar efficacy and you are better tolerated as well? So what's good and what's really good?

And could I also just squeeze in a clarification, not a question, but just normally, there's an OpEx guide, but I didn't see a formal guide this year. Should we assume a similar pace of OpEx growth this year as last year, so '25 similar pace of '26 and maybe more R&D and less SG&A? How do we think about spend this year, please?

Yes. Thanks for the questions there, James. And so I'll open. I'll hand over to Luc to provide some more color on myositis and then Karl on OpEx. But the first thing that I just wanted to frame is when you think about myositis, it's right out of the argenx playbook. I mean there is so little options available to patients here, really limited innovation in the market. And so what we're looking for is a statistical significant benefit coming out of this study. In the DM, in IMNM, there are no approved therapies available. And you heard in the script that there are 20,000 patients with IMNM. So for them, any benefit, I think, is clinically meaningful. But maybe, Luc, you could talk about how we're thinking about the study.

Yes. Thanks and also for laying it up that this is not a singular indication. So this is a constellation of indications that each have somewhat different pathological drivers. We continued our Phase III program based on the strength of a robust Phase II, which gave us the confidence that we could provide meaningful benefit across the 3 subsets. Ultimately, the data will speak once we complete Phase III.

With respect to relative benefit compared to others, of course, studies are hard to compare. And the DM result of brepo certainly is encouraging for the DM patients. But we believe that in DM, multiple modes of actions could play a role. And therefore, we will go on the strength of our own data. In any event, positive data in these diseases is always good for the patient.

Thank you, Luc. And maybe, Karl, a comment on the OpEx.

James, thank you for the question. Yes, in 2025, we spent around $2.7 billion on combined R&D and SG&A. That is around 30%, 3-0 percent increase over 2024. Looking ahead, you can expect the combined R&D and SG&A to grow at a similar rate with most of the growth in R&D because that is where we're going to invest to set the company up for the long run, investing in our very exciting pipeline. So thank you for the question, James.

Your next question comes from the line of Alex Thompson from Stifel.

Maybe on Graves, I was wondering if you could comment on where you're at from a regulatory discussion perspective on starting the pivotal and whether you think that a single pivotal could be sufficient for an sBLA or whether you might need 2 studies.

Yes. Thanks for the question. We're excited about our Graves program, and it's well underway. Luc, do you want to comment on our strategy around the single study?

Well, I mean, the ability to run a single study has sufficient evidence of efficacy and be able to define a benefit risk is actually not new. That always existed, but it was at the discretion of the individual divisions as to how much they accepted that or not. This particular division has asked us at this moment for 2 trials, which we are executing on.

Your next question comes from the line of Matt Phipps from William Blair.

Congrats on the quarter and progress here. Just wondering if you might be able to give us any more details on the auto-injector, how you can position that versus the PFS and maybe if that can just continue the continued expansion you're seeing from that PFS launch across indications.

Yes. Thanks for the question. We're excited about the auto-injector, and I think it just reinforces our innovation playbook, right, just continually bringing more and more innovation as we drive leadership in the MG market. So auto-injector is on track. We have planned for 2027. And the way we've talked about it is it won't be such a step forward in the way that PFS was because if you recall, the big step forward for prefilled syringe was that we moved from HCP administration to patient administration, and that was a meaningful and important step forward for many patients, giving them the freedom to self-inject. So auto-injector doesn't provide that step change, but it does provide an important step, for patients that provides a better experience for those patients and especially those that are needle phobic.

Actually, we mentioned earlier, we're here at the U.S. National Field Meeting. We had a patient just yesterday that was talking to our team, and she was sharing that she wanted to wait for auto-injector because the prefilled syringe needle was something that she was a little nervous about. So it does provide value to patients, but it's not such a step forward that you should think of it as an accelerator in the way that the prefilled syringe was.

Your next question comes from the line of Akash Tewari from Jefferies.

This is Amy on for Akash. Maybe just a quick one on your 2 next-gen FcRns 124 and 213. Are you seeing an accelerated path to registrational study? And can you give us a sense of how you're thinking about the indication and then the size of these trials?

Yes. Thanks for the question and the interest in our future portfolio. Maybe I can start. The way that we think about our leadership of FcRn over the coming decades is that we know there is a lot of opportunity for FcRn, in fact, probably more than we can explore with VYVGART alone. And so we see the opportunity of having 2 next-generation molecules as opening up the opportunity to provide a better patient experience in some of the indications we're already in, but also start to push the biology even further and expand the indications that we can -- that an FcRn is making a difference to patients. So I think that's the strategy that we're planning. We think each of the next-generation molecules brings -- will bring that benefit to patients. Thanks for the question.

Your next question comes from the line of Yaron Werber from TD Cowen.

Congrats on the ocular study. If you don't mind, maybe a couple of questions. For EMPASSION, you switched the primary endpoint to grip strength. In the previous study in ARDA, you gave us sort of the ranges of grip strength. So maybe help us understand how is it powered? Is it superiority sort of head-to-head? What's clinically meaningful?

And then secondly, Karen, we have a huge confidence in you, and congrats on the role. Tim, we're just -- we continue to get questions on the timing. I know, obviously, Peter is retiring as Chair. So maybe give us a little bit of a sense what drove your decision to kind of step up the chair.

Thanks for the questions, Yaron. I'll hand it over to Luc first to talk about EMPASSION. And then, Tim, maybe you can take the follow-up question.

Yes. So in fact, this is a story of growing insights in data as they matured. As we looked at ARDA and ARDA plus, so the Phase IIs, the signal we saw in grip strength gave us increasing confidence that this is really a real and patient-relevant outcome with an increasing separation over time or improvement over time, which in these patients was not seen before. And that's ultimately why in discussion with agency, we started utilizing this endpoint as the primary. You asked about superiority. The study is set up as a non-inferiority study, but with a prespecified option that if noninferiority is met, that we can formally test superiority. The data will ultimately drive that [ tree ].

Thank you, Luc. And Tim?

Thank you for the question. I think we're doing this transition out of a position of strength. I think now is the time to do the transition because the business and the organization is in a very healthy and a very strong state. You have seen the pipeline. You know the profitability, which we achieved during the course of last year, very strong foundation of the business. Also from an internal candidate point of view, we are ready. Karen knows the innovation playbook. She's a very strong carrier of the culture of the company, and she's ready to help us scale into our future because she know new therapeutic areas will come on back relatively soon. So consider this as a proactive move based on a position of strength. Thanks for the question.

Your next question comes from the line of Thomas Smith from Leerink Partners.

I was just wondering if you could provide a bit more color on the Phase IIa results for adimanebart in ALS. Obviously, really difficult indication, very complex biology. But just wondering if there are any learnings from this study that could be applied to the Phase III CMS program or potentially other indications.

Yes, I'll let Luc comment on the data.

Yes. Thanks for that question. Evidently not an outcome we were hoping for. We felt we had the moral obligation to explore ALS as an indication given our mode of action, trying to -- in this disease where there's very, very limited treatment options to see if we could move the dial. From our POC, the data, unfortunately, don't supports progressing, but we learned a lot, not in the least about how novel endpoints could be used, and we hope to share that knowledge with the field.

With respect to impact and learnings on CMS, the context of treatment is fundamentally different. And CMS is directly in the biology of this molecule with the DOK-7 and other mutations affecting the mask receptor. And so that's a much more direct application of this molecule. So we don't think there's a read-through.

And on our SMA program, likewise, there is a backdrop of approved treatments. The gene therapies are very well established. And we are going to evaluate whether we can have an add-on efficacy there, which is a different situation than ALS altogether.

Your next question comes from the line of Rajan Sharma from Goldman Sachs.

I had just a question on VYVGART growth dynamics through 2026. So just thinking about kind of the underlying growth outside of potential new indications, how should we think about growth across the various formulations of the drug? And if you could maybe just comment on competitive dynamics. I realize there's been a recent new approval in myasthenia gravis. Could you just talk to your confidence in the VYVGART profile and to what extent you think you may be impacted by that emerging competition?

Great. Thanks for the question. What -- I'll provide just one comment, which is one of the things that I think is incredible 5 years out from launch for VYVGART is that what we're seeing is continued growth across all indications, all geographies and all product presentations. And I think that's a sign that there's space for all of the different product presentations, and it's important that we're bringing those innovations. But Sandrine, maybe I can hand over to you to talk about the growth outlook for MG and CIDP.

Yes. Thank you, Karen. And I can maybe also help answer the question on the competition but that was a second question. So I think for MG, I mean, we have seen an amazing growth year-on-year. And we have, as I mentioned earlier, healthy fundamentals. I mean, our product, VYVGART is being used earlier and earlier. I mean, as I mentioned in the opening, 70% actually are coming from orals.

And then on VYVGART, when you have 10 patients coming on biologics, 6 of them are actually starting with VYVGART. So this shows that this is the molecule that patients start on when they are starting on biologics. PFS is the one that has been driving and helping us drive strong growth last year. And as Karen just mentioned, we expect to continue to grow across all mode of administration, including PFS. And then the label expansion, of course, is going to help us this year, starting with seronegative.

If you look at CIDP, I mean, we have -- we are still early in launch. So we have launched roughly 1.5 years ago, and we are still have a lot of room within the 12,000 patients that are not fully well managed. And beyond that, we are working very, very hard to lift any challenges either with payers or the inertia of prescribers to start earlier with VYVGART. So overall, very strong dynamics expected for this year like we had in the prior years.

So now going to your question on the competition. Actually, we welcome competition. For me, this is -- and for us, this is a sign of progress, and this is a sign of innovation, and that's great for patients to have multiple options. This expands the overall market and VYVGART benefits from a market expansions. I just mentioned that 6 out of 10 patients starting on biologics go on VYVGART. So the more the market expands, the better it is for us.

And as we are a data-driven company, all the data we have generated support our confidence that VYVGART profile will help us continue leading that category and remain the #1 prescribed biologics in MG from an efficacy viewpoint, and we are the only one that can really show the strong MSE, the robust safety that fosters earlier use, the ability to meaningfully reduce steroids and then as we mentioned, multiple flexibility on either IV subcutaneous or PFS. So when you take that all together, I mean, we believe that we have a very, very strong profile for continuing our leadership there.

Great. Thanks, Sandrine.

[Operator Instructions] Your next question comes from the line of Sean Laaman from Morgan Stanley.

This is Morgan on for Sean. Maybe one on the financials. So with VYVGART delivering $4.2 billion this year in net sales and 90% year-over-year growth resulting in the first year of operating profitability. How should we think about the sustainability of this growth profile as penetration deepens in MG and CIDP throughout this year and next year?

Yes. Thanks for the question. Karl, maybe you want to talk about the growth profile?

Yes. I think what we're building here is a long-term sustainable business, as Sandrine already mentioned, we see a lot of growth in MG and CIDP going forward. And the way we look at the financials long term is that revenue growth should exceed OpEx growth, which basically will return operating margins, which will increase over time. That in itself, of course, is not the objective of the company. We have very clear capital allocation priorities, and we're executing on those priorities. But what we should see is that we're going to build on our very strong balance sheet. We currently have $4.4 billion of cash in the bank. And going forward, that number should increase. So I think you can look forward to a long-term sustainable and profitable business. Thank you for your question, Morgan.

Your next question comes from the line of Sophia Graeff Buhl Nielsen from JPMorgan.

So just on the Phase III readout for VYVGART in myositis, could you clarify, would you have data to support approval by subgroup? Or will this largely be dependent on the overall data? I think you've been very clear on that the high unmet need within IMNM and the large patient population that could be addressed there and also the heterogeneity within DM. Given these dynamics, would you see these as relatively equally sized commercial opportunities despite the differences in addressable TAMs you've highlighted?

Yes. Thanks for the question. Maybe, Luc, you can talk to the basket trial and our approach, and then I can comment on the commercial opportunity.

Yes. So the Phase III setup is indeed that we can make statements on all 3 subsets. And of course, the ultimate reflection of that in label will be connecting the data with the regulatory discussion. But in principle, all 3 could be in scope.

Thank you, Luc. And then in terms of the commercial opportunity, the way I think about it, I mean, the total myositis population that we're studying, we think about in terms of it being an MG-like opportunity. But obviously, there are other subtypes. And I like to think about the 2 bookends of the subtypes.

So we talked -- you mentioned IMNM. So IMNM, there are no other approved treatment options. There's about 20,000 IMNM patients. So what you can imagine there is that from a commercial perspective, you could imagine that we'll be able to gain a high portion of those patients because there are no other treatment options and the biology is so clear.

On the other end of the spectrum, you can think of DM. There are more patients in DM, but it's also more heterogeneous in dermatomyositis. There's also more innovation coming to the dermatomyositis space. So that will grow that patient population. Innovation is good for patients. And I think let's see the data, how it reads out, but I think we should have a good value proposition to be able to compete in that population if the data reads out. So overall, total population MG-like, but the subgroups provide quite different dynamics from a commercial perspective. Thanks for the question.

Your next question comes from the line of Suzanne van Voorthuizen from Kempen.

It's one on empa and MMN in particular. There was a change in the dosing regimen between the Phase II and III and the Phase III is also head-to-head. Could you elaborate on how you navigate the potential risks that these 2 changes introduce? What gives you comfort that the study can confirm empa's non-inferiority? And I'm also wondering if you can give some color on how you went about setting the non-inferiority margin in this progressive disease?

Thank you. I think that's for you, Luc.

Yes. Thanks for that question. And I can tell you a lot of thought went into that based on the data again from ARDA, where we tested multiple regimens, and we're able to model and look at an exposure response relationship, which ultimately made us choose the dose regimen we went for.

In terms of then choosing or choosing to go head-to-head, here, the thinking was if we were taking placebo-controlled study, we could have a lot of events because people on placebo in this progressive disease, as you say, will need rescue. And therefore, we said, well, why not just do them straight head-to-head? So that was that decision.

The second one, how do you determine a non-inferiority margin? And this is actually also where the data on grip strength come in because the only available data on IVIg are on grip strength. So that's why we use that measure to determine the non-inferiority margin. Given the data we see from ARDA, one of the features that is different is that we continuously seem to improve grip strength, something which is not seen in the experience with IVIg. And that gives us confidence that we can at least meet but hopefully beat IVIg.

That's great. Thanks, Luc. And when you zoom out, I think what you can see with your answer is the approach that we take for -- with our programs, strong biology rationale, derisking with a Phase II. And I think we're well positioned for success commercially with this head-to-head data that in the way that you've laid it out. So look forward to that data in Q4. Thanks, Luc.

Your next question comes from the line of Allison Bratzel from Piper Sandler.

Just a follow-up on ocular MG and the potential for early treatment with VYVGART to prevent progression to generalized disease. Is that something you're able to capture in Part B of the oculus trial? Or just how long of a follow-up do you need to confidently be able to make that claim? Just any more color there would be appreciated.

Yes. Thanks for that question to allow me again to go on one of my favorite topics, which is can we slow MG progression. So the open-label extension following Stage B, which we call Stage B, is going to give us over 2 years of data, which if you look at extent epidemiological data, et cetera, should give us enough window to capture these people progressing and whether or not it's to the rate that's there in the outside world. The caveat, of course, is this is noncontrolled data. So any expression of this delaying might have to be in a publication or if the real-world evidence is deemed strong enough in a discussion with the agency.

Yes. I think that's what's exciting about this data, along with some of the other evidence generation that we're doing, a Phase IV study in early disease to be able to see that progression. But I think regardless, one thing that's important is with ocular MG is the symptom burden is significant and the opportunity to transform lives of patients suffering from ocular MG is significant even without the disease progression. So I think we can demonstrate that benefit in the short and the long term. Thanks, Luc.

Your next question comes from the line of Luca Issi from RBC Capital.

Congrats on the progress. Maybe, Luc, if I could circle back on ocular myasthenia gravis here. Again, I appreciate this is a fresh off the press, but how should we think about the kind of clinical significance of the data here, again, in the context of the p-value of 0.012. And then maybe related to it, can you confirm the use of steroids or other therapy was relatively well balanced between the 2 arms, so we can kind of definitively say that the benefit here is coming from VYVGART and is not confounded by any other therapies?

Yes. Thanks for that question. And of course, we don't share too many detailed data because we want to make sure that the representation in an external conference isn't impacted by doing so. But to come back to the -- yes, we have significant p-value, but that was driven by, in our mind, a very relevant treatment difference between active and placebo.

Remember, these endpoints range is between 0 to 18 and to show an active 4-point difference for that individual patient is certainly a relevant outcome. So we feel that in totality, this is a meaningful signal that we have shown. And with respect to balancing on steroids, steroids were allowed but had to be stable. And we are confident that there's no imbalance in the outcome based on anything there.

And maybe just to add to your question on clinical significance. I mean, Luc mentioned in the script, what -- when you think about what the impact that ocular MG has, what patients will tell you is that it strips them of their independence. They lose -- because of the double vision, they lose the ability to drive, they lose the ability to work. And so it has a real impact on their quality of life. So there's no other treatments available other than steroids. So any benefit that we can provide and certainly this a 4-point benefit that we've seen is demonstrable benefit for patients and I think clinically very meaningful.

Your next question comes from the line of Justin Smith from Bernstein.

Just a very quick one, if you could talk about the commentary with regards to switching off subcutaneous Ig on to VYVGART and how that's changed over the last 3 months?

Yes, I'm happy to. Well, I think what you're asking about is there was an -- FDA looking into real-world evidence around switching and CIDP worsening. Actually, we had good news that we have completed that review and the label has been updated with some helpful guidance to HCPs around when switching from IVIg to VYVGART. So I think we're well positioned moving forward. That label update reinforces what we knew from ADHERE and reinforces the risk-benefit profile of VYVGART. Thanks for the question.

Your next question comes from the line of Samantha Semenkow from Citi.

Just one on the ocular MG opportunity. I'm wondering, can you speak to the mix of treating physicians that you're expecting for this patient population? Are they mainly managed by neurologists, ophthalmologists or even neuro-ophthalmologists? And I'm wondering how much education you think you need on the opportunity to drive VYVGART utilization in this segment?

Yes. Thanks for the question. Maybe, Sandrine, you can talk about that and also related to seronegative because we have the PDUFA date coming up in May. And just is there -- are there any changes for our field or the targeting strategy with this label -- with these potential label expansions?

That's a great question. Actually, we have a big overlap between the current prescribers and the target group we are visiting and the people that will be prescribing for MG in both seronegative and ocular. So it's mostly a neurologist-driven disease. So we don't expect to have to change our footprint.

And actually, we increased our footprint early 2024. If you remember, we doubled our footprint to be able to not only target academic medical centers, but then to also be able to visit the community neurologists where we feel the majority of the patients are being taken care of. So you won't see a change of our approach there. And with the big overlap, we're confident we can target the majority of the potential and the prescribers.

Your next question comes from the line of Victor Floch from BNP Paribas.

One question on ARGX-213. So I believe the last time you've updated us on time lines where you were pointing out Phase I results sometimes in H1 this year. So I was just wondering whether we should expect you to discuss those data or to a broader extent, your -- like the development program of that product later this year.

Yes. Thanks for the question. And again, the interest in our next-gen. We are excited. So we're moving forward with 213, and we've shared that update previously, and it is in the clinic. We're working on the indication strategy at the moment and our path forward, and we'll certainly share that when we have an update to share. Thanks for the question.

And our final question today comes from the line of Douglas Tsao from H.C. Wainwright.

