argenx SE (ARGX) Earnings Call Transcript & Summary

Ladies and gentlemen, please welcome, Beth DelGiacco.

Hi. Welcome to the 2024 argenx R&D Day. Thank you for coming. Especially, I know there's more temperate places to be than New York City in July, when it's 100 degrees. So we appreciate the effort. We have the AC pumping in here. We're going to keep the room cool. We have cool content on stage. It's going to be a worthwhile 3 hours. We're going to be making forward-looking statements today. I also just want to take a quick opportunity to welcome everyone who's tuning into the webcast, especially our colleagues, many of them are tuning in globally. So the last time we had in R&D Day in person was 2019, and I remember very clearly, Keith stood on stage and he committed to launch after launch after launch. And this is before we even had Phase III data. So it was a pretty ambitious plan, and I'm really happy to be here on the other side of that today. Briefly on the agenda. We have -- in addition to the prepared remarks, we have 2 KOL panels, one for Sjogren's and one for MMN. We have 2 Q&A sessions. One is before a quick coffee break and then one at the end of the event. And we also -- you might see around the room and out in the foyer there, our digital poster setups. And we encourage you during the break after the event to really spend time with our scientists who are here, clinical development, discovery teams looking at some of those posters. Here is the argenx team that's here today. You know Tim and Karen and Luc and Peter. But importantly, this is an R&D day. We're here to talk about our discovery engine, our clinical development engine. And I'm so excited that we have colleagues joining us who are really close to that innovation mission. We have Karen Silence, who is our Head of Preclinical Product Development. She's been at the company for -- since its founding, so almost 16 years. And she is really the force behind almost every single molecule in our pipeline. So really grateful to have her here today. We also have 3 of our clinical scientists, Julie Jacobs for Sjogren's; Inge Van de Walle for MMN; and Leentje de Ceuninck for myositis. And we have our Head of Clinical Development for our Neuromuscular franchise, Dr. Jeff Guptill. Before he joined argenx, he was a practicing neurologist, treating MG, CIDP and MMN. We also have 2 external speakers here who will join the panels. Dr. Simon Bowman, who is from the University of Birmingham, he's a thought leader in Sjogren's; and Dr. Patrick Kwon from NYU. Dr. Kwon treats MG, CIDP, MMN. And importantly, he is a VYVGART prescriber in MG, and he notified me as of yesterday, also in CIDP. So I really want to talk about -- today, we're going to get pretty technical on the science on some of the clinical development. So I want to focus on some key themes that you should leave remembering. And it all starts -- a core theme today is our innovation model. And this emerged from our founding story. Tim is going to talk about that. And it exists today as our immunology innovation program. I think you know it well. We like novel targets. We develop them in collaboration with disease biologists, and we bring differentiated antibodies to patients, but it also exists in every corner of our company. I think the best example of this is our leadership in FcRn. The blueprint that we built around FcRn development is now taken through every other molecule. We had a novel target. We developed it with a pioneer of FcRn science. We've built a really thoughtful antibody. We talk about the fragment, the ABDEG and it's now in 10,000 patients globally. We are going to take this model and now, we recognize the opportunity for FcRn. And we recognize that we want multiple FcRn antagonists in development. You're going to learn about the first one today, ARGX-213. We've also taken the attributes of efgartigimod and created an antibody engineering platform out of it. A platform of [ sweet ] being antibodies, you're going to learn about the first one today, ARGX-121, which targets IgA. Another