Just on oMG as a follow-up, we have heard from clinicians who have tried to use it in patients presenting with ocular symptoms, but they've had pushback from payers just given the fact it wasn't sort of on label. I'm just curious if you could provide some perspective on when you think it might start to become a contributor? Will it be sort of getting it added to the label? Or will there be a process where you need to also then talk to payers? Just sort of trying to understand the sequencing when we should think about this because it does seem to be a fairly meaningful commercial opportunity for you.

Yes. Thank you. And I agree it is a meaningful opportunity and a meaningful benefit for patients. So what you can expect, I mean, we'll file as soon as we can based on this data, and I think we have a well-oiled machine. So we'll do that as soon as possible, and then we'll see when the PDUFA date is, assuming the submission is accepted by the FDA.

What we normally guide to is because we will need to have conversations with payers, and we will need to change those contracts. What we usually guide to is that it takes about 2 quarters after approval to get those payer policies in place and to really start to see the impact of the opportunity. So we'll take it step by step. And step number one will be preparing the filing as quickly as possible. Thank you.

And this concludes today's conference call. We thank you for your participation. You may now disconnect.

Welcome to the first day of the 44th JPMorgan Healthcare Conference. I'm Richard Vosser, European pharma analyst at JPMorgan. It's my great pleasure to introduce argenx CEO, Timothy Van Hauwermeiren.

Just a few housekeeping rules. We will take questions from the room after Tim's presentation and/or you can submit those into the portal. So with that, Tim, welcome to the conference.

Thank you, Richard. Thanks for having us. It's great to be together and kicking off this fantastic week at JPMorgan. Very warm welcome, by the way, ladies and gentlemen, to the argenx presentation. And let me kick it off with an important question each biotech entrepreneur should ask himself.

The question actually is, who would miss you if you wouldn't exist? And in our case, that question is leading us straight to our patients on VYVGART. And I couldn't be more pleased to bring Sam today to this meeting. We're going to listen to a 30-second video from our patient, Sam.

[Presentation]

And Sam is not the only person who undergoes a transformation when he's on VYVGART. By the way, Sam is now on PFS, and he's traveling the world.

What happens is the transformation of a patient life. And the way that happens is by offering breakthrough science to our patients. We're an immunology company. We think we're just at the beginning of our understanding of human immunology. And therefore, we think that the opportunity in front of us as bio entrepreneurs is infinite.

Patients are also central to Vision 2030. We have the bold mission to impact 50,000 patients by 2030. We would love to do that through 10 labeled indications. And because we're in the business of building a sustainable biotech company, we have the ambition to have 5 new molecules in Phase III by 2030.

I'm very proud to tell you today that we are well on track. Actually, we have 19,000 patients on VYVGART today. We're running 10 registrational trials in 2026. And last year, we advanced 4 new pipeline molecules. I'm very proud of this. When patient transformation happens, financial success follows. I couldn't be more proud of the commercial team, which gave us such a strong Q4 in 2025.

We sold about USD 1.3 billion, which is 14% up from last quarter. And that means that we almost doubled the business in 2025 compared to 2024. Last year was also the first year where we reached structural profitability. So I believe we're in a position of strength to execute on Vision 2030.

Let's look at our strategic priorities for 2026. We have 3 of them. First, we want to impact more patients with VYVGART. Second, we want to shape the long-term future of FcRn. And third, we want to deliver on the next wave of innovation. In my presentation today, I will be unpacking each of these priorities step by step.

Let's talk about impacting more patients with VYVGART. Our playbook in the indications where we are is very clear. First, we redefine biology, then we redefine the treatment paradigm and then we redefine patient outcomes. For example, in myasthenia gravis, we have redefined biology. Regardless whether you're seropositive or seronegative, we have proven for once and for all, this is an IgG-mediated disease.

In CIDP, after 30 years of no innovation, for the first time, we have shown this is an IgG-mediated disease and potentially a subset of patients with an IgM mediated disease. I'd like to believe VYVGART is not just first-in-class, but also best-in-class.

When it comes to redefining treatment in MG, we have changed the bar. The bar used to be at, "Oh, my patient is doing fine because the patient is not hospitalized." That's not good enough. We have established a whole new gold standard, which is called MSE, minimum symptom expression. That means that these people can live a life with no or minimum symptoms. 60% of VYVGART patients in the real world achieve MSE.

In CIDP, as we could see from Sam, we can see in the subset of patients a spectacular regain of function. Sam is not the only patient who's sending me his step counter through FaceTime or WhatsApp. Many patients are doing that. I would also like to applaud the commercial excellence of the team. Our secret power is market access. We made a promise not to leave any patient behind. I can assure you that we're serving the broadest possible population of MG patients and CIDP patients.

And then we redefine patient outcomes. We constantly out-innovate competition. We're announcing today that we are in combination studies in MG. I will explore that later in this deck with you. But we're also bringing a second mechanism of action into the CIDP space.

Raising expectations also means that you delight your customer with your product presentation. Sam is traveling the world with his prefilled syringe. Many people are enjoying the prefilled syringe. And actually, the PFS has been a real driver of growth in 2025. What that results into is that VYVGART is the #1 prescribed biologic in MG. It's driving 60% of the biologic growth in MG.

We continue to penetrate the treatment paradigm. 70% of the patients are coming straight from orals. So we get earlier and earlier and VYVGART becomes the go-to therapy for a newly diagnosed MG patient.

In CIDP, we already achieved blockbuster status in Q3 of last year, and we continue to penetrate the prescriber base. I'm very proud of the fact that now there are more than 4,700 active prescribers here in the United States, which is a 20% growth year-on-year.

Playbook in MG is crystal clear. We landed in a TAM of 17,000 refractory patients, and we have articulated clear stepping stones to move into that 60,000 patient TAM.

First of all, the seronegative patients. We made a promise to them, which we kept. We run the biggest ever seronegative trial, strong data, and we believe we are on track for a potential approval and launch second half of this year.

The next data cart to turn is ocular MG. That data point is around the corner. It will happen in Q1, and we're going after significant unmet need in these ocular MG patients. And then we continue to build the market by generating real-world evidence. We have pretty spectacular data in terms of steroid sparing. We have pretty impressive data in terms of eliminating hospitalizations and dramatically reducing stays in the hospital. And we continue to innovate with things like, for example, the auto-injector and the combination trial, which is now public.

Also in CIDP, there is a clear path of growth. There's no reason VYVGART should stay in the 12,000 refractory patient population. Actually, we're already entering in the 24,000 patient population of people who are currently on steroids and/or IVIg. We do a ton of translational work unraveling the biology behind the disease. That is why we're bringing a second mode of action into the disease with empasiprubart going complement after complement C2.

And based on the regain of function data, the real-world evidence data, we think there is upside potential into that 42,000 CIDP diagnosed patients.

Guys, I couldn't be more excited about rheumatology in 2026. First of all, autoimmune myositis. This is no longer idiopathic myositis. It's an autoimmune disease. We know it is driven by pathogenic IgGs. And actually, today, the fingerprint of your pathogenic IgGs is determining the subtype of myositis you suffer from.

We had solid Phase II data with significant improvement in muscle strength on the TIS score. Sjogren's disease, 2 independent Phase II trials have shown for once and for all that pathogenic IgGs and the circulating immune complexes they form drive this disease. Pretty remarkable impact in systemic disease activity. And what both rheumatology indications share is these are both sizable patient populations in very high unmet medical need with treatment toolboxes, which are virtually empty.

Let's talk about priority #2, shaping the long-term future of FcRn. Today, we're in a position of strength. We have a very clean, very powerful IV product. We already have 2 subcu product presentations, one HCP administered, one self-administered. They have a unique formulation, thanks to the exclusive partnership we have at Halozyme, and we continue to innovate on the product presentation side, not just with a one-of-its-kind PFS, but also with the first of its kind auto-injector, which is well on its way for launch in 2027.

And as I said, we're venturing into the combination trial, which is public on clinicaltrials.gov. That's not enough. Tomorrow, we will be advancing ARGX-213, our first next-gen FcRn, which I will showcase later in this presentation. We have a second next-gen ARGX-124, which is currently in Phase I clinical trials, and we are building more molecules in typical argenx fashion, which means in close collaboration with the best out there with whom we partner.

We also believe there is more combination potential in the pipeline of argenx. Combination therapy has been the standard in oncology. It will become the standard in autoimmunity.

Priority #3, the next wave of innovation. Guys, this is the year of MMN. We spoke about it multiple times. This is an underdeveloped market. It's already a blockbuster market today, driven by the plasma fractionators. These patients are in bad shape. There are about 12,000 patients in our key markets, difficult diagnostic path. Lots of misdiagnosis. These patients are getting the diagnosis of ALS, sometimes the diagnosis of CIDP. There is 0 targeted therapies out there today. 60% of these patients progress despite being on the highest dose of IVIg, 20% of patients ending up in permanent disability. I couldn't be more excited about the opportunity which is waiting for us to transform the life of MMN patients.

A couple of data. This would not be an argenx presentation without data. 2 panels on this slide. The left panel is the randomized controlled portion of the Phase II ADAPT trial. The right-hand part of the slide is new to you. This is the first time we're showing the open-label extension data from this study.

Remember, on the left panel, we randomized MMN patients at their best on IVIg onto empasiprubart in blue, 2 different doses or placebo in yellow. What you see is the immediate jump in functionality, the improvement in grip strength. This is a dramatic gain in function, similar to what we have shown with VYVGART in CIDP. And now comes the cool part, when these guys roll over into the open-label extension, you see again the same jump for the placebo patients, then enjoying the same instant effect of empa. And the blue curve show you that the longer you stay on drug, the more function you recover.

Guys, what you're seeing is a remarkable ability of the human peripheral nervous system to recover function when you take away the toxic pressure of these pathogenic IgM autoantibodies. So we spoke about efgartigimod, which is being developed in more than 15 indications.

I now spoke about empa, which is being developed in more than 3 indications. Adimanebart had its little moment of glory in a mini R&D Day in Boston, not such a long time ago. I will not talk about it today, but it's advancing into Phase III for CMS, and it is currently in Phase II for ALS and for SMA.

I want to spend a few minutes on ARGX-213, our next-gen FcRn, the first of many and ARGX-121, our IgA sweeper. What I brought to the presentation today are PD data. So on the left-hand side, you see ARGX-213. The ask to the scientist was make a molecule, which with a single monthly subcu push can replicate the PD effect of weekly efgartigimod dosing. The child can see that the curves overlap. This is the outcome of the healthy volunteer study. We are ready to go into advanced clinical development. The curves overlap mission accomplished.

On the right-hand side, we see ARGX-121, our IgA sweeper. This is a single subcu push, which is instantly and completely eliminating IgA selectively, including all the pathogenic forms of IgA. There are many of them. This molecule can grab all of them. And you can see that it would be easy to achieve monthly dosing, if not less frequent dosing. This molecule has successfully completed Phase I, clean safety profile, ready to venture into a number of IgA-driven diseases, including IgAN.

In the press release this morning, we also spoke about a deal, which we did with Tensegrity. You know our formula of innovation. Our innovation engine is constantly looking for novel biology, typically in the hands of strong translational biology labs in academia. We started to open up the aperture and started to work with biotech companies. The Tensegrity deal is the first of many, and that basically means that we are pushing 3 new molecules into the pipeline, ARGX-118 going after Galectin-10, ARGX-125, a bispecific antibody against undisclosed targets and then TSP-101 targeting FM14 in muscle regeneration. All of this is summing up into a pretty exciting pipeline.

Today, we have 10 molecules in clinical development. We have 4 molecules in Phase III development, and we have built an engine, which can crank out INDs at a cadence of about 1 new molecule per year, each time going after pretty cool biology with black belt antibody engineering. The news flow for the next months, the next quarters is going to be busy. That's why we only limit this to the Phase III readouts. But for efgartigimod, we are waiting now for the ocular MG data, which will come on back in the first quarter of the year, followed by the myositis data in the third quarter of the year, followed by ITP in the fourth quarter of the year. And of course, Sjögren's is well underway to give us data in the second half of 2027.

For empa, we're waiting for the MMN data to come out in the fourth quarter of 2026, and the first CIDP data will start to emerge second half of 2027. And I can confirm today that we did submit the sBLA for the seronegative MG patients. We are on track, we believe, for a potential approval second half this year. Where this leaves us is a company, which I think is a sustainable innovator.

We have this wonderful IIP machine, this engine, which is cranking out these waves of innovation. Very proud of the new programs entering the clinic, very proud of the advanced clinical development assets being empa and [ AbbVie ] and of course, the FcRn franchise, which we're building out as the leader in the space.

And with that being said, I would like to open the floor to questions with the panel, but I would like to ask Karen to join us on the podium. Thank you.

So are there any questions from the floor? If not, I'll start. Welcome to the panel, Karen. Thanks, Tim, for the presentation. Maybe we can start just from -- we've just seen '25 results, but how are you thinking about -- or '25 results for VYVGART? How are you thinking about the growth of VYVGART into '26? Where are we? How do you think about that?

Thank you. Happy to take the question. From my perspective, we're still at the beginning of the growth journey with VYVGART. And I think that is incredible 16 quarters since the launch that we continue to see double-digit growth quarter-on-quarter. And when you look at the underlying fundamentals for MG, for CIDP, for the PFS launch, what we see is consistent momentum, consistent patient growth and really strong performance across the board.

When I look forward to 2026, I think you continue to see MG growing. We have opportunities with seronegative that Tim just referenced. We have ocular MG as another market expansion. potential. And of course, we continue to grow the biologics market with VYVGART and MG. And at CIDP, we're very much at the beginning of the launch story. And what's exciting in 2026 is that we start the journey into rheumatology with the first data readout in autoimmune myositis.

So I think it's clear to say that -- or it's clear to me that VYVGART is at the beginning of the growth journey. And certainly, our FcRn leadership is also at the beginning with the exciting molecules to come.

And when you mentioned the ADAPT SERON data that is going to be filed and come to -- come on the label in the second half of '26. Are you already seeing a change in the way physicians are and the competitive profile? I mean one of your competitors had a slightly broader label, which may have let them into the market a little bit. Are you already seeing a benefit from that in MG for VYVGART?

Yes. I mean, obviously, we don't promote off-label, and we don't see broad use off label in terms of payer restrictions. But what we do hear is a lot of questions and a lot of unmet need in seronegative. I mean the study enrolled very quickly. By the way, that's the same for ocular MG. The study enrolled very quickly. And I think that's a really good sign of the unmet need that is out there. And we received a lot of questions and a lot of excitement from the community.

I think it's important to note that we had positive data in seronegative from our pivotal trial, and we made the commitment to the patient community that there will be no patient left behind. We're going to go back and do a study and pursue the approval for seronegative. And I'm really proud that we're so close to delivering on that promise to patients.

And on ocular MG, 2 questions really. One, if we think about the ADAPT trial, the ADAPT trial, I think, had some patients in there. What can we learn from that in terms of the readout and the confidence in the success? I think, Tim, you had -- you breeded confidence on the readout, but just some thoughts there. And also in terms of commercially, are you seeing some use already on the back of ADAPT and how broad -- how much of a broadening could ocular -- the readout bring?

I'll give the second part of the question to Karen, but this is a database company, and we're marching on the back of strong data. So there is a peer reviewed publication from Vera Bril, the leading MG authority in Canada, which did a post-hoc analysis of the ADAPT data, where actually she was looking at the impact of VYVGART for each individual muscle domain. And what we saw is that the impact of VYVGART is equally strong on the eye muscle domain as it was on all other muscle domains. It's a post-hoc analysis, but the data are pretty clear.

There are also stories reaching us from the real world where physicians report to us a pretty spectacular improvement in ptosis and diplopia. So now the question is, can you prove that in a controlled trial in a way that is convincing to regulators. Typically, we precalibrate with the FDA and the regulators on trial design, on endpoint. So I think this experiment is marching on strong data, has been very well designed. But of course, there's always intrinsic risk in any clinical trial.

Maybe, Karen, you can comment on commercial.

Yes, happy to. I mean our strategy in MG is to get the broadest label in MG. So we updated the addressable market from 17,000 at launch to 60,000. And a big driver of that is ocular MG and getting the expanded label in ocular MG. We do hear to your question, from neurologists that -- of course, they're not using VYVGART off-label, and we're not promoting it. But in generalized MG, they see the impact on ocular on the eye symptoms. And so they're excited given the fact that there's no other treatment options, no other than steroids for these patients.

And what you hear from patients is that ocular MG is a devastating disease and that often they're not taken seriously enough. So the impact on the health care system is large. These patients have trouble working. They have trouble driving. They can't use a laptop. So the patient impact is big. And for us, the real opportunity is, can you imagine in the future that you can treat ocular MG with VYVGART and these patients never progress to generalize. They never experience the symptoms of generalized MG.

And we won't know that from the data that we get in Q1. What we'll see is the impact on the eye domain. But we'll follow these patients with open-label extension. And I think that's in the style of argenx to see how do we provide -- demonstrate the long-term benefit of our treatments.

And we saw last year a third FcRn get approved, but it doesn't seem to have done anything to really affect your momentum with VYVGART at all. I think you've already broadened the opportunity in terms of patient number once maybe a couple of years ago now. Just is this evidence that there's a broader opportunity for FcRns? What do you think about competition from other FcRn?

Yes. I mean I think what we see in -- whether it's MG, and I think we'll see it in the future indications that we're in as well is a few different things. The indications that we go into as argenx are white space indications where there's significant unmet need for patients. You're talking about MG, and we've seen how we transformed outcomes there.

In CIDP, we entered there had been no innovation in terms of mechanism of action for 30 years. And so with that comes growth in the market and the ability to transform patient outcomes. And I think in these white space indications, there is room for multiple different mechanisms and medicines because what we're trying to do is transform patient outcomes.

Within that, I think we've demonstrated that VYVGART is not just first-in-class, but I believe, like Tim, best-in-class in terms of how we -- what we deliver to patients, whether you look at the efficacy, we've redefined the standard of efficacy in MG, establishing MSE and then more broadly looking at steroid reduction and disease control. More -- the breadth of our safety data and the consistency of the safety data and then out-innovating the competition, bringing the first the butterfly execution, then prefilled syringe, we have auto-injector coming.

So I think you can see in our playbook that we raise the bar, we out-innovate, and that allows us to grow these markets, build these markets and certainly be #1 within those markets. And I think that will continue.

You touched on the expansion of the CIDP market. How is patient retention going? How is that rollout going? And maybe just generally?

Yes. We're definitely at the beginning of the launch curve for CIDP. And what we're seeing in the real world is actually mirrors what we saw in the clinical trial. So we had a 70% response rate for CIDP in the clinical trial, and we had data where in a subset of patients, you see functional improvement. And we heard that from the patient earlier today. And I'd say that's what we're seeing in the real world.

So we see patients starting on VYVGART. We see generally a similar response rate to what we saw in the clinical trial. And then they want to stay on VYVGART, especially because they're seeing the efficacy. But most importantly, with prefilled syringe for self-injection, they're not tethered to the infusion chair any longer. They can go out and get back to living their life and being with their loved ones and doing what they love.

Maybe we could pivot to the myositis data and that's upcoming. The placebo response in Phase II was a little bit higher than we've seen in IVIg trials. Just maybe you could talk through what you've seen in the Phase II and why that gives a little bit more color than earlier on why that gives confidence into that readout later this year.

Yes. Thank you for the question. Of course, it's very difficult to compare between trials and the IVIg trial was a very short trial and was just done in dermatomyositis. So we're running a longer study in Phase II or we have been running a longer study, and we did a basket trial. So actually, we looked at different subsets of myositis, IMNM, ASyS, DM.

And what is important, I think, is the efficacy, which emerged from that study. We hit that primary endpoint with a very convincing p-value. But what gives me even more confidence is actually then when you look at the this 20, this 40 to 60 readout, where actually you just blow placebo out of the wall. So I think that this for the proof-of-concept study, mission accomplished. It's not a Phase III, but it's pretty strong and gives us conviction that we have a winning Phase III clinical trial design. So I think we're ready for success. Every clinical trial, of course, involves some intrinsic risk. We cannot exclude it.

I should ask any questions from the floor? Yes, we've got one question. Go ahead. We have to wait for the mic these days blindly.

Congratulations, tremendous talk and just all the innovation, very impressive. My question is about just following up on the immediately prior discussion. If you have anything you can share so far about early data or if you've had a look at the data so far from the Phase III myositis with regard to the TIS, the steroid sparing as well and any toxicity data as well and how that compares to IVIg and toxicity in this population?

Yes. Thank you for the question. It's too early to tell. So there is no early look at data in this trial. It was a seamless -- operationally seamless Phase II, Phase III. We can monitor in a blinded fashion, the steroid tapering protocol. I think steroid tapering is important in these patients.

The steroid burden across autoimmunity, I think, should no longer be tolerated. I think we have to actively work on it. So now we have to wait, of course, for the unblinded data. But I think the sterotyping protocol is carefully watched and I think it's being implemented according to the protocol.

From a safety point of view, blinded look at the data, we don't see any emerging safety signal. We now have a safety database, which is very sizable. And actually, across indications, we see the same consistent safety pattern. So nothing really standing out. But again, let's wait for the unblinded data. Thank you for the question.

Any further questions from the floor? Maybe moving to ITP. There was some mixed data, I think, in previous trials. Maybe you could just give an idea of the learnings that went forward into the design of the upcoming Phase III that's going to read out and what we should read into that?

I will take the responsibility for that, Karen. You're right. We had 2 registration trials, one with the IV product, one with the subcu product. The IV product was a clear win. The subcu product was flat. We published on it. There's a bit of speculation about what really derailed that study, but the IV study was a clear win.

Remember, we are on the market in Japan now for quite some time with IV product. I personally visited the physicians dosing the product to the ITP patients. It's pretty interesting. The efficacy in the real world is spot on as what we have seen in the clinical trial. This is a very refractory patient population, 50% response rate. And the 2 things which stand out and which really differentiate VYVGART and ITP is the speed of onset and secondly, the clean safety profile.

So this is a later line drug also because it is IV administered, but it's clearly finding its place in the treatment paradigm.

What we have learned in the clinical trial is that we have to pay attention to the use of background medication, how it is used, when it is used. There are certain rules on how you can change the dose for the TPO receptor agonist, et cetera. There were also some geographical biases. So we have taken all these learnings into account in the Phase III trial design. I think the FDA gave us a much more powerful endpoint, cumulative platelet count and this weird construct of the earlier primary endpoints. So I think this company is investing in a responsible way in ITP IV, and we can now wait for the data.

Makes sense. Maybe moving to empa in MMN. You recently changed the primary endpoint there. Maybe you could talk through -- I mean, you showed strong data just now. But maybe you could talk through the reasons for the change, what that brings to the study and how we should think about that.

Yes. Happy to. I'm excited for empa for this year. It's a pivotal year for empa in MMN. So the change to the endpoint was relatively straightforward. It was in partnership with the FDA. Actually, they requested the change to the endpoint. And we were very happy to do that given the fact that, that was our Phase II endpoint, and you saw the data that Tim shared earlier, not just short term, but long term with grip strength being a good endpoint for empasiprubart. So pretty straightforward from that perspective.

From an MMN perspective, I'm excited for -- to see the data. It should be coming in Q4. And I think this is really another opportunity like MG, like CIDP, where we can truly transform outcomes for patients.

And I think you touched on the combination in CIDP as well with VYVGART and empa together. What's behind that decision? Maybe give us a bit of color to what we can think about the additivity of the 2 mechanisms, et cetera.

So when we venture into an indication, we really do a lot of bet to bench research. So we do a lot of translational biology work, also trying to write or rewrite the textbook on immunology for these indications. No one has done that in CIDP. And we have actually presented a poster at PNS last year where you see a pretty sizable cluster of autoantibodies of the IgG type going after a certain type of autoantigen on the myelin sheath, but we also saw a distinctly different cluster of IgM autoantibodies against their own auto antigens.

So we believe there could be opportunity for a complement blocker to push the efficacy envelope above and beyond the 70% Karen just mentioned. So let's first see what empa can do as monotherapy in CIDP. Then we will be able, based on the serology of these patients, determine whether this is an overlapping patient population or a different one, and that will then set the strategy going forward to develop in CIDP.

Makes sense. Makes sense. Maybe on 119, I think we've got -- maybe I'll characterize it as high risk, but in ALS. I think there is a Phase II readout this year as well. Maybe you could talk about the mechanism and how that reads into ALS and what you could see in this disease, what it's trying to do.

Yes. This is a high-risk area, don't get us wrong. But we're moving in there again in a database fashion, I think in a responsible fashion. We're working with the world experts as we always do on this target, MuSK. It is remarkable what knowledge we're tapping on the MuSK in biology, and there seems to be a mechanism involved when you activate MuSK, you enhance the communication between the muscle cell and the nerve cell, which is important for the innovation.

Now the first step in ALS is the denervation, the nerve cell and the muscle cell decoupling, which is the beginning of the disease process. And we believe based on the preclinical work we did is that by activating MuSK, we can keep the 2 together longer. So this is not a curative approach. It is an approach where maybe you can slow down the disease in a significant fashion. And we feel confident moving into a proof-of-concept study also based on some precision measurements we're doing, which are way better equipped to measure the effect of the biology than that endpoint, that typical ALS clinical endpoints.

So eyes wide open. It's a high-risk, high-reward indication, but we will be looking at the data in this year and make a decision that we continue to expand the Phase II clinical trial or not. Stay tuned.

And do you ensure -- I mean, patient selection presumably is going to be very, very important in terms of having early enough stage patients that you can slow down the disease. That's presumably built in.

That's built in. It's a proper study. It's placebo-controlled. It's dose finding. We have been very thoughtful about inclusion/exclusion criteria with the world experts on ALS. So I think this is a high-quality experiment, but we need to manage our expectations.

Maybe one final question for me, maybe a slightly more boring one than the pipeline. But the pipeline and the burgeoning pipeline has implications, financial implications on costs. So maybe how should we think about R&D costs going forward for argenx?

Yes. I would say, as you say, you can see with that pipeline slide that Tim shared how our late-stage pipeline is growing and also the early-stage pipeline. And it's really exciting. And they're all pipeline in a product opportunities. So what you can expect is as we advance those pipelines -- those products through the pipeline that our investment in R&D will continue to increase. And that's part of our strategic agenda. We're a growth company, we're an innovation company, and we're going to continue to invest to fully develop our pipeline.

Fantastic. There's maybe 1 minute left for a question in the room? And if not, I'll say thank you very much to Tim and Karen. Thanks very much. Thank you for presentation.

Good morning. My name is Rob, and I will be your conference operator today. I would like to welcome everyone to the call.

[Operator Instructions]

I'd like to introduce Beth DelGiacco, Vice President, Corporate Communications and Investor Relations. You may begin your call.

Thank you. A press release was issued earlier today with our third quarter 2025 financial results and business update. This can be found on our website, along with the presentation for today's webcast.

Before we begin on Slide 2, I'd like to remind you that forward-looking statements may be presented during this call. These may include statements about our future expectations, clinical developments, regulatory timelines, the potential success of our product candidates, financial projections and upcoming milestones. Actual results may differ materially from those indicated by these statements.

Argenx is not under any obligation to update statements regarding the future or to conform those statements in relation to actual results unless required by law.

I'm joined on the call today by Tim Van Hauwermeiren, Chief Executive Officer; Karl Gubitz, Chief Financial Officer; and Karen Massey, Chief Operating Officer. Luc Truyen, our Chief Medical Officer, will be available during Q&A. I'll now turn the call to Tim.

Thank you, Beth, and welcome, everyone. I'll begin on Slide #3. At the start of the year, we set a bold growth agenda anchored in our long-term road map for value creation, Vision 2030.

Today, VYVGART is delivering meaningful impact in 2 blockbuster indications with MG and CIDP. Our prefilled syringe is now approved in most major markets, fueling new patient and prescriber adoption. We've also made significant pipeline progress and will enter 2026 with 3 Phase III assets. At the same time, we are investing in our next wave of growth with 4 new molecules in Phase I development by year-end and a vibrant immunology innovation program driving future opportunities.

Slide 4. Today, I'm joining you from AANEM in San Francisco, where we are engaging with the neurology community and sharing new data that reinforce our commitment to continuous innovation in rare neuromuscular diseases. I would like to briefly highlight several key data sets presented this week that underscore our leadership in gMG. VYVGART has set a high bar in gMG, driving rapid, deep and sustained responses. Our gold standard for patient impact is for patients to achieve minimum symptom expression or MSE. New data from the ADAPT subcu study showed that up to 60% of patients reached MSE with 83% maintaining it for at least 8 weeks, highlighting the durability of VYVGART responses.

We also know that steroid reduction is recognized as a critical outcome for both patients and prescribers. Building on earlier data showing meaningful steroid reductions with VYVGART at 6 months, we now see this sustained through 18 months with over 55% of VYVGART patients reducing steroids to below 5 milligram per day. We also presented data from the ADAPT SERON study, which met its primary endpoint, showing significant improvement in MG-ADL at week 4 compared to placebo.

Importantly, we observed increasingly pronounced and clinically meaningful improvements in both MG-ADL and QMG scores across subsequent treatment cycles in the overall population and across all patient subgroups. These positive results support our plan to file for a label expansion that includes all 3 seronegative subgroups, MuSK-positive, LRP4 positive and triple seronegative.

This is a landmark moment in advancing our scientific understanding of MG as the results indicate that pathogenic IgG autoantibodies drive disease regardless of antibody status. Additionally, we continue to showcase the strength of our ADHERE data in CIDP, while introducing new HEOR insights that highlight the severe disease burden, long diagnostic journey and the urgent need for innovation for these patients.

Slide 5. We now have 3 first-in-class molecules in Phase III development, efgartigimod, empasiprubart and ARGX-119, each representing a true pipeline in a product opportunity. We continue to maximize the FcRn opportunity by advancing efgartigimod in severe IgG-mediated autoimmune diseases while building the future of this target with the next generation of molecules. As we grow our understanding of FcRn biology, we're building out our capabilities to address patient needs in therapeutic areas beyond neurology.

We're also reinforcing our leadership in neurology with empasiprubart, now in Phase III development for MMN and CIDP. With its selective approach, blocking C2 at the intersection of the classical and lectin pathways, empasiprubart is uniquely positioned to address a broad range of autoimmune diseases.

Lastly, ARGX-119, our MuSK agonist, has now advanced to Phase III in CMS. It is designed to restore neuromuscular junction function, opening the door to indications like ALS and SMA and underscoring our commitment to pioneering new biology in high unmet need indications. Pipeline and the product molecules are designed with built-in optionality, giving us the flexibility to prioritize indications and allocate resources to programs where we can deliver the greatest patient impact. In line with this strategy, we've made three disciplined development decisions.

First, we stopped development of empasiprubart in dermatomyositis due to operational challenges with study enrollment. That said, DM remains an area of commitment for us. This is a population that has seen little innovation and unmet need further validated by the strong pace of DM enrollment in our ALKIVIA study with efgartigimod.

Second, we decided not to advance efgartigimod into a registrational study in lupus nephritis based on the results of the Phase II data. Efgartigimod was well tolerated and safety in line with established profile.

Third, we are rolling out our next efgartigimod indication, which is Graves' disease. This expands our reach into thyroid-driven autoimmunity and allows us to move directly into Phase III in a disease where there is a high need for a new treatment option. We expect to initiate the registrational studies early next year. These are well-informed decisions to ensure we focus our time and capital on indications where we can deliver the most value. We're also thinking in terms of long-term growth horizons for our core assets, which means that even though we are moving forward in certain indications today, we are a data-based company and we will be ready to revisit our decisions as new evidence emerges.

Slide 6. The progress we have made positions us for 5 registrational readouts next year. Each reflects our disciplined approach to indication selection, a clear biology rationale, trial designs anchored in robust clinical endpoints and strong commercial potential to address an unmet patient need. Ocular MG will be the first of these in 2026. We have established a strong biologic rationale, supported by encouraging ocular domain data from the ADAPT study and real-world case reports. The Ocular study will assess the MGII ocular score and if successful, could expand our label to include MGFA Class I patients.

Myositis and TED studies extend our reach into rheumatology and endocrinology. With myositis, the Phase II portion of the registrational ALKIVIA study demonstrated meaningful improvement in muscle strength and physical function using TIS, which we will evaluate over 52 weeks in the Phase III. In TED, we're stimulating TSHR autoantibodies drive disease, we leveraged peer data to advance directly into Phase III. Across both indications, we see a clear opportunity for VYVGART to deliver differentiated efficacy and safety.

MMN will be our first registrational readout for empasiprubart. With IVIg as the only available therapy today, there is a significant opportunity to disrupt this market with a novel treatment. In consultation with the regulatory agencies, we've changed the primary endpoint to grip strength, which should capture meaningful functional improvement for patients. Lastly, in ITP, which is already approved in Japan, we designed an efficient confirmatory trial to enable regulatory submission in the U.S. and EU. Translational data continue to show that efgartigimod reduces platelet destruction and supports platelet production and maturation.

Slide 7. As part of Vision 2030 and in support of our ambitious goals, we're making investments across our business to ensure long-term sustainable growth. We're actively scaling our operations in the U.S., including an expanded collaboration with FUJIFILM through a new manufacturing facility in North Carolina. This move strengthens our global supply chain and supports our manufactured in a region for the region strategy, ensuring we can meet growing demand for VYVGART and future pipeline therapies. At the same time, we are investing our pipeline innovation engine, doubling down on our pursuit of novel biology because this playbook is working. We remain on track to have 4 new pipeline assets in Phase I by year-end with more expected to advance from our 20 active IIP programs, each representing a potential breakthrough in immunology.

With that, I will now turn the call over to Karl.

Thank you, Tim. Slide 8. The third quarter 2025 financial results are detailed in this morning's press release. We are proud to report an outstanding quarter, reflecting exceptional execution and sustained momentum in our business. In the third quarter, we reported total product net sales of $1.13 billion, marking a historic milestone for argenx as we surpassed for the first time $1 billion in VYVGART sales in a single quarter.

We achieved growth of 19% or $178 million in product net sales when comparing to the previous quarter of this year and 96% or $554 million in growth when comparing 3Q on a year-over-year basis. If you look at the breakdown by region, product net sales were $964 million in the U.S., $60 million in Japan, $94 million across our rest of the world markets, including our partner markets and $9 million for product supply to Zai Lab in China. The product net sales in the U.S. specifically grew by 20% quarter-over-quarter, reflecting the impact of our investments in the PFS launch earlier this year. PFS is now firmly established as a growth driver in our markets, supporting our continued momentum in gMG and CIDP. The gross to net adjustments in Q3 and the net pricing in the U.S. are in line with the prior quarter.

Next slide. Total operating expenses in the third quarter are $805 million, representing a 5% increase compared to the second quarter. Our R&D expenses increased by 9% or $28 million and our SG&A expenses by 4% or $11 million. Building on our solid revenue performance, we continue to invest in our growth opportunities. Therefore, expect our expenses to continue to grow in the single digits for the rest of the year. This will result in our combined R&D and SG&A expenses to land just north of $2.5 billion at between $2.6 billion and $2.7 billion. Cost of sales for the quarter is $109 million.

Our year-to-date gross margin remains consistent at 11%. Our operating profit for the quarter is $346 million, and the quarterly financial income is $43 million, which results in profit before tax of $386 million. The year-to-date effective tax rate is 13%. After tax, the profit for the quarter is $344 million and $759 million on a year-to-date basis. Our cash balance at the end of the quarter, represented by cash, cash equivalents and current financial assets is $4.3 billion, which represents a nearly $1 billion increase in cash since the beginning of the year.

I will now turn the call over to Karen, who will provide details on the commercial front.

Thanks, Karl. Let's go to Slide 10. As we close the year, it's inspiring to reflect on how far we've come since VYVGART's first approval 4 years ago, reaching more than 15,000 patients globally across 3 indications and 3 product presentations. We're transforming patient outcomes, redefining what patients can demand from their treatments and pioneering an entirely new class of medicine with our first-in-class FcRn blocker. This quarter is a continuation of delivering that transformative impact. Today, I'm excited to share how our commercial strategy continues to turn innovation into access and impact for patients and how we plan to sustain our growth momentum into 2026.

Slide 11. Once again, the team has delivered an outstanding quarter, reflecting growth in all indications across all markets. The prefilled syringe is performing exactly as expected, driving increased VYVGART demand among patients and prescribers who embrace a more flexible treatment option. More than half of patients starting on PFS are new to VYVGART with the rest switching from Hytrulo vial or IV. Since the launch of PFS for self-injection, over 260 prescribers have written their first ever VYVGART prescription, expanding our prescriber base and setting the stage for continued patient growth.

We've also strengthened payer access, securing additional policies to enable more patients to initiate treatment. Growth outside the U.S. is strong with the PFS approved in most major markets. I'm excited to now share how we're executing on our strategy to strengthen our MG leadership and build the momentum to establish an equally strong foothold in the CIDP treatment landscape.

Slide 12. In MG, we have consistently delivered new patient growth for 15 quarters while executing on our strategy to unlock the full 60,000 patient opportunity, advancing 2 label expansion studies in seronegative and ocular MG and driving earlier adoption of VYVGART to expand the biologics market by an additional 25,000 patients. Today, we're the #1 prescribed and fastest-growing biologic in MG. Where we see the biggest opportunity to maintain this leadership is to reach patients earlier in the treatment paradigm. We're already seeing this shift take place with the percentage of patients coming from oral therapies increasing year-over-year now at 70%.

The PFS is fueling this momentum, opening doors to new segments of younger, more active patients and our strong safety and efficacy remain the foundation of physician confidence, driving earlier prescribing decisions. As Tim highlighted, we're excited to be moving closer to potentially expanding our label to include seronegative gMG patients following positive top line results. The unmet need here is significant, especially for triple seronegative negative patients who experience diagnostic challenges and currently have no approved therapies.

Ocular MG is next. Patients often struggle with symptoms that make everyday activities like working or driving nearly impossible. Many are heavily reliant on steroids in the absence of treatment options. These programs reflect our commitment to address underserved populations and redefine care in MG, setting a higher bar for what patients can expect from treatment.

Slide 13. In CIDP, we continue to deliver innovation that translates into patient impact. We're seeing consistent growth in both patient starts and prescriber engagement, driven by physician trust in the safety profile of VYVGART Hytrulo and its ability to deliver meaningful functional improvement. We're on track to grow towards our 12,000 addressable market of patients not well controlled on current therapy. We continue to hear stories from patients about their positive experience to date. The prefilled syringe is driving additional demand as patients opt for the convenience of self-injection, and our activation efforts are empowering patients to ask their neurologists about VYVGART Hytrulo.

Here's the story of one of those patients. Sasha is a mother of 4 in her 30s. She was hospitalized for over 3 months earlier this year given her symptom progression. She shared the frustration that came with CIDP, completely dependent on her spouse for even the simplest daily activities. After starting VYVGART Hytrulo and later switching to the prefilled syringe, she said, "I can live my life." She's walking her children to the school bus, something she deeply missed. And thanks to the flexibility of the PFS, she's thrilled to plan a 10-day cruise without worrying about having to be home for an injection. While this is just one patient experience, these stories give us confidence to expand our reach and serve more patients over time.

We're now gearing up for 5 Phase III readouts next year, actively engaging with patients and physicians to ensure that if the data are positive and approved, we'll be ready to expand into these markets and deliver broader patient impact. As an example, we're strengthening our rheumatology presence through deeper engagement and increased visibility at major medical conferences with our clinical data. Our focus remains on finishing this year strongly while laying the foundation for multiple future launches.

With that, I will now turn the call back to Tim.

As the heart of our success is our commitment to transforming patient outcomes, with multiple pathways to realize Vision 2030, we're not just positioned for sustained growth, we are building a legacy of long-term value for patients and shareholders. We have the strategy, the signs and the momentum behind us. But most importantly, we have the passion and purpose to redefine what's possible in immunology.

With that, operator, we'll open the call up to questions.

[Operator Instructions] Your first question comes from the line of Rajan Sharma from Goldman Sachs.

Just one clarification actually just on the formulation mix. It obviously seems that the PFS is driving the growth. But could you just confirm that all of the other -- or the other 2 formulations are still growing underlying in both CIDP and MG? And then just on the pipeline, I know it's a little bit further out for you at the minute, but I'd be interested to get your perspectives on Sjogren's disease. We saw some Phase III data from Novartis ianalumab yesterday. I'd be keen to get your thoughts on that and how you think VYVGART could potentially differentiate and what represents a clinically meaningful signal?

Yes. Thanks for the question. Maybe I can take the first one on the PFS and Tim, if you want to comment on Sjogren's. So you're right, prefilled syringe is the major driver of growth this quarter, and that actually continues the trend that we've seen over time since Hytrulo launched or since we launched the subcutaneous version. Having said that, the IV does continue to be an important contributor to the business and to the results that we saw this quarter. There is definitely a segment of patients and physicians that prefer the IV option. So the fact that VYVGART has all 3 presentations, and they're all contributing to our performance is important for both -- for obviously, for MG, whereas for CIDP, the focus is on Hytrulo as approved in presentation.

Tim, do you want to comment on Sjogren?

No. Thank you, Karen, and thank you for the question. So I think it's important and great news for patients, Sjogren's patients to see the Novartis data, which clearly showed a statistically significant win in Sjogren's. When we look at the efficacy, we believe a 2-point improvement is considered clinically meaningful, so there's definitely room for improvement. We have strong conviction, of course, in efgartigimod based on our own Phase II data and peer data in Phase II. This is a precision tool, which we believe is going straight after the circulating immune complexes instead of a more broad general B-cell suppression. So the data need to speak and the trial is well underway. Thank you for the question.

Your next question comes from the line of Tazeen Ahmad from Bank of America.

I wanted to get some color about how you're thinking about the CIDP launch. Specifically, our survey work indicates a high level of excitement from physicians to want to move efgart into frontline therapy ahead of IVIg. I wanted to hear what your feedback from the sales force is and what efforts would be needed in addition to what you are already detailing in order to make efgart the first-line option for patients in CIDP.

Yes. Thanks for the question, Tazeen. And we're hearing very positive feedback from prescribers about the CIDP launch as well. And what -- the feedback that we're hearing is that the real-world experience for CIDP patients reflects what we see in the clinical trials and importantly, around efficacy and safety. And then obviously, we have the convenience. You'll recall that in our clinical trial and in our label, we have the approved indication for all patients. And so what we're seeing at the moment is that the early experience is from IVIg switch patients, so 85% of our patients are coming from IVIg switch.

But we are seeing some of the patients that are starting naive where they haven't started with IVIg, they're not switching and we're having -- just like in the clinical trials, we're seeing good real-world experience with that. So we see that we're at the beginning of the growth curve for CIDP. We see continued momentum. We see continued expansion of the prescriber base. And I think that over time, we'll start to see more penetration in the market across all patient segments.

Your next question comes from the line of Derek Archila from Wells Fargo.

Congrats on the progress. Just as the narrative shifts to VYVGART pivotal readouts in '26, I mean, can you give us a sense of the revenue potential for those indications and how they may compare to MG and CIDP? And I can sneak in a second, I guess, what diligence got you excited about pursuing Graves with VYVGART. I know there's been some debate about the unmet need there.

Yes. Thank you, Derek, and thank you for the question. What we have been saying publicly is that revenue potential-wise, each of these Phase III indications roughly represent an MG-like opportunity, and we will be giving more detailed information when we come closer to the market. You know that Graves has always been on our indication list. I think there's a clear biology rationale. It's established how you do the clinical trials, and we have been digging deeper into the unmet medical needs.

So whilst it is true that it is a subset of patients doing well on the cheap available medication, there's a substantial subset of patients which are not doing well. And again, from that point of view, it may resemble MG, but a subset of patients is in bad need of an alternative medication because there's not much left once you feel the cheap available medication today. Thanks for the question.

Your next question comes from the line of Alex Thompson from Stifel.

Congrats on the quarter. I guess on the empasiprubart discontinuation in DM, I wonder if you could speak about sort of the trial issues, the enrollment issues you had there. Was that due to the IV presentation and how that compared to the myositis trial with efgartigimod? And maybe you could also comment on the CIDP, empasiprubart enrollment as well and if that's being affected?

Alex, thank you for the question. We have the benefit of having Luc with us, our colleague and Chief Medical Officer. So Luc, why don't you take the question on the discontinuation of DM and the excitement which we have about ALKIVIA.

Yes. Thanks, Tim, and thanks for the question. Yes. So most of the -- this is also a POC trial, Phase II trial that we were running, of course, in a highly competitive enrollment environment. And of course, it didn't help that C5 read out negatively. And we set the bar high for what we want to see, so our inclusion criteria are pretty robust to make sure that we can have a readout that would be predictable for Phase III. And the enrollment just stumbled on that. And then we, of course, have to make decisions within our portfolio with all the work we have, what we keep trying or what we say, okay, DM is an important indication and ALKIVIA during which DM enrolled pretty well. But right now, for the C2, we felt we had to reprioritize.

And then on your question on CIDP enrollment, we just started those empasiprubart trials, so are still too early to say on how our enrollment is projecting there.

Your next question comes from the line of Yatin Suneja from Guggenheim.

Just a quick one from me. With regard to the thyroid eye disease studies, could you just talk about the expectation in this indication, how you're thinking about the potential positioning? And then I think also just talk about -- is there a way to capture some of the TED patient population with Graves' study that you might be running now?

Yes. Thank you, Yatin. For TED, we decided not to disclose too much about positioning. I think we first need to wait for the data to speak. We think there is a convincing proof of concept out there from a peer molecule. And the jury is out to know how this mechanism of action is going to differentiate itself from the available mechanisms of action. And it's fundamentally different biology, fundamentally different mode of action, but the data need to speak for themselves. I think there is ample of room for improvement, both on the efficacy side and the safety side.

And you know we're running this trial as well with the prefilled syringe. TED and Graves are basically presentations of the same spectrum, the same disease biology, underlying disease biology. And so with venturing into Graves, which we announced today, we are actually increasing our efforts in the thyroid space. Thank you for the question.

Your next question comes from the line of Yaron Werber from TD Cowen.

Congrats all. Really nice quarter. I have a couple of questions. Maybe the first one, can we -- any chance to get an update on 121, the IgA sweeping platform and then 213, the long-acting VHH of efgartigimod? And then secondly, maybe when we look at sales, sales essentially have now quarterly sales more or less doubled since about a year ago, as you noted, when you launched also CIDP and obviously, PFS is now launched. I'm just trying to get a sense, can you -- how much of the growth is driven by CIDP versus gMG?

Yes. Karen, why don't you start with the commercial question on the relative growth drivers that impact? And I will take the pipeline question.

Yes, absolutely, happy to. Yes, so you're right, we saw when you zoom out, nearly 100% growth year-over-year, as you said. And what we see in the underlying fundamentals of the business is strong growth across both MG and CIDP, both contributing to the growth that we're seeing for the quarter and over the long term. So if you look at MG, in particular, I think it's important to note, we're the #1 brand of biologic at this point, and we're growing faster than the market. And that market is expanding quickly with biologics being used earlier in the treatment paradigm.

And then, of course, in CIDP, just a year out from launch, we're seeing expansion in our market share there as well. And I spoke earlier about the increased penetration into that market. So I would see -- I would say what you can expect moving forward is continued growth in both MG and CIDP, and contribution from across the different markets and geographies as well.

Thank you, Karen. And then, Yaron, on your question on the pipeline, which I really appreciate, both ARGX-121 and 213 are swiftly progressing through the Phase I studies. Remember, in the dose escalation, single dose, multiple dose, we are, of course, first and foremost, interested in safety and tolerability, but these are also molecules which are going to unveil their potential to the PD effect.

So you know that the ambition level for ARGX-213 is to move to monthly dosing with an equivalent PD effect as VYVGART and no compromise on safety. And for ARGX-121, the IgA removal sweeper, the objective is to have a very fast and very deep IgA reduction. So these Phase I trials will disclose a lot about the potential of these molecules, they're on track, and I would say stay tuned for the first data disclosure soon. Thank you.

[Operator Instructions] Your first -- your next question, sorry, comes from the line of Danielle Brill from Truist Securities.

Congrats on the quarter. Maybe I'll ask a question about the seronegative opportunity based on our conversation yesterday. Can you talk about your confidence in the opportunity from a commercial standpoint and the approval based on the subgroup data that you presented? And I'm also curious if you could share any MSE data findings given the importance of that endpoint to prescribers?

Thank you, Danielle, and we have the benefit of having Luc on the phone. So look, maybe you show some color, you share some color on the path into submission and then how -- from where you sit, the likelihood for an approval? And then maybe, Karen, you comment on the importance from a commercial point of view.

Yes. And Danielle, thanks for the question. So we are very excited by the outcome of the SELON study because we invested a lot in running the biggest trial in seronegatives with a rather innovative design, including diagnostic adjudication. And they really -- the overall results really enforces VYVGART's potential to really move the dial in this underserved population, as Karen already said. So we met the primary endpoint, which by design was on the overall population with a clinically meaningful and highly robust statistical significant reduction in MG-ADL score.

And we also, as we showed at AANEM with James Howard presenting, showed that over consecutive cycles, this impact with benefit accrued deeper and deeper. Now this was seen across the 3 subgroups. So the MuSK, which -- coincidentally, we have one of the biggest MuSK data sets here, triple seronegatives and then LRP4. And across these 3, the benefit moved towards the same direction. And that for us is the basis that we have quite some conviction in the benefit we are providing to these patients. But of course, ultimately, it's going to be a review decision by the agency. But we feel pretty confident that we can have a great discussion on the real benefit that we're bringing to this underserved population.

Thank you, Luc. And Danielle, on your MSE question, there's a ton of data to unpack. So the long-term follow-up, the deep dive into these patients, there will be much more data sets disclosed going forward into the future. So please stay tuned. And Karen, why don't you comment on this significance from a commercial point of view?

Yes, happy to. And I think this is a significant opportunity from a commercial perspective, and we're certainly very pleased to see such strong data from the SERON study. So as you know, we're the leaders in the MG market, and our strategy is to expand that leadership with the broadest label possible. So SERON or seronegative opportunity is one angle for that. The other is ocular MG, and we know that we have the data readouts coming next year for that. So we're well on our path of executing our strategy of expanding our market leadership.

And the opportunity that we see in seronegative with the 11,000 patients is very high. One of the indicators that we think is important is how fast this clinical trial enrolls across all 3 of the subtypes. And I think that really demonstrates the unmet need and the enthusiasm about VYVGART in these subtypes. So I'm looking forward to the approval, if we get the approval, and I know the team is looking forward to being able to bring transformative impact to patients -- in seronegative patients as well.

Your next question comes from the line of Akash Tewari from Jefferies.

This is Amy on for Akash. Congrats on the quarter. Just a quick question on myositis. Curious to see what your bar for success is across the 3 subsets and how you are thinking about integrating the new steroid tapering protocol while still mitigating placebo risk?

Thank you, Amy, and thank you for joining us on the call today. So of course, the first thing we want to achieve in this basket trial is to achieve statistically significant separation from placebo. It is generally understood in the community that a total improvement score of 20 represents a clinically meaningful benefit. You may recall the Phase II data, which we presented where we did a sensitivity analysis looking at TIS of 20, but also TIS of 40 and even 60, where you just see an increasing effect of VYVGART, which is very exciting. So that's how you should frame or look at success in the clinical trial. Thank you for your question.

Your next question comes from the line of Richard Vosser from JPMorgan.

Maybe you could talk a little bit more around the rationale for the change in endpoint for the EMPASSION trial for empa and MMN, and give us an idea of what you're looking for around the group strength endpoint.

Thank you, Richard. Thank you for joining us and great question. Luc, this is a great question for you, right?

Yes. Thanks for that question. So we made that change in close consultation with the agencies. On that endpoint had a precedent and felt that this could indeed be an indicator of a meaningful outcome. And so that's why we made that switch. We had strong data on this endpoint, by the way, from our Phase II trial where there was accruing benefit over time on this measure. So we feel pretty confident that with this switch, our probability to show the benefit of empa is more or less unchanged from the prior endpoint, the MMN routes, on which we also keep doing the work, which is going to be a key secondary, which will provide further insights in the dimensions of benefit.

Thank you, Richard [indiscernible], I think this is a great advantage for us because the alternative was MMN routes, which was still going through an important validation step. But now we see CBUR and CDUR using the same endpoints in a specific indication for IVIg in the past and now VYVGART going forward. So we're welcoming that harmonization. Thanks for the question.

Your next question comes from the line of Samantha Semenkow from Citi.

I wonder following the lupus nephritis data that you've seen, is there anything you can take from that data set to help inform additional indication selection for efgartigimod or even 213 going forward? And then just relatedly, how are you thinking about additional indication expansion for empa? And do you have any plans for subcutaneous formulation development there similar to your playbook that you have for VYVGART?

Yes, Samantha, thank you for the question. From a playbook point of view, it is indeed the intention to leverage our subcu platform across all indications. But maybe, Luc, you want to comment on the lupus nephritis data?

Yes, yes. And thanks for that question. So we're still fully digesting it. But just from the top line evaluation, it was clear that right now, there isn't a path forward to a registrational study. And given that we want to be transparent about these things, we put it in here, but we're still trying to fully understand the data, which, to your point, may inform further decisions on a path forward potentially with another asset in the portfolio.

Your next question comes from the line of Myles Minter from William Blair.

Congrats on the quarter. My question is back on the ianalumab data that we just saw and placebo responses in Sjogren's disease. I'm just wondering whether that 5.5, 5-point change from baseline in ESSDAI, is that within your expectations for your ongoing UNITY study? Or just saying that data change your expectations and potentially powering assumptions for that trial?

Thank you, Myles, and that's a great question. In Sjogren's, I think we badly need better endpoints. That's why in the Phase II proof-of-concept study, we explored the effect of the drug across an entire spectrum of endpoints, also some of the new endpoints which are coming. But unfortunately, today, the regulator still forced to use ClinESSDAI because the CRESS and STAR endpoints haven't been fully validated yet. I think the placebo effect which you see in this study is actually quite consistent with the placebo effects, which we have seen in historical trials. So it's the ballpark which we expected when we were designing the clinical trial and powering the clinical trial. Thank you for the question.

Your next question comes from the line of Sean Laaman from Morgan Stanley.

Congrats on the quarter. This is Morgan on for Sean. We have 2 questions. So first, just wanted to get your thoughts on J&J announcing the head-to-head for Imaavy versus VYVGART in gMG.? And then second, I know you provided guidance on OpEx for the rest of the year. But given all the pipeline indications and trials you have going on, I wanted to know if you could provide any guidance on OpEx and the potential lift over the next 12 months or so?

Luc, do you want to first comment on that study from J&J, please?

Yes. Thanks, Tim. Thanks for the question. So I want to start by saying at argenx, our goal is always to prioritize evidence generation that will really add significant value to the patient and the community. And if we look at this design of this head-to-head trial, I'm afraid it will not provide that much new information that benefits patients because of the primary endpoints chosen and the timing of the readouts, we already know that when you stop dosing VYVGART or [indiscernible] for that matter, that IgG's will return to baseline. That is not novel.

So this study will just prove different PD effect of 4 doses of VYVGART versus continuous dosing. And I don't think that, that really adds. And it's also not in line with how VYVGART is actually used in the real world today. And at AANEM, for example, we have poster # 12 for those who are interested to show the long-term data on subcus that shows that with a regimen that really triggers new treatment when the start of deterioration happens that you can keep people well below the significant difference of minus 2 points.

So to me, that, therefore, creates this question how much added value will this study bring and understanding, and overall, our perspective on competitive landscape hasn't really changed with this. We welcome competition because it's good for patients, and we get to better outcomes ultimately for that patient community, but we have not seen really meaningful differentiation being offered here. And so we continue to be confident in the bar we have set. The accumulated data shown at AANEM with all the data out there across both pediatrics, long-term data, the seronegatives are really in line with our mission to present data that really add value.

Yes. Thank you, Luc. And I want to remind the audience that for the long-term follow-up in the subcu study, we now reached 60% MSE in our patients, 85% of these patients have sustained MSE of 8 weeks or longer. I think that's what matters to patients most. Thank you for the question.

Morgan, thank you for your question on operating expenses. Just to repeat what I said earlier, this year, we will end between $2.6 billion and $2.7 billion. Our capital allocation priorities is clear. We're investing in growth. We're not going to talk about the operating expenses and guidance for next year now. But what we will say is that the increases you saw in Q3, you can expect that to continue going forward. Thank you for the question.

Your next question comes from the line of Jacob Mekhael from KBC Securities.

With $4.3 billion on your balance sheet, how are you thinking about external innovation in the future? I believe you did an early-stage deal earlier this year, but should we expect more of those going forward? And are there any technologies that you think would be a good fit with your internal efforts?

Yes, Jacob, and thank you for the question, and thanks for joining us today. Just as a quick reminder, all innovation at argenx starts with the collaboration with external world. So at the core of each pipeline asset is a very strong fabric of collaborators. It is true that with the increasing cash balance, our aperture for novel biology, which we're hunting for is opening up. We are no longer just looking in academic labs, but we're also involved in a number of constructive discussions with young biotech companies, typically not a place where you find exciting biology. So we're looking for the same biology. The hunting ground just increased, thanks to the balance sheet. So stay tuned. In our innovation mission, more of that biology will be coming in.

Your next question comes from the line of Luca Issi from RBC Capital Markets.

This is Cathy on for Luca. Congrats on a robust quarter. And we have a question on VYVGART for gMG. We've been hearing from a few KOLs that patients are receiving the drug using shorter off cycles compared to the label. And that is because these physicians are worried that these patients relapse towards the end of the off cycle, so they prefer to restart the next cycle sooner rather than later. Is that consistent with your understanding? And if so, this is an important tailwind that is partially offsetting your gross to net headwind? Any color there much appreciated. And if it's okay, we have a quick follow-up on seronegative MG for Luc. Any rationalization around why triple seronegative patients are not as responsive?

Cathy, thank you for the questions. So first of all, in the ADAPT trial, we adapted the cyclical dosing of the drug to the individual need of the patient. And that's also what the label says. So the label is not prescriptive in how you use the cycles, you redose based on clinical judgment. So it is possible that there is a subset of patients which needs the drug more frequently. There's also a tail of patients which needs to dose much less frequently and there's the whole individualization concept behind VYVGART. So your information is correct. Actually, we presented these data in the poster where you see the total distribution of patients with an average cycle of 5.2 per year, with a number of patients needing it more frequently and a long tail of patients needing it less frequently. The seronegative question is intriguing, right? Luc, why don't you pick up this one?

Yes, yes. And it's important to realize that triple seronegatives often have a longer diagnostic course and therefore, present often also with a more severe disease, which is actually what we have observed in ADAPT SEROM. And therefore, and talking through, of course, experts in the field, our hypothesis is that the initial signal may be lower because repair mechanisms need to kick in and so forth. But what is really encouraging for us is that in the subsequent cycles, they really get to meaningful benefits. And in that sense, that story is not too much different from what we've seen in non-seronegatives.

And so we find that encouraging. We -- of course, we'll continue to look into the data, as was already said, around can we get to MSE also in these patients given their longer disease journey. But overall, we feel the totality of the data fully supports a robust benefit here.

Your next question comes from the line of Thomas Smith from Leerink Partners.

Let me add my congrats on the strong quarter. Just on Graves, we recently saw some long-term follow-up data from a competitor FcRn suggesting a potential to drive long-term disease remission in this disease. I was just wondering if you could comment specifically on that data set and how important the potential disease modification was in your decision here to pursue Graves with VYVGART. And then you mentioned some excitement around the market potential. I was just wondering if you could maybe expand on that and share some of your initial assessment around the potentially addressable market here?

Yes. I will start with taking the answer and maybe, Karen, you can shed some qualitative color on our excitement around the size of this opportunity. It is correct that there are data out there from a peer in the FcRn space. We shared the passion for FcRn with our peer group. Whilst it is interesting, we have to be very careful because this was a very small sample. So I think it warrants further investigation in a large properly controlled clinical trial. So stay tuned for more data coming out of more advanced clinical trial work.

And maybe, Karen, a few words on excitement around Graves.

Yes, happy to. I mean whenever we select an indication, we look through 3 lenses: the biology, can we develop the indication, and we always look at the commercial opportunity through the lens of what is the real unmet patient need in this indication? And can we bring transformative outcomes in the patients. And so when we looked at the Graves indication, what we saw was that there's a large prevalence of the disease, and there is a subset of patients that has a clear unmet need that we think they've got based on the proof of biology study, based on the convenience of our subcutaneous dosing that we think we could fulfill that need. It also creates that franchise, if you will, opportunity given the connection to TED that Tim talked about earlier. So we see that there's a significant commercial opportunity here and look forward to seeing the clinical data readout. Thanks for the question.

Your next question comes from the line of Douglas Tsao from H.C. Wainwright.

Just maybe sticking to the subject of Graves' disease. I'm just curious just -- obviously, it is a spectrum along with TED. And so just given the start of the study, I mean, are you thinking about targeting a particular time point in that progression? And do you think it's realistic or possible to potentially show that you're able to sort of modify the course of disease in terms of progression to TED?

Yes. Thank you for the question. We're not going to comment in this call specifically about the trial design. The trial will come live relatively soon, and we will be presenting trial design, inclusion/exclusion criteria, et cetera, in the appropriate conferences, so stay tuned. On the potential disease modification, it's an interesting hypothesis. I think we need more data to come to a firm conclusion there. But thank you for the question.

Your next question comes from the line of Victor Floch from BNP Paribas.

Actually, a quick follow-up on the peer assets that one of the analysts was mentioning before. That's exactly the one you've actually used to leverage their Phase II data to go straight to TED a few years ago. So I was wondering that is that asset is going to report some Phase III data in the not-so-distant future. So I was just wondering whether these data sets was a relevant proxy for [indiscernible] out of success in TED or if you have any comments to be made?

Yes. Thank you. It's hard for us, Victor, to comment on the time line of clinical trials of third parties. I think we're best off asking the question to them. The way we look at this type of Phase II work is it is a proof of biology. I mean it is an FcRn antagonist. It is firmly establishing the role of FcRn and autoantibodies in the disease. And we know these diseases are autoantibody-driven. I would be very careful jumping to conclusions because as we know, in the FcRn class, not all FcRns are made equal. I think VYVGART is a unique Fc fragment. It's uniquely engineered based on a unique understanding of the biology. So I would not just cross-compare between molecules in the same class. We have already seen in other indications that actually it is just not appropriate to do. So strong proof of biology, stay tuned for the argenx data, I would say.

Your next question comes from the line of Xian Deng from UBS.

So I have a question on VYVGART Phase II data in myositis, please. So just wondering for the Phase II data, there were about 23% injection site erythema. So just wondering if you could share any comments on that and any strategies to mitigate that. And so in general, just wondering how serious do you think that is?

And in terms of physician feedback, given in a small subset of patients, they might have interstitial lung disease. So just wondering what's your mitigation strategy there?

And if I may also squeeze in very quickly, Roivant recently announced a positive Phase III data for their JAK/TYK2 inhibitor, brepocitinib in dermatomyositis. I mean, of course, you are running the trial in a much broader general myositis overall, so just wondering what's your comment on the competitive landscape, please?

Yes. There's 2 questions in one, right, but that's not a problem. Luc, yes, we have seen the data in DM. This is, I think, a large market, huge unmet medical need. There will be multiple molecules which will be playing in this marketplace, and we are welcoming this molecule. It's going to help us shape and build that market. It will not be the solution for each patient. I think you will need a portfolio of therapies to adequately deal with these patients. They're very complex patients.

Back to the erythema, it's much to do about nothing I would say. These are very mild erythema. It's typically your first administration where it can happen and then it disappears. This is nothing new. We have reported that as well in our MG and CIDP patients. So we know the phenomenon. It's not unusual, atypical. And I think it's mild, it's transient, and it's certainly not stopping us in commercialization of this product in other indications to the contrary. Thank you for the questions.

Your next question comes from the line of Charles Pitman-King from Barclays.

I've got one just on the patient numbers. I know you've not provided us with an update today on kind of the total number of patients tried on therapy. But I'm just wondering kind of what the next milestones are that you could be announcing? I mean, can we assume from today that you've not kind of hit 20,000 across all indications or, say, 5,000 for CIDP, just given the kind of prior 15,000 total ex-China and 2,500 guidance that you gave us at 2Q? And also just related to that, I wonder if you could give us some commentary on just the quarterly patient add dynamics, given you now got MG, CIDP and PFS launched, when should we expect kind of patient adds to peak ahead of the next indication approval?

Thanks, Charles. Yes, we did not provide a patient number this quarter. The last one we provided still stands, which was from 2Q. We did a similar communication rhythm with MG and that we provide patient numbers as we cross certain thresholds. We're not going to share what those thresholds are, but I think it's important to know that we have seen consistent growth and that the revenue in this situation really speaks for itself. And Karen, do you want to talk about the patient growth?

Yes, absolutely. Happy to talk about the patient growth. I'm pleased for the question because I'm really excited about the continued momentum that we see across all indications in terms of patient growth this quarter. And I think when you zoom out, I mean, certainly for MG, it's been 15 quarters of consistent momentum in terms of patient growth as we bring more innovation to patients. And most recently, obviously, the PFS has contributed to accelerating that growth.

I think what's really important to note is that with prefilled syringe, 50% of the patients are new to VYVGART, and that's across both indications. And don't forget the 260 prescribers since prefilled syringe launch 2 quarters ago are new to VYVGART. They had never -- these prescribers had never written before prefilled syringe launch. So what you can see is both patient growth very consistently across the quarter with momentum as well as prescriber growth consistently. And that prescriber growth is important because it opens up new pockets of patients in both MG and CIDP and indicates that we're at the beginning of the growth curve for both indications. Thanks for the question.

And your final question today comes from the line of Colleen Kusy from Baird.

This is Nick on for Colleen. Congrats on the quarter. If you could comment on the progress you made in the ex-U.S. launches, whether you think that could be a meaningful top line growth driver for the next year? Or whether you think focus will be more so on deepening penetration in the U.S. and what you view as the eventual market opportunity for ex-U.S. relative to the opportunity in the U.S.?

Yes. Thanks for the question. What you will see is that we have growth across all geographies or all markets. And what we're pleased to see, certainly, if I go through those markets, in Japan, we've launched CIDP. We recently got the PFS approval, and we're pleased to see continued demand growth for both MG and CIDP. So Japan is a very important growth driver for us, and we see that continuing in the future with the PFS launch. If we turn our attention to the other major markets in Europe, in Canada, what we see is that in MG, as you'd expect, it takes a little more time for those markets to come online as we negotiate pricing and reimbursement agreements.

We have a narrow price band, and we have good pricing and reimbursement agreements in place. And what we are starting to see is those revenue contributions for those HTA markets increasing. We recently received the approval for CIDP, that's launched in Germany, and we expect that there'll be further launches for CIDP in additional markets in the upcoming months and years. So we expect that there will continue to be growth ex-U.S. But of course, the U.S. will continue to be a strong growth driver for us as well. Thanks for the question.

And with that, that does conclude today's conference call. Thank you for your participation, and you may now disconnect.

Good afternoon. Welcome. My name is Beth DelGiacco, I'm the Head of Communications and Investor Relations at argenx. I want to first give a warm welcome to everybody in the room. We have some of our analysts and investors. Many of our colleagues here today, our Board members. So yes, a big welcome. This is our first of what we're calling an R&D Spotlight, and we're spotlighting today ARGX-119. This is our MuSK agonist. And I want to spend a little time quickly on why we've decided to host these series of events.

For those who have a bit of a longer memory, early in the days of efgartigimod development, we would host these pretty often. And it was usually around rolling out a new indication or ahead of data, and we actually had the request to bring this concept back. And we're happy to do it. I think it's very much core to who we are. We're very science-based. We're data-driven. So you're going to see more of these next week.

It's also the right time to really be spotlighting ARGX-119. We had a go decision in this molecule into CMS in June. So we're moving into a registrational study in CMS. We'll have data, top line results in an ALS study in the first half of next year. We're also kicking off our SMA study. Also importantly, we're going to be retiring the ARGX-119 name soon and rolling out a generic name. So that's exciting. And I can't tell you what it is today, but I can promise you, it will be very hard to pronounce. If you do after this, have feedback on what topics you would be interested in hearing, we would love to hear that.

We're going to be making forward-looking statements today. We have a lot of people in the room who we'll hear from. Tim, Luc, Peter. You're also going to be hearing from Roeland Vanhauwaert, our clinical scientist on the asset, ARGX-119; and Rebecca Shilling, our clinical development lead on the asset; and Jeff Guptill, who also presented last year during our R&D day, he is the clinical development lead for neuromuscular indications.

We're very fortunate to have two key opinion leaders here. We have Professor Steve Burden, he is our IIP collaborator on ARGX-119 and a true pioneer in neuromuscular junction biology. He identified many components of the neuromuscular junction. So you'll hear from him during a panel. And Dr. Ricardo Maselli, he is a neurologist from UC Davis, and he treats and is a researcher in CMS. So you'll also hear from him during a panel session.

We're going to start with, of course, where we always start, biology, and talking about how we designed 119, then we're going to move into the proof of biology from that Phase Ib study in CMS. And then we're going to look forward, looking at what this pipeline and a product potential could be across all indications. And of course, we'll save time to hear from Tim and our Q&A session.

We rolled out our Vision 2030 last summer, and you'll all remember this, we want to be by 2030 in 50,000 patients across all of our medicines. We want to be in 10 labeled indications. And we want to be in 5 new late-stage studies with new molecules. And actually, this was on top of efgartigimod and empa. So 119, now that it's in Phase III is contributing to that 5. But really, the message today is that 119 is part of this vision. It's in a Phase III. It's in 3 indications, and we're working on bringing this transformational biology, potentially transformational medicine to patients.

You know our innovation playbook. This molecule is really a prototype of our IIP. We like novel biology, and we like it around foundational components of the immune system. Why we like novel biology? It typically means we're first. So when you're first, that means that we can really bring transformational benefits to patients. Why do we like it to be around foundational components of the immune system? Because that often means that it's relevant in many different indications. So we have this pipeline and a product potential.

We rely on external researchers, typically academics to source this novel biology because they have decades of experience around a specific disease target, around a pathway. This is experience that we could never recreate in-house. So this is taking with our antibody engineering capabilities, their depth of disease biology insights. Together, we can really drive transformational outcomes to patients. It also positions us not only to be first in class, but to be best-in-class, hopefully, with our molecules.

All of our pipeline programs actually emerge from our IIP and there's amazing stories of collaboration around our IP, and 119 is no different. I think the key here is Steve brings his expertise in the neuromuscular junction biology. And you're going to see how this collaboration comes to life during the panel and that interaction, these are not transactional relationships. These are really partnerships through the entire life cycle of the molecule. And the reason we do this is because we believe there's power and the know-how of the person. So it's not just about the molecule. So Steve bringing his depth of biology. And together, we were able to kind of apply this know-how to how we're going to bring these medicines to patients.

This approach is also creating an innovation ecosystem. This is something that is dynamic. We make connections between our collaborators. We can tap into the connections of our collaborators into their relationships around the science, around the disease and really the currency of this economic or the economic -- this innovation ecosystem is data. And we can take the data that we generate in the clinic. We can take the data that we're generating in the real world and bring that back into our development plans. And that's what that ecosystem really looks like in action.

I want to spend just quickly, before I move over to the official program, on 5 takeaways that you should remember from today. First off, we are pioneering innovation with ARGX-119, pioneering. You're going to hear that word a lot today. We're pioneering a new understanding of the biology at the neuromuscular junction. We're pioneering in our development for CMS to ALS, SMA. And this is really important to kind of how we bring these molecules forward. We're going to be doing it, and we're going to be doing it fast.

The second thing I want you to remember is actually around 119 itself. 119 is a MuSK agonist. It is serving as MuSK in this situation. And MuSK plays two important roles at the neuromuscular junction. One is that it serves to cluster and anchor acetylcholine receptor. So it actually primes the muscle to receive that signal. The second thing it does is actually at the presynaptic differentiation, where it induces the signaling. Why this is important is you're going to see how our development plan plays out that we are creating a development plan across both modes of action.

The third thing is that CMS is severe, and there's no precision treatments. You're going to hear from a patient during this session. And we talk often about this disease being ultra rare. It is also ultra severe. And with no effective treatments, there's low awareness. There's a long path to diagnosis and there's also not enough systematic genetic screening. And I think that what we're hoping to do today is really talk about all the learnings we're going to generate that hopefully will bring more awareness, more innovation to CMS, which brings me to number 4. We're taking a very data-rich, bold approach to how we're developing CMS.

Remember that with 119, we didn't have a Phase I where we could take a biomarker and check that proof of biology with our Phase I study. That's what we did with our Phase Ib. So not only do we have now the justification to go from the Phase Ib into a Phase III, but we also have proof of biology of the molecule. It's doing what we expected it to do.

The other thing I want to mention on our development approach is we're really arming patients here with -- well, actually it's with digital sensors because we don't just want to get data from they go into the clinic and get their assessments. We want data from when they're home and going through the regular activities because that's going to be how we're going to learn the most about this indication. We're going to take this exact same playbook and apply it to what we're doing for the rest of our ARGX-119 because I think this is how we're going to maximize the opportunity and really elevate the positioning of 119 in our portfolio right alongside efgart and empa. So that is all I have for today, and I'm going to bring up Roeland to talk about the biology.

Hello, everybody, and thanks, Beth, for a nice introduction. I'm really excited to show you some of the science behind the program and also to explain to you why we've chosen MuSK to target. So let's dive right in.

As you can see here on the left of the screen, the motor neuron is innervating a muscle. This connection is called the neuromuscular junction, as you probably know. The signals from your brain go to your spinal cord and then go into your muscle to have a muscle contraction. This allows you to breathe, to function and to walkabout, everybody has this. So argenx really pioneered development at that neuromuscular junction already with efgartigimod in myasthenia gravis; with empa, for example, in CIDP; and now also with ARGX-119 in CMS, ALS and SMA. Also importantly, some IIP programs are in the pipeline targeting novel disease biology at the neuromuscular junction.

So how does this neuromuscular junction biology come about? It's just -- it's not there in 1 day. This was actually the work of Steve Burden. He uncovered from the 1970s onwards this full pathway on how a neuromuscular junction is formed, but also proteins that are important to play at that neuromuscular junction. He unraveled each of one of these and how they function. So there is, for example, rapsyn, agrin, MuSK, Lrp4 and Dok7.

So why did we choose MuSK then, or muscle-specific kinase? Well, MuSK activation is really important for the formation, the maintenance and the maturation of a neuromuscular junction. I'll guide you through this. Upon MuSK activation, acetylcholine receptors will cluster together on the muscle surface. During embryonic development, these batches of acetylcholines -- of acetylcholine receptors are now primed to receive the innervating motor neuron.

When MuSK gets activated more, this connection gets consolidated, and the neuromuscular junction will mature to a full functioning state. Also later in life, MuSK activation remains important because if it's -- if you don't activate MuSK anymore, the neuromuscular junction will disassemble, and you get denervation and all kinds of neurovascular diseases.

So let's dive in into the signaling pathway. And what happens when you activate MuSK with a MuSK agonist antibody, for example, ARGX-119.

[Presentation]

So I hope you understand the signaling pathway now and I don't need to explain it again. But it's crucial that impairments in every step of this signaling pathway cause disease. You might know myasthenia gravis. The autoantibodies, either block clustering of acetylcholine receptors or block MuSK activation in MuSK-MG. For congenital myasthenic syndromes, this is the same. Mutations in any of these proteins will cause muscle weakness. We are studying Dok7 congenital myasthenic syndrome and they cause truncated Dok7 protein, which can lower MuSK phosphorylation, and a MuSK agonist exactly repairs that kind of deficit.

So I hope now that you understand that MuSK is a master regulator of the neuromuscular junction and that targeting with an antibody, the extra cellar domain is quite easy to turn on the system and activate MuSK and get mature functional neuromuscular junctions again.

So how did we develop ARGX-119? Well, it was not that easy. It took us 3 iterations. And the idea came actually via the IIP program. Dr. Huijbers and Dr. Jan Verschuuren from the Leiden University came to us with an idea. They had an idea that they could turn the inhibitory MuSK antibodies from MuSK-MG into activating antibodies. So using the patient's own inhibitory antibodies, converting them to activating antibodies as a therapeutic treatment.

That was quite innovative. So we jumped with them in that kind of antibody campaign. However, we hit some roadblocks. And then we started discussing the biology with Steve Burden. We'll get more into that into the panel. But this co-creation of the 3 groups together really laid the foundation to the development of ARGX-119. The biology expertise of the neuromuscular junction, the biology expertise of mask and the antibody capabilities of argenx that was really a true combination that made ARGX-119.

So ARGX-119 is derived from the SIMPLE antibody platform. It is llama derived. And as you can see here, it will activate MuSK at the frizzled domain which in turn clusters the acetylcholine receptors. That clustering is important to have efficient transmission across the synapse. In addition, there's a second mode of action of a retrograde signal communicating with the motor neuron that will modulate the synaptic architecture.

So we were quite excited of having this lead antibody candidate. So we went as quick as possible to dose the first healthy volunteers. That happened in 2023. Already then, we had in our mind that we wanted proof of concept in Dok7 congenital myasthenic syndrome because of the biology that I explained to you. So not to wait for that. We already started the natural history study, identifying these patients and characterizing their deficits. When we have sufficient safety data from the healthy volunteer trial, we immediately started dosing these patients with ARGX-119. And within 1 year, we finalized the treatment period and analyzed the data, and I'm super excited to show you today the clinical trial outcome data of that trial.

But first, let me tell you a bit more about the biological rationale of congenital myasthenic syndromes. Congenital myasthenic syndromes is a -- that is a genetic disease. It's characterized by mutations in any of these neuromuscular junction proteins. There are over 35 genes identified. And here, we've shown you the most commonly identified proteins involved. For those, genetic tests exist and are used to establish the diagnosis in parallel with the muscle weakness observed in these patients.

We will focus on Dok7, LRP4, MuSK and agrin because those are involved in the clustering of acetylcholine receptors and likely amendable for treatment with ARGX-119. As I told you, mutations in the Dok7 gene will result in lower MuSK phosphorylation. And activation of ARGX-119 actually fully compensates for that. We've tested that in a mouse model. This was the work done together with Steve and his postdoc in the lab.

And as you can see, he had already developed a mouse model for Dok7 congenital myasthenic syndrome. These mice bear the most common patient mutation inside the genomic locus of these mice. So it's a humanized model. Importantly, because they have lower MuSK phosphorylation, they have smaller neuromuscular junctions, which is also observed in patients. As you can see in the lower -- in the graph on the left, if they're untreated, these mice have a very severe phenotype and die within 2 weeks after birth.

If you now dose these mice pups at postnatal day 4 with ARGX-119, you see an immediate increase in body weight, suggesting that we activate the neuromuscular junction, these mice get stronger, can eat again and also increase in body weight and just a single dose has a potency to keep these mice alive for over 60 days.

What we also saw is that these smaller neuromuscular junctions now get healthy again, fully matured. However, after 60 days, the antibody is cleared out of the system, the neuromuscular junction collapses again, and you see this little drop in the middle. The mice lose their ability to walk around, lose their ability to eat and they drop in body weight. Upon that time, we give them a second shot of ARGX-119. And within the week, they start to eat again, increase in body weight and live for another 100 days.

Interestingly, on the graph on the right, you see that prior to the second dose, these mice cannot run on a rotating wheel. However, within 4 weeks, these mice are fully capable of running on this rotating wheel similar to healthy mice. Do keep this graph in mind when you look at the Phase Ib clinical trial data. But first, let's have a conversation with Steve. Steve and Peter, do you want to come up?

Thank you, Roeland. Welcome, everybody. Special thank you to Steve, our collaborator, so shortly after your surgery. And glad to see that your neuromuscular junctions are still fully functional. Steve, Roeland already introduced you as the world's expert in neuromuscular junction biology. He's covering a lot of these important elements. How did you start that research? And how much do we know more now than when you started?

Well, I've been working in this field a long time, almost 50 years. And at the time that we began, we knew a lot about synaptic transmission. And as Roeland and Beth have pointed out, that involves acetylcholine release nerve terminals and activating acetylcholine receptors and ultimately causing muscle contraction and muscle movement. But we really knew very little about the mechanisms around forming the synapse and maintaining the synapse.

And as has been pointed out, over that time, we've identified and studied how -- identified agrin, LRP4, MuSK, Dok7, rapsyn and not identified them but tried to understand as much as we can about how they work. And understanding in detail about how these molecules work is critical for developing, understanding disease and developing therapies for treating them.

And you immediately have a therapeutic focus in the back of your mind when studying all these components.

Sorry?

You immediately have that therapeutic applicability...

No, no, no. At the time we were carrying out these studies, the type of translational studies and clinical studies that can be done now were not in our mind at all. We were just trying to understand the basic mechanisms for building a synapse and maintaining a synapse. And I think the clinicians who are working on diseases, and you point to -- we've talked about congenital myasthenia and Roeland has pointed out their mutations in multiple genes that cause congenital myasthenia. But at the time that we were working on this, the clinicians were simply classifying these patients as having some form of congenital myasthenia, and they didn't know what the cause was.

And at the time that they were studying them, unlike other diseases like Duchenne muscular dystrophy, where people were for genetic mapping and walking, trying to identify the culprit genes, for whatever reason, those clinicians didn't do that. And so it was a [ follow ] area where the disease was described, but the cause was unclear. And I've learned from the clinicians who work in this area, what they did is they waited for labs like mine and others to identify genes like MuSK and LRP4 and Dok7. And once we had identified those genes and studied them in mice, they then used as candidates to go back to those patients and ask were they defectively mutated in those patients.

So the discovery of nearly all of the patients with congenital myasthenia came from these basic science studies that we were doing in the absence of any real pursuit of the diseases.

We learned a lot. I think we identified a lot of these components mutations as a cause of several diseases. What are according to you, the biggest unknown on that neuromuscular...

The biggest unknowns. I'd say there are -- in my view, two, is we pointed out that once agrin binds LRP4, stimulates MuSK and Dok gets recruited, then magic happens. Then the synapse gets organized, assembled, stabilized. But we really don't understand the mechanisms that follow the activation of MuSK and lead to Dok7 recruitment and activation. That's really a black box.

So that's what we scientists that's where magic happens. We don't know it.

That's one. And I'd say the other one has also been pointed to is we found some years ago that you need to activate MuSK and you need to cluster LRP4 in order for LRP4 to serve as a second role. It's not only a receptor for agrin, in itself, the protein signals back to motor neurons and stimulates the differentiation and attachment of motor nerve terminals to the muscle. But we don't understand how that works. We know LRP4 is critical, but how motor neurons respond to it, recognize it and then stimulate differentiation and attachment. That's a big mystery to me.

And if I may -- can add, now it's quite interesting. We have these two big questions. And we're not developing this therapeutic because of the therapy, but we're still doing the research in the lab to really understand these mechanisms. So hopefully, more to come soon.

So that to me is the power of IIP. I think you start with a very concrete project. And based on that collaboration, you can expand and further pioneer the biology. Roeland, how did we get connected with Steve?

How did we -- connected with Steve. I know you so long already, it's kind of hard to think when we first met. But I think the connection came when Maartje Huijbers from Leiden came to that roadblock where unexpectedly male mice started dying. And she worked in your lab. She was a postdoc there. So she said, "Yes, I mean, let's just go talk to Steve." And I think we few -- we even visited you in New York and we started chatting and you even had these synthetic antibodies already laying around. And then we did then the second antibody campaign. So yes, it was quite natural actually as scientists to discuss new data and unknown data.

And what that moment is -- why did we decide to continue the journey despite that setback?

Well, Steve had a reasonable explanation for why the patient-derived antibodies did not work because they bind to this upper most domain and they block likely the agrin signaling. And you already had new synthetic antibodies to this lower frizzled-like domain, which does not block that signaling. So it was kind of -- yes, you move on, you build on to the new knowledge.

Steve, anything you remember argenx knocking on your door?

I concur with Roeland. I mean, again, this comes back to just basic fundamental hard science. We had done a lot of work trying to map what pieces of MuSK did what? What was the function not only of the molecule, but the different domains. In the first IG-like domain, it has 3. We knew that was critical for binding LRP4. Whereas we had studied in mice, we had mutated and deleted the frizzle domain, and that was dispensable.

So for us, this was an aha moment. If you're going to tinker with MuSK by stimulating it and using antibodies, you want to target the frizzle domain, it's dispensable. You don't want to touch the IG-like domain. It's critical for it to bind the LRP4. So for us, it was obvious that if you want to make agonist antibodies, you want to target the frizzle domain and avoid the first IG-like domain.

And Roeland, what do you experience in that collaboration? What made it unique for you?

I mean, I came from academia where you just discussed everything openly. And I had the same experience with Steve. We -- although we were on different continents, we would just hop on a call whenever and discuss new data. I think we're sometimes on the phone 4 or 5 times a week. It was quite exciting. We had a lot of data coming out and trying to interpret all those kind of things.

And Steve, for you, did we bring any value in your research?

No, absolutely. I've had a lot of interactions with biotech companies over the years, quite a lot with Genentech and quite a lot with Regeneron. This was unique. So the nature of the communication, both being regular and being very open, neither of us was holding our cards close to our chest. We were very open about what we were doing and what we should try to do. We were very open to changing views.

It made it very easy not only for myself, but in an academic lab, you depend upon your graduate students and your postdocs who are both heavily involved in the work and committed to the work, and they need to feel that they're involved and they're not being set aside. And they're aware of what's going on both in the lab and outside the lab. And in this case, it worked really well, and it hasn't always worked like that.

So this was a real delight. And this was with Roeland, but also with everyone in Roeland's group. These are just really excellent scientists and easy to communicate with, pleasure to talk to. And...

And it progresses the insights. I think you've -- we now have the 119 data. You talked about the unknowns. I kind of understand we're doing further research there. Something you can tell about that?

I'll let you start.

I mean, yes, it's -- we're doing further work. And out of this new ideas come and so new discovery programs are set up. It's interesting to see that feeding also back to new discovery programs. Yes.

Yes. So basically, a 219 molecule is coming our way.

You're the CSO, you can say that.

Well, the one thing I can add to that is we're -- we've mentioned other diseases other than CMS or other forms of CMS as well that are reasonable targets for 119. I've also mentioned that I think one big black box area, an important area is how nerves respond to LRP4 to stay attached. And there's -- we're working on this together with argenx to try to find out more about what that receptor is, how it works and whether it can be targeted and help sustain attachment of nerves to muscles. To me, that's a big area.

Maybe I would end with this question, Steve. So you've seen the CMS data, obviously. What was your feeling? And how do you see the opportunity for 119 in CMS and beyond?

Yes, that's interesting. We published a paper and Roeland referred to it an earlier version where we had generated our own in-house antibodies to MuSK that had -- they rescued the mouse model, but they had these problems of aggregation and having off targets.

But even at that time, there are patients with CMS who read the literature and there were several who would write me e-mails. And they are touching because as Beth pointed out, this is a very severe disease. People really have a difficult time with this. And so when I started to see the clinical data, there's just very little substitutes for them. It's just very humbling to think that anything you can do in basic science to really help patients, it's powerful.

So was I surprised? The preclinical studies we had done, I thought were really, really solid in every way, both for safety and effectiveness. And there are a lot of similarities between -- maybe not in all the diseases, but in the neuromuscular junction between mice and human. So I really believe it worked so well in mice in so many different situations that it was going to work as well in humans. But you never know until you do the experiment. So was I shocked? No. Was I delighted? Absolutely. Yes.

And how do you see the opportunity beyond CMS? What's your opinion on the biology in different indications?

So I've worked a long time on ALS. And our first actually adventure in trying to tinker with MuSK was not in Dok7, CMS, it was in ALS. And we published a study in 2012 showing that if you activate MuSK in a mouse model of ALS, you can improve the phenotype of those mice. The disease is less severe. And then we went on to use our -- an antibody to MuSK to activate it in the same ALS mouse model. And it did the same thing. It lessened the severity of the disease symptoms. So we all know this is a terrible disease. So I certainly have great hope that the ARGX-119 can provide some benefit to ALS patients. As we all know, there is really nothing that's available for ALS patients right now.

Okay. Thanks. I would like to thank you, Steve, for being here in this panel, of course, for being a very important collaborator to us. Also thank you, Roeland. I will invite Luc Truyen, our CMO, on the stage to talk about the clinical data. Thank you.

Yes. Well, isn't science cool? So I'm going to digress for a second. When I was in the process of talking to argenx, of course, you get information about the assets in the portfolio. I knew about VYVGART. I learned about empa. But then the third one that I -- it was just a lead selected, I believe, at that time. And I said, argenx did what? They built an agonistic antibody for MuSK. And I thought to myself, if they actually did that and that works, that has a lot of potential. Well, that was 4 years ago. Really exciting.

Roeland already spoke about why we studied Dok7 CMS. But let me give some color as to what it means to be a patient with Dok7 CMS. The name, congenital myasthenic syndrome already contains a lot of information. It's congenital. That means these people don't actually know what normal is. Myasthenic fatigability of the muscles and the reasons why it should be clear from what you heard before.

Now these syndromes are very rare, but they are very severe, as I -- was already said. It can start at younger age or in adolescence, but it does progress slowly, and it ultimately leads to significant disabilities. These disabilities will often require the use of aids, wheelchairs and so forth. And what also creeps in there is respiratory problems, difficulties talking. And you will see an illustration of that in the patient video. And I would like you to look at that video and know that there's no FDA-approved treatments for this particular patient. Can I have the video, please?

[Presentation]

Well, if this doesn't give you a sense of urgency, I don't know what will. So using our playbook of innovation, building this molecule, thinking about how can you accelerate development we embarked on the timeline that already was shown, to make sure that we could answers as fast as possible too, can CMS Dok7 be helped by 119?

And we used our playbook that we talked about last year's R&D show. And if I apply that to what we did in this clinical trial, so there are very few patients, right? So how do we maximize the impact of every single patient in our evidence generation? First thing is, of course, because there were no dedicated measures, we borrowed from our learnings in autoimmune MG, we took those scales with us.

But we felt that might not be enough because we actually don't know what they will pick up really in a setting of an interventional trial. So then we said, we want to have more documentation of what happens outside of the clinic. Let's apply digital sensors, actigraphy of these patients. We also thought, well, ambulation is a problem. Let's use an instrument that's more well known, the 6-minute walk test. But let's pair that with some more sensors to see, well, what is actually at the source of any change.

Part of our playbook is also empowering patients through the whole arc of setting up the understanding what the need is, how we're going to now measure with an intervention and success and get the story of the patient back. We first, as was already mentioned, invested in a natural history study to better understand how do these scales evolve and therefore, get some more information for our intervention part. And then we also bookended that with exit interviews after the intervention as to what patients really felt.

I already spoke about small numbers. At this stage of development, typically, you try to do dose ranging, trying to find minimum effective dose, maximum dose and those things. Given the low numbers, we said we cannot do that in this traditional way, and we are going to do intra-patient dose escalation. Our [ Clean Pharm ] people assured me that they could get to an exposure response relationship. And therefore, that's what we did.

Now this natural history study, it's not the first time we make an investment in this. We think it's an essential tool to understand the disease you're actually trying to effect. And what we learned here, and this goes to the normalcy of these patients, is these patients are actually chronically severely disabled.

And 85% require devices to help them around. And therefore, that realization to us said, "Wow, yes, yes, I hope we can see an inflection point with our treatments." We're going to evolve this natural history study. We're going to include other genotypes. Also look earlier, as Taal said, it started as a baby, of course, to get more information. You're going to see the results of this Phase Ib clinical trial.

And at first blush, you could look at this and say, "Well, that doesn't look very innovative at all, two parallel groups, small sample." But it's again because of the factors I said before, a large number of measures, high frequency of measuring, intra-patient dosing, that we can get real answers out of this small, I'm not going to say it's big, experiment and that allowed us to make -- well, the decision we made you already know about. But Rebecca will tell you more about the data that underpin this. Rebecca? Thank you. Thank you.

All right. Thanks, Luc, and welcome. It's great to show you our data. So I'm going to, on behalf of the team, walk you through our Phase Ib study results. So in this study of Dok7 CMS patients, we enrolled 16 patients, we were able to see a favorable safety profile and looking at measures focused on mobility and weakness, we see what we think of as proof of biology. And taking these data, we believe we have the reason, and we can also convince the regulators that we're ready to advance into our registrational study.

So on this slide, I'm showing you the demographics and the baseline characteristics. So we enrolled 13 patients in the 119 treated group and 3 placebo patients. And what you can see is the majority of the patients were stable on beta agonist as the patient Taal mentioned, albuterol is one of the anecdotal medicines that's used in these patients, patients do require assisted devices and the patients were enrolled, we targeted patients who had evidence of weakness. And on the next slide, I'll show you a little bit more about this.

So using the quantitative myasthenia gravis score, the QMG, you can see the components that are most affected at baseline, shown here by each component and then the colors signify the severity. So you can see on the left, looking at Orange was just moderate, or severe was red, that the patients were most affected in their arms, legs, and the weakness that they had in these components as well as the head, whereas the speech and swallowing components of the QMG were less affected.

So we focused on where these patients are most affected to see if we can have an effect with 119. And on the next slide, what you can see here is the levels of weakness in the legs and the arms. So in the dark blue is the 119 treated group and in the gray is the placebo patients. And so we see, over time, as we're dose escalating within the patients, an increase in the ability of these patients to hold up their legs and their arms.

So in the legs, the patients are getting towards what is considered normal on the QMG, which is 100 seconds. And on the right, with the arms, there is a doubling of the amount of time they're able to hold their arms up, but they haven't quite reached the normal range, which would be 240 or above. But this is really showing that the areas of this limb-girdle phenotype that we're improving, and their patients have less weakness.

But we wanted to understand more about how they're functioning, how are they doing with walking. As Luc mentioned, we used the 6-minute walk. So on the next slide, I'm showing you the total distance walked. And we -- when we saw these data, now we're focusing here on the ambulatory patients. So patients who didn't report a need for wheelchair at baseline, but were able to -- and were also able to walk at the beginning of the study.

And we see that over time, in the dark blue in the 119 treated patients were getting a median distance of 75 meters. So in other neuromuscular diseases, which I have here on the light blue is the clinically -- what's been considered a clinically meaningful range, which is between 15 and 50 meters. So this was quite exciting for us to see this magnitude of a change in the small study in these patients.

And the other thing is that we don't think that we don't see a plateau, so we're continuing to following these patients off drug. So we'll have more data in the future. But we're also encouraged that if we can in the next phase when we treat for longer that we'll have an even greater magnitude of improvement.

Now the other thing we did, as Luc said, is we had patients wear sensors so that we could really measure different parameters of their gait. So we can understand not just that they're walking longer and maybe actually having more endurance, but also are they moving better. And so one of the measures that we looked at is cadence. So this is a measure of the steps per minute. And so we see that in the 119-treated patients that we're getting a difference in the cadence relative to placebo. And again, extrapolating for other diseases where a clinically meaningful change of at least 5 steps per minute is considered clinically meaningful. So this also shows us that we are really starting to see patients moving better and able to improve their gait parameters.

Now in order to put all the data together, we did also look at a correlation between what we see with the distance in the 6-minute walk. And with the leg weakness, and we see that the patients treated with 119, there is a positive correlation, whereas with the placebo patients, we do not see the same pattern. So this helps us understand how the data are all being synthesized in these patients and the coherence in the data.

Now another way that we wanted to look at these patients because as you heard from Taal that she has a hard time with her day is what is happening outside the clinic. Because it's this one thing for us to measure how they're doing in the clinic, but it's another thing to take a look at what's going on at home.

And so in the next slide, we -- this is data from patients wearing just a very simple actigraphy watch that could measure multiple different parameters of activity at home. And the -- each column is an individual patient, and the A marks the patients on active drug 119 and the P marks the patients on placebo. And this is a hierarchical clustering that has separated the patients into different groups.

So you can see on the left are the patients who reported wheelchair use and one cluster and on the right are the patients who didn't report any need for a wheelchair. And so what we see just overall is that in the patients who were on 119 that we actually see in the red, an increase in activity. The blue is a decrease in activity. So that was very encouraging.

But then when we look at specific clustering in the green box in the patients who reported wheelchair use, what we see is an improvement in short-term activity parameters, such as the best 1-minute cadence. So that was very interesting. And then when we look in the dark blue at the patients who didn't require wheelchair assist, we see an improvement in the what are called longer-term activity parameters like their best 4-minute effort. So this is interesting that we saw these patients clustering differently depending on their baseline activity, but in both sets of patients, we're seeing improvements.

And then the last thing I'm going to show you on here is the rectangles around the patients who are the 3 placebo patients. And we really don't see that they are really changing much. And if anything, some of them are actually decreasing. And this is consistent with what is reported in the literature with these patients that over time, they're relatively stable and also consistent with what we have seen in our natural history study.

Now this is exciting data for us to see the activity of 119, but also important for this -- the preliminary of Phase Ib study is the safety profile. And we actually saw really favorable safety profile in that 119 IV was well tolerated. We didn't have anybody discontinue due to an AE. There were no serious or severe AEs, nobody developed anything that would suggest that we were inducing a myasthenia type phenotype. So this is very encouraging for us as we move forward with 119.

And this last data slide, I'm going to show you is we want to understand in any study, especially in a small study in an ultra-rare condition where we don't have established end points is what are the patient -- what's meaningful to the patients, is what we're measuring actually something that matters to them. And so we used a qualitative analysis of the patient exit interviews to understand if they felt that the study was capturing what mattered to them, did they feel like they were improving, were they satisfied, was the watch acceptable to use and if they were having increase in mobility. And all of these responses were positive, and you can see some very lovely quotes that are quite inspiring just like that patient, Taal.

So putting this all together, we feel that we have the confidence and the data and the story to tell to the regulators so that we can move on to targeting Dok7 CMS patients aged 12 and up in a pivotal trial, and we're going to expand to the additional subtypes that its biological rationale. We're going to focus on the 6-minute walk as the primary endpoint, but we also want to go discuss with the regulators about our digital health technology-derived end points. And we're also going to expand our natural history study so they can really understand fully the disease.

And with that, I would like to bring up one of our collaborators as well as Luc for our panel. And thank you.

So while we're getting arranged, I'll just introduce the session. So for this part of the session, we're going to have a panel discussion about -- a little bit more about the CMS patient journey and experience as well as talking a little bit more about our data and future strategy.

So I think we've already met Luc and Rebecca already, but I think maybe first, we'll start with introducing our guest here, Dr. Maselli, and I've been very fortunate over the years to learn a lot from Dr. Maselli from prior talks that he's given educating neurologists about congenital myasthenic syndrome. So maybe you can just introduce yourself and talk about your practice.

Sure. Thank you, Jeff, for such a nice introduction. My name is Ricardo Maselli. I'm a Professor of Neurology at the University of Chicago -- University of California, Davis. I was trained at the University of Chicago. And so most of the things -- and that's where my interest in congenital myasthenic syndrome started more than 30 years ago. So I've been very active in the not only in the clinical practice of congenital myasthenic syndrome but also in the research of congenital myasthenic syndrome. And in my interaction, I've been interacting a lot with Steve Burden for many years.

It's a small community, I guess.

Yes.

Can you tell us a little bit about your clinical practice and the patients that you see in clinic?

Yes. So most of my patients are neuromuscular patients. And although I do have -- as a general neurologist, I do have responsibilities of seeing patients in the hospital as well when I'm on call. But most of my patients -- my outpatients are patients with congenital myasthenic syndromes. And I see all kind of congenital myasthenic syndromes, including the most rare diseases, extremely, and we're really talking about, I would say, Dok7 is a rare, but it's not that rare, actually. I would say it's probably one of the most common form of congenital myasthenic syndromes.

But I've seen patients with very, very rare, ultra-rare diseases that we are talking about 3 or 4 cases reported in the whole world. And some of my patients are contacting me, some of the parents are so motivated because the reason that we have seen that this is a terrible disease. And some of the patients are really so invested to the point of contributing to my research. And so in answering your question, yes, most of my practices in congenital myasthenic syndromes.

And before I joined argenx, I actually remember referring a patient specifically, this is Dr. Maselli for a second opinion. So maybe you can talk a little bit more about the diagnostic journey of that patient's experience with congenital myasthenia.

Sure. Well, in doing so, I'm kind of aging myself because I've been doing this for so long. And so that remind me when I was a fellow at the University of Chicago. And that was -- I think that was the golden age of congenital myasthenic syndromes, even we didn't know the generics of congenital myasthenic syndromes, up to, I will say, the 1980s. Congenital myasthenic syndromes, we knew one thing that were completely different from the autoimmune type of myasthenia. There were patients that they're clustered in families with congenital myasthenic syndromes, we knew that autoimmunity playing overall in that disease. And ergo, we didn't treat them with immunosuppression.

But we didn't know the types. So the first challenge was to separate all these bunch of patients that were referred -- were reported over the years and say, well, what is this and what is this and what is medication for each type of the congenital myasthenic syndromes.

And the only way that we had those days to make the diagnosis is to do a muscle biopsy, take the muscle actually, and keep the muscle alive actually, you can do that. And in the muscle alive, [ get ] microelectrodes on the neuromuscular junction, stimulating the nerve. And by doing that, you can establish the amount of [indiscernible] or synaptic vesicles being released and the amount of what was the impact of a single vesicle at the neuromuscular junction. And by establishing that ratio, we can determine if the condition was pre or post synaptic, which was a major accomplishment.

Then we also had electron microscopy, so we can correlate that with electron microscopy. And so we established in doing so a group of patients with pre- and postsynaptic and we knew the medications that those patients will respond depending where the condition was pre or postsynaptic. So that was really the first accomplishment and was the first challenge that we faced back in the 1980s and beginning of 1990s. Was not only until 1995 that the first linkage to a genetic defect was established and was the variant that is called the slow channel syndrome.

And up to that point, from 1995 and after that, there were really not too many laboratories in the world that can do the genetic. And there was the Mayo Clinic and most of the things that we are learning was from the Mayo Clinic, from Dr. Ed Lambert and Andy Engel. And then it was our group at the University of California, Davis that we had the technology to determine the genetic defect. And that was almost I would say for 10 years, we were really the only two laboratories in the United States that have the interest and the technology to determine the genetic, what was the genetic cause of these syndromes.

But the challenge that we had at that time that only about half of the patients that we perform the genetic testing, we can determine the condition. There was a huge amount of patients with congenital myasthenic syndromes we cannot determine what they had was not only until the 2010 that next-generation sequencing became available for clinicians. And that made a tremendous difference in the field of congenital myasthenic syndrome.

There's a tremendous impact, just to tell you, and I think that in the past, we interacted about a patient with presynaptic congenital myasthenic syndrome. And at that time, before next-generation sequencing, we knew linkage to only one. And now we have 15 conditions that we know associated with presynaptic congenital myasthenic syndrome. So that made a tremendous impact. And I think that the next challenge is what we're really facing now is the treatment.

Yes. So maybe, Luc, do you have a comment on that?

Yes. Just in your experience, how long does that typical journey last for the patient to get the diagnosis. So the technologies have evolved, but from a patient journey, how -- what do you think that is?

Yes. No, I can echo what the patient mentioned that many of these patients, I would say, really even maybe patients with DOK7 syndromes as the children has been characterized as lazy that they really didn't want to practice. And some of them we were talking about some of my early patients that they were really punished at school because they were really -- they interpret as they were lazy that were not really wanted to do any physical activity and those sort of things.

And so there is a big range. You can see patients like that, that they have been a big, big journey without any diagnosis until -- and then in comparison, we have patients that we establish a diagnosis now with next-generation sequencing in months. It's born in three months after we have the diagnosis.

So I think we can also say it's underrecognized though, still even with the genetic testing available.

Very, very so. I mean there's a lot of patients and that the awareness of congenital myasthenic syndrome is not universal.

So maybe we can just turn quickly to treatments that are available currently. So can you talk a little bit about the limitations of treatments that are currently available for CMS patients?

Sure. And I think that this is really relevant to the introduction of this new therapy. And the treatment of congenital myasthenic syndrome is different from the one that we apply for autoimmune myasthenia. And autoimmune myasthenia gravis, we use immunosuppression and inhibitors of fetal receptors like efgartigimod. And -- but for continual myasthenic syndromes, the only strategy that we use is to increase the amount of acetylcholine. And we use very old medications, inhibitor of the cholinesterase in other words, acetylcholine is just taken back to what has been explained. Acetylcholine is being released and interact with the receptors. And once that interaction occurs, then the muscle is activated.

So -- but if there is a problem with the receptor or the problem with the aggregation of receptors, one way that we can correct that is by increasing the amount of acetylcholine. So one strategy that we use is to inhibit the enzyme that hydrolyzes acetylcholine. That strategy sounds like innovative, but it's nothing new, have been around for almost 100 years. It was developed by Mary Walker, a Scottish neurologist that established that medication inhibitor of the cholinesterase work in myasthenia and in congenital myasthenic syndromes.

The other strategy is to force the nerve to release more acetylcholine. And we do that by inhibiting another channels, potassium channels, and that increases the polarization time and forces the neuromuscular junction to release acetylcholine. So those are two things, and we tend to use those in presynaptic form of congenital myasthenic syndromes.

Now the problem with that is there are certain forms of congenital myasthenic syndromes that acetylcholine is not good. And in a long run, it produces more damages than good. Because there are two forces. I think that Dr. Burden has alluded to that. There is the acetylcholine and the forces that are acting to get the receptors aggregated, the nerve itself, agrin, MuSK, [indiscernible] MuSK and all of that.

But there are some forces that tend to disperse the receptor. So they're kind of counteracting. And acetylcholine, believe it or not, is one of those negative forces, right? So by treating patients with DOK7, LRP4, agrin, with these medications that are available now, we are really in the long run, producing more damage than good things, okay? So this is something that needs. It is a realization that we can little by little because patients initially, if you give an inhibitor of the cholinesterase or 3,4-diaminopyridine that releases more acetylcholine, they really like the medication because they have an immediate gratification. They have more strength. Then in the long run, it has a very negative impact.

So I'm so really so impressed and so related about this new way because it's the first time that we see something that goes away from that equation of increasing the amount of acetylcholine, because acetylcholine in this particular group of congenital myasthenic syndromes is not really good.

There is another group of -- there is a specific form, you know that, that is of congenital myasthenic syndrome, which is the deficiency of cholinesterase. There is a condition of a congenital myasthenic syndrome that results or is characterized by deficiency of the cholinesterase, okay?

So evidently, if you give more acetylcholine to a patient that doesn't have the enzyme to process the acetylcholine, those patients then get worse. Whether this medication will work in those patients, I do not know, but this is in the future, if we -- if you are thinking about expanding the...

Maybe something to think about in the future.

So maybe I'll turn to Rebecca now. So, Rebecca, have you -- so up to this point, you showed the data up through 12 weeks of the Phase Ib. Can you talk a little bit about what the team hopes to learn like from the rest of the data that's accumulating now?

Yes, yes. So one of the things we learned from the mouse model is, as Roeland showed, you dose the mice and then the activity, at least in terms of looking at how well the mice function on -- was the road around, right?

Yes.

Yes, yes. Going back from mouse to human, that it got -- it was sustained and their weight was sustained. So we believe, and as Roeland explained, the biology, if you activate the neuromuscular junction in these patients that the activity of the antibody may outlast the actual ability of us to develop -- to measure the antibody in the blood.

So we're very interested to see how long these patients maintain the level of function that we've seen them improve to. And then that will help us as we build on the plan for the next study.

Great. So maybe, Luc, now a question for you. So now as we think ahead to Phase III, like is there anything in particular that you would take from our learnings from Phase I and the relationships that we've established with Dr. Burden and Dr. Maselli and others as we plan for Phase III?

Yes. So the obvious one is science always leads, and we have been able to demonstrate that in a very particular model and that connection with the animal model is to me, that is a beautiful strong connection that we can also bring forward to the regulators in terms of plausibility that together with this is ultra rare, we shall forge a part a path where we're going to continue to have the focus on how do we demonstrate this in the most efficient way, the benefit so that a benefit risk assessment can be made by a regulator.

Now we need to negotiate that. And there have been recent pathways alluded to that might be an opportunity for this particular setting like the plausible mechanism and all those things, which here is evidently 100% present, and it is a severe disease.

So we're going to have this push to work in the argenx way, data-driven, science-based and learn from this that high-density measurements, digital measurements contribute to our understanding of the benefit.

Thank you. So I wish we had more time to have more questions, but I think we'll move on to the next segment. I think Roeland will be coming back up to speak to us.

So thank you, Dr. Maselli and Rebecca and Luc for joining us.

Well, that was interesting. So I guess you're all wondering now what is the opportunity for ARGX-119. You know that we're developing an ALS and SMA. So let's first recap that a little bit, and then I'll tell you more.

So ALS is this progressive motor neuron disease. It is characterized by the loss of motor learning from the muscle. And as you remember, ARGX-119 can slow down this denervation pathway. So there's a high unmet need and activation of MuSK by, for example, ARGX-119, slows down muscle denervation and improved motor function.

As Steve alluded to, he has shown in ALS mouse models that MuSK activation slows down the denervation and improves motor function. We took a slightly different approach. We took ALS patient-derived motor neurons. We culture these in a dish and let them innervate onto human muscle cells. Now in this kind of setting, we can use an electrical stimulus at the motor neuron and look at the muscle contractions on the other side. And in the ALS setting, the muscle contractions are reduced by 50%, showing the muscle weakness observed in patients. If you now give a therapeutic treatment with ARGX-119, these muscle contractions are fully restored, suggesting that the neuromuscular junction in that dish is fully functional again.

So I'm very excited that in the first half of 2026, we'll have this first top line readout in ALS patients. And we do this with the trials experts in the trial. So how did this trial look like again? Our Phase IIa trial is a dose-finding trial, but more importantly, it's a proof-of-concept study. We include all the typical ALS measures in the field, but we will look at how ARGX-119 functions in these patients. We will capture its mode of action by using a novel innovative endpoint that is called M-Scan. I'll explain that to you.

We will use M-Scan as a precision tool to quantify motor unit loss in ALS to really capture if ARGX-119 can slow down denervation. So M-Scan is a surface myography approach. It's a neurophysiology approach, where as you can see there in the M-Scan setup, you use stimulating electrodes on your wrist. Those stimulating electrodes will excite the full nerve bundle that is innervating in your muscle here and your tongue. We then record all the excitability from that muscle. What is then -- what can then be measured there? So you see there a recording from an ALS patient at baseline, you see this S-shaped curve and every dot there is a stimulus. So every dot represents an innervated neuromuscular junction.

From that kind of graph, we can measure several parameters, for example, the MUNE or motor unit estimates. That patient has, if I look right, 30 neuromuscular junctions innervated in its tongue muscle. You can also measure the maximum CMAP and CMAP is the compound muscle action potential, so the signal across the neuromuscular junction. If you -- if this patient waits now 7 -- after 7.5 months, you see this curve drop down, the signal across the neuromuscular junction is lower.

But also you see the MUNE here is only 8. That patient lost a significant amount of motor neurons over 7.5 months. You also see this step-wise staggering in the graph. That means that the remaining motor neurons have expanded because they need to compensate for all the loss of the other motor neurons. So MUNE or innervated motor units can be tracked over time. You see in the left graph below the progression rate over time. So we will have a 24-week study. There's a significant decline after six months. We hope to see with the treatment of ARGX-119 that the slope has a positive deflection. More interestingly, this biomarker can be used as a kind of prediction for clinical outcome as there is a correlation with the clinical outcome scores in ALS, for example, the ALSFRS-R score. So a positive effect on M-Scan can result in a beneficial effect in the clinic.

SMA, you all know spinal muscular atrophy. It's affected in children. It's very severe. It's characterized by neuromuscular weakness and motor impairment. You probably think there was this massive breakthrough with SMN upregulating therapies and the disease is cured. It's not. It was a great breakthrough. These patients don't die anymore. But in partnership with Cure SMA, they reported that patients are still feeling weak. They want to improve in muscle strength in motor function and they want to reduce their muscle fatigability.

If you look at the science, that all comes back to a defective neuromuscular junction. There are several publications show that even on these SMN upregulating treatments, they have reduced neuromuscular junction maturity and transmission defects remain. So we hypothesized that activating argenx -- activating MuSK with ARGX-119 can mature these neuromuscular junctions and improve the transmission.

So together with the SMA Foundation, we've conducted mouse experiments. We've used the SMA delta 7 model, the very severe model. We gave them SMN upregulating therapies and looked how well they can use their muscles. We've measured the muscle force in a specific muscle. And as you can see on the graph there, the black line is the muscle force in these mice that were treated with SMN upregulating treatments, it's still very weak.

With ARGX-119 treatment on top of that, you fully rescue the force in these mice. Interestingly, we've seen that the increase in muscle force preceded the increases in muscle weight, suggesting that muscle function might be more important than muscle size. So we're going to initiate a Phase II study pretty soon.

So ARGX-119 and what other diseases can it work? We think it can really be a pipeline and a product. As you know, we've discussed these two modes of action. In the blue there, it can really increase the clustering of acetylcholine receptors and increase transmission across the synapse. That's applicable in neuromuscular junction diseases like we've shown in CMS. You could think beyond that. That's also applicable in muscle diseases, muscle dystrophies, muscle myopathies.

The second mode of action, this retrograde signal, keeping the neuromuscular junction together, restructuring that is very applicable in motor neuron diseases like ALS and SMA and others, but also in peripheral neuropathies. So we're doing all that work now and more to come soon.

So currently, this is the path forward for ARGX-119. I'm very proud that we've shown the proof of biology in our Phase Ib trial, and we're going to get ARGX-119 to patients as fast as possible with a straight to Phase III approach. In ALS, we have this exciting data readout in the first half of 2026, and the M-Scan data set something -- will be something to look forward to. In SMA, we already have a name for our study. It's called SPARKLE, and it's going to initiate soon, and that will actually broaden the age range from adults going to pediatrics.

So with that, I hope we've given you a lot to think about. And therefore, we're going to have Tim on the stage for some closing remarks.

First of all, welcome to the company. Here, you're in the belly of the beast. So whenever we meet you in your offices, you want to hear about IIP and we get lots of interest in IIP. I think today, you saw IIP alive. I could not think of a better example to show you today live with our trusted collaborators, how really IIP works.

I'm very proud today that you gave us the time to talk about science because it always starts with the science. I don't know how you feel about the patient which we saw, but I'm deeply impressed by the patient, so weak and still so strong. And then IIP being the formula of connecting deep science with that fundamental patient needs and trying to create the innovation, which, frankly speaking, is our raison d'être, the reason of existence. The only reason we exist as a company is because this is the type of work which we're doing with your full support over these past years.

What I would like to do now is get into Q&A. We have the huge advantage of having Steve here, having Ricardo here. Thanks again, guys, for joining us today. But this is your opportunity to get into the questions you may still have after this session. We will reserve the questions only for our investors and analysts. Employees can hold the questions for the reception, okay?

So why don't we start. Yaron, thank you for kicking off.

Good afternoon. Thank you so much for hosting this event. I'm Danielle Brill from Truist Securities. I guess my question is pertaining to the CMS trial. From my understanding, CMS symptoms fluctuate. They can wax and wane at different times. Can you contextualize for us what impact this might have on metrics like 6-minute walk distance and what risk that may pose to a Phase III?

Thank you for the question. But unlike autoimmune, MG, you don't really have the waxing and waning. I think what we tried to say with the natural history study is that when we started to study these patients over certain periods, they were pretty stable.

And I would like to give the floor to Luc to maybe give a bit more color to what that natural history study has actually shown in terms of the stability of these patients because it is a key question you're actually touching on. Luc?

But you already gave the answer. No, that was a remarkable part that, by and large, they stay quite stable, which is why one of the other reasons we thought this could be useful is to show that inflection point, right? So you have a certain so before and then after treatment. But they were within the confines of that natural history what we measure, quite stable. Was there variability between patients? Yes, of course.

Maybe a couple of questions. Yaron Werber from TD Cowen. Maybe the first one, I don't know, Luc, if you want to take it or somebody else. In the Phase Ib, did you look at 6-minute walk test? And can you share with us kind of what that data showed?

And as you think about sort of powering the Phase II based on the natural history, what's -- it sounds that patients are stable in 6-minute walk, so you're looking for a net gain from baseline. You're not looking for -- you're not expecting deterioration in placebo.

And then maybe for one of the KOLs, what percentage of patients have postsynaptic CMS of the overall syndrome that you're targeting? And how many patients are there in the U.S.

That's a four-part question, I think. So the 6-minute walk test you saw, it's definitely not stable, and it's actually our biggest signal we have of the effect with the effect being of a clinically relevant size. So within the natural history study, we wish we had had 6-minute walk test, so we would have that comparison, but we didn't do that because -- well, we just didn't do it, okay? And in -- and I'm being told in the amendment, we are adding it. So -- that was actually the most encouraging part.

And for me, but this, Rebecca, you actually beautifully show this, the connection with cadence also going up, right? So these patients upped their speed of walking also, not further, but within the distance also faster. So we found that as a pretty compelling that something is happening in one of the most affected limbs.

Yes. And thank you, Luc. So a lot to unpack and pioneer in CMS, big learnings is this is a limb-girdle phenotype, weakness in arms, legs, and head that translates into that walking test that translates into that cadence of step. And I think we're very well equipped with this data set to now actually go and meet with the regulators and discuss what suitable endpoints could be in the registrational trial. Your other question is also very relevant. Maybe Steve, do you want to address the question or Ricardo, what percentage of all these congenital myasthenic syndrome patients would actually qualify for the MuSK agonist therapy.

Well, if I understood the question correctly, the question was congenital myasthenic syndromes, what is the proportion of postsynaptic patients. And that is actually is a majority of patients with CMS, they have postsynaptic defects because defects of the genes that encode the subunits of the receptors and rapsyn and Steve alluded to rapsyn, those two molecules -- well, five molecules, four subunits of the acetylcholine receptor and rapsyn, those are the most common. Actually, it's more than 50%, I will say, 60% of the patients resolve from that.

Now if the question refers to do DOK7, specifically DOK7 as agrin MuSK and LRP4 has a two component, the pre- and the postsynaptic component. We know a lot about a postsynaptic component because the technology that we have is suited to study that, but there is a lot of questions about the presynaptic component and I was so glad that Steve was mentioning that they are really focusing on that because this is really very, very important.

And I can tell you, the more severely affected patients with CMS doing the microelectrode recordings are the one that has a very severe presynaptic component. So in answer to your question, yes, they have the two components, the postsynaptic and presynaptic component, postsynaptic is by far the most common.

Steve, anything you want to add to that?

Mostly just a similar view. I think about -- my guess is about 25%, 30% of patients have mutations in DOK7 and a similar number in rapsyn. And so as you say, adds up to more than 50% of the patients. We've started to look at mouse models of mutations in rapsyn and COLQ, which is the attachment protein for the cholinesterase that Ricardo mentioned. And it looks like from our preliminary phase that a mouse model of congenital myasthenia caused by mutations in agrin might be rescued by the agonist antibody as well.

And again, anything that's upstream from us, it acts to activate MuSK you might expect would be treatable by the agonist antibody. So the first evidence of the mouse model in agrin is that, that works. We've looked at a no mutation in COLQ, so there's no COLQ at all. And that looked like it wasn't affected. And that was consistent with the way we were thinking. And again, with rapsyn, which is downstream, again we've looked at a no mutation, so there's no rapsyn and that looks like it wasn't rescued by the agonist. So that's kind of what -- that fits with the biology.

Which is logical if you understand the biology, right?

Which would suggest still leaves open the possibility of the patients with mutations in LRP4 and mutations in MuSK could be, so it had the potential of being treatable with the agonist antibody.

But ballpark, roughly based on what we know today, 50%. Yes.

Leland Gershell from Oppenheimer. I want to ask just in terms of dose, do you have clear visibility on dose entering the Phase III in CMS. If you could remind us in the Phase Ib was that ascending dose or different doses? I ask because at some point, you start to see an inverse dose response from -- given the dimerization mechanism.

Thank you for the question. And maybe, Luc you want to comment on the key question on dose finding and how we went about it.

Yes. Again, so we're in a situation where the classical paradigm of placebo, low, mid, high dose really wasn't feasible in a reasonable amount of time in our sense of urgency that made us say, we can get to this information with intrapatient dosing and some very clever modeling. And so we have a PK/PD model that gets at the exposure response relationship from which we will select a dose for the Phase III. Again, in conversation with the agency, they will have something to say about this as well.

And it goes back, Luc, if I can say that to have an innovation mission and the way we design innovative clinical trials, based on that intra-patient dose escalation with that exposure model, we can really triangulate what exposure we think we need in order to fully activate MuSK and have the maximum benefit from a functional point of view.

Okay. And then just secondly, I know you've been focused on DOK7. Is there any opportunity for use outside of DOK7 CMS based on biology or would that require different strategy?

So I think that's what Steve said. So basically, in that pathway, anything which is leading up to MuSK activation and which has a defect could be overcome by forcing the activation of the antibody. Thanks for the question.

Tazeen Ahmad from Bank of America. I wanted to get a sense about how you're thinking about additional indications. So you obviously are moving forward with CMS. You've talked about moving potentially in many directions, but you've highlighted SMA and ALS specifically today. What is the sense of confidence sort of that path that's leading you to highlight those two because there are other therapies available right now for those. And historically, argenx tries to go where there's a big opportunity, but not necessarily too crowded. So would love to hear your thoughts on that.

Second, have you had any initial conversations with FDA regarding the path forward. You talked about all the innovative ways you've tried to collect data. but I think it's standard protocol now to ask how conversations are going with agencies and level of confidence in what they're telling you. And then lastly, when could study for SMA that you're starting yield data?

Three great questions. I will try to quickly address them because we're short in time. So unmet medical need and ALS, we don't need to elaborate. I mean that's obvious, that's a pretty high-risk indication to venture into and that's why we really wanted to show you that precision instrument we're using to venture into ALS and really get a clear cut answer, so whether we move the needle on the biology, yes or no, based on this, you would advance in your clinical development.

So I think that's a reasonable derisking. And I think that's a responsible use of capital to do it, strong belief in biology, clear way of measuring effect, but we need to do the experiment. If you move the needle, even if you're just slowing down disease, I think for ALS patients, that would be big.

We have never seen a clinical trial, which enrolled so fast as the ALS trial. [indiscernible] maybe did a lot of work with the specialists and with patients because indeed, from the outside, it looks like in SMA, the unmet medical need has been mainly satisfied. That doesn't happen to be true. There's a ton of function which still needs to be regained from a muscle point of view.

So we're really looking at the mechanism of action, which can be additive or maybe even synergistic to the therapies out there. So we don't seek to compete with them. We seek to complement them and further regain muscle function. And then to your last question, we're leading up to an interaction with the regulators. I think we're very well equipped with data. But let us talk about an interaction after we've had it. And I get a signal here that Steve, you would like to add to the comments.

Yes. Just to clarify, for ALS, the idea is that in ALS, as many people don't appreciate the earliest first step in the disease before motor neurons die is that nerve terminals withdraw, and it detach from the muscle. So it's that phase, the early phase of the disease, which is sufficient to cause the paralysis that we're trying to address with the MuSK agonist antibody.

We're not trying to save motor neurons. We're trying to keep the nerve attached to the muscles so it can function. And in mouse models, if you play genetic tricks and keep the neurons alive so they do not die, but the synapse still detach, the phenotype is the same. So it's a very important feature of the disease.

Thank you, Steve. Maybe we go to the final question of the session.

Yes. Patrick Culliton, Stifel. I know you've shown at least preclinically that 119 doesn't interfere with the agrin pathway. But is there any evidence that chronic MuSK activation could result in some sort of down regulation of the agrin-LRP4 pathway? And then -- just considering that? And maybe just more broadly, how are you guys thinking about dosing and maintenance treatment with 119.

Two great questions. Roeland, do you want to comment on the longer-term DOK7 studies, which we have been doing in the run-up to the Phase Ib study.

Yes. So we've done sign-off studies and a 26-week tox study at very high doses, very frequent dosing. And there, we have not picked up anything suggesting that the molecule even with chronic dosing is safe.

Yes. And then on the second question, the durability of the effect is, of course, speculation, but it's being studied in the OLE based on the suggestion of the mass data, right?

Yes, correct. So the patients after 12 weeks stop dosing, then the PK will go down, as you know, it has a half-life of about 30 days. That's why it's a 7.5 month follow-up so that the PK is fully down. And if we then see still function remaining that will give us a massive insight into further development of the dosing strategy, yes.

Maybe the final question.

Delma Caiati from Guggenheim. Thank you for this great event, really insightful. So Dr. Maselli was making a very interesting point about some subtypes not responding to acetylcholinesterase inhibitors. How well is that understood? Like is it associated to specific genetic subtype first and what is the mechanism underlying that? Is it associated to the down regulation of the muscarinic receptor -- to the acetylcholinesterase receptors themselves? And is there any risk that activating MuSK can over long term lead to a similar risk, similar effect? That's the first question. And then if I may, on SMA. For the study, are you targeting both type 2 and type 3 patients?

Two great questions. I'm so happy we have the experts here to answer question #1.

Yes, I will take only the first one because I don't -- so yes, there is a condition that is actually the first congenital myasthenic syndrome described completely 50 years ago by Dr. Engel was deficiency of cholinesterase, in other words, you don't have the cholinesterase, as it turned out it is not due to a defect of the gene of the cholinesterase but the gene that holds the cholinesterase at the end plate. And that gene is called COLQ, okay? So the deficiency of COLQ is a very well-established congenital myasthenic syndrome that evidently doesn't respond to inhibitor of the acetylcholinesterase because they don't have acetylcholinesterase to start with.

So this is a condition that is being treated, and there is a well-established linkage to a gene defect, but the other condition that Steve mentioned, LRP4, agrin, MuSK and DOK7, those do not respond to -- the only medication that we have available is salbutamol. Salbutamol is a medication -- it's not an approved medication, but it's a medication that is effective. We actually don't know exactly the mechanism how those patients respond, but this is the only medication that is available. So I don't have any comments about the other component.

Thank you so much, Ricardo. We need to be respectful all of time. We're going to close the formal session here today. The experts are here in this section. We have drinks, so what I would suggest we do next is we close the formal session. We go into the mix and mingle, and you really use the opportunity to talk to the experts and continue with Q&A, okay? Thank you so much.

Good morning. Welcome to Morgan Stanley's Global Healthcare Conference. I'm Sean Laaman, Head of SMID-cap Biotech Equity Research here at the firm. Before we proceed further, for important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures. And if you have any questions, please reach out to your Morgan Stanley sales representative.

For this session, we have from argenx, a pleasure to host the CFO, Karl Gubitz. So welcome, and thank you for your time today, Karl. And maybe just to kick off proceedings, I'll get a few minutes from you just to set the scene. We'll have some macro-type questions, and then we'll go into the guts of it. So welcome, Karl. Thank you.

Thank you. Thank you, Sean. Good morning, everybody. Bright and early. It's a real pleasure to be here. At argenx, we are on an innovation mission. We know that is the only reason we exist. Patients are waiting. In doing this, we set ourselves very ambitious targets at the beginning of the year and when we go out and execute on those. Biotechs many times falter at execution. At argenx, it is one of our core strengths. For this year, our targets were, firstly, commercial execution. I think our Q2 revenues, product net sales of $949 million answered that question. We are doing really well.

On the clinical side, in the first half of the year, we had 2 targets. CIDP CHMP approval, we've done that. And the second one, which was really important was the PFS launch in April. Again, we achieved that. In the second half of the year, we started off with a Phase I data in CMS, congenital myasthenic syndrome, which was successful. Very important, the Phase III seronegative data, where we achieved the primary endpoint, clinically meaningful results in all 3 subtypes. And then later this year, we still -- we are on track to do efgartigimod, lupus nephritis study, empa study in delayed graft function and one Phase I study on track.

And then as the CFO, I'm very proud to say that we've achieved profitability at the end of last year. And now we have revenue growth outpacing OpEx growth, generating profitable margin, increasing quarter-over-quarter with free cash flows increasing quarter-over-quarter.

Sorry, that's a long introduction, but thank you for the opportunity.

No, that's wonderful. Maybe just to jump sideways a little bit before we go back to the central discussion. But we've been spending quite a bit of time thinking about China and the rise in biotech innovation that is going on in that country. And how do you think about argenx competitive position here? And does it influence your R&D and your business development strategies?

Yes. In China, we use Zai Labs as a partner. And by the way, Zai Lab is doing a really good job for us. They commercialize VYVGART. They also run Phase II proof-of-concept studies and also contribute patients to our Phase III studies. Of course, we are always on the hunt for novel biology. We take a global approach. Our discovery and business development teams are focused on this and of course, also on China.

I think what is now differentiated by China is the speed and efficiency they can do clinical study. And secondly, I think the biotech boom in China is disruptive. And as a company, we are evaluating and putting in plans to capitalize on that.

Wonderful. Another big topic of ours is AI. We're starting to publish a regular piece on that called [ looking for my mom ], the maximally optimized molecule. We thinking really long term. But how are you currently leveraging AI or thinking about AI's future disruption potential?

As a company, we are, of course, on a journey. The journey starts with isolated pilots and when we shift to end-to-end transformation, leveraging AI across commercial, R&D and of course, the corporate functions. We have a dedicated team focusing on this and collaboration is in our DNA. So therefore, we also have a strategic partnership with one of, I would say, best-in-class companies where we explore to put in place a vendor-agnostic platform to capitalize on this.

And I think areas we're focusing on is, first of all, on productivity and efficiencies, then quality and risk management. And I think then where we also need to get to is using AI to do our studies cheaper and quicker.

Wonderful. One more macro-type question before we get on to the real guts of the business and I guess, what most people really here for. But what has been the most impactful topic on argenx on the regulatory side? Would it be from changes to the FDA? Would it be potentially MFN or tariffs?

I think across all 3 of those, I mean, we pay a lot of attention to it. On the regulatory side, I will just say that our interactions with the FDA continue to be positive. There's continuous interactions, and it's all fine from the company's perspective. On tariffs, we do manufacture in the U.S. already. So I think there's -- we should be in a good position to mitigate against that. And with MFN, I think it's very difficult to comment. Our strategy is really focusing on pricing in a narrow band. And I think if we're executing on those strategies, we're in the best possible situation to navigate that going forward.

Wonderful. And we'll steer right back on to argenx, but thank you for that, Karl.

Now turning to your pipeline. Can you provide an overview of the key milestones expected from, I think, there's 6 Phase III and 6 Phase II trials that you've got coming up over the next 18 months?

Yes. I think if I can focus on the Phase IIIs, we also have a couple of Phase IIs and a Phase I, which is also, of course, very important. But for a company of our size, to have 5 Phase IIIs reading out, let's say the next year. That is significant. We have one Phase III in empa, that's our C2 sweeper in MMN, multifocused motor neuropathy. You've seen the Phase II data. This is going to be -- I think this is really important for us because we need to show the Street that what we've done with VYVGART, which is a transformational drug is repeatable and scalable, and we want to show you that with empa, our second drug.

And then with efgartigimod, where we have TED, we have myositis. And of course, we have ITP, which, of course, are all really big opportunities. And the first up will be the ocular study in the beginning of next year.

Wonderful. And I guess next question, thinking about those market opportunities. Maybe just help investors size it against the current opportunities that we've got in myasthenia gravis and CIDP.

Yes. So I think the first one, of course, is, as I said, seronegative. Think of that as label expanding for MG, which I think is really important to help us maintain that impressive growth curve for MG. But if you then think about myositis and TED, in my mind, think of it as MG-like opportunities. Myositis has got the 3 subsets and 2 of those subsets, IMNM and ACIs, there really is no options for patients. The unmet need there is significant. We can be transformational.

In dermomyositis, yes, there's IVIg, but I think we all know that we can take on IVIg, and I think we can also really be beneficial for patients, a really big opportunity. And TED, yes, Tepezza is a very successful drug, but I think there's a place for class-to-class differentiated where we, with our drug, which is rapid response, clinically differentiated and then with our safety profile could be really transformational. MG-like opportunities in all of those.

Wonderful. I have a question here about empasiprubart, but maybe for those less familiar with your stock, what is empasiprubart? And how do you think about the opportunity in MMN and CIDP compared to VYVGART?

Yes. As I said earlier, empasiprubart is a C2 sweeper. For us, it's really important that we replicate VYVGART. So we're currently in 2 Phase IIs and 2 Phase IIIs with empa. empa, the first one is in multifocal motor neuropathy. The Phase II data, which we disclosed last year at the R&D Day, is truly transformational. I think that opportunity, call it, around 10,000 patients in the top 5 markets. They are very heavy users of IVIg. It's about $1 billion market. And in our study, we take on IVIg head on. So if we can replicate the Phase II, what we've done in Phase II, I think there's a significant opportunity. Then we're also in CIDP and then we're in 2 Phase IIs, delayed graft function and dermatomyositis.

Wonderful. And if empasi is indeed successful in CIDP, how do you think it coexists in that CIDP market with VYVGART?

I think the data should speak. We are, at this stage, not trying to niche empa. What we know from our VYVGART study is that 70% of the patients responded in Phase A of [ TR ] study. So I think there is -- what happens in the other 30% of the patients, I think we need to do the study. We are not niching empa in the study. So we don't position it as VYVGART refractory. We're going to do the study. We'll let the data speak, and then we'll get to it.

Can I just take a bit of a temperature check on how much inbound you may get from investors on empasi? Do you think it's a relatively undiscovered piece of the argenx story or...

Absolutely. Yes, absolutely. I think -- I'm sure we'll talk about it more later. But if we look at the valuation today, it is really only VYVGART and even for VYVGART, it's only MG and CIDP. Very little focus on the other indications and very little focus on the other assets in the pipeline and empa gets -- if I look at the valuation from the Street, you see very little value for empa.

Wonderful. Thank you, Karl. And I guess getting back on to VYVGART and the CIDP story. There was some [ further ] step in the stock on the back of the Q1 result. And maybe talk to us on what we thought were pretty strong CIDP patient numbers at Q2 at 2,500. Maybe give us a bit of a flavor of how you see the launch trajectory going on from here and maybe remind investors why not -- why the decision to not provide patient numbers back in Q1?

Yes. We're not going to provide patient numbers every quarter. I think we're going to provide patient numbers when we exceed certain thresholds. I think the revenue number should really speak, and we want to get out of a detailed quarterly focus. I think we can focus on the long term here.

In terms of CIDP patients, yes, the 2,500 patients at the end of Q2 is a global number. Clearly, that's largely U.S., but it also includes a handful of German patients because we launched just before the end of the quarter and Japanese patients because in Japan, we launched in January, and we had a really strong launch. But I think the way to look at it is that in the U.S. alone, there are 40,000 diagnosed CIDP patients, 24,000 of them are being treated. 12,000 of those patients are the patients which are not adequately treated with standard of care and whether it's from efficacy or tolerability issues. And so therefore, the -- call it, 2,500 of which the majority is U.S. patients is a very small number in that journey, and that is just refractory patients. My point is 4 quarters into the launch, it's still very early days, and there's a lot of growth ahead of us with CIDP.

Sure. And on the refractory patient angle, do you see some developments where VYVGART might become standard of care? What should we think about for that to happen?

I think with all launches, especially in rare disease, you start with a refractory patient. Those are the patients that the doc gives you because there's nothing else available for that patient. And over time, you move up into the treatment paradigm. That's exactly what we see with MG today. But with CIDP, I think it will take a long time. It will take a few quarters, maybe a few years to get there.

There's also a payer hurdle. Not all but most payer policies do require you to step through Ig around 85% of our patients today do have Ig experience. But ultimately, Sean, you're right. Longer term, I think the drug has the potential to move up in the treatment paradigm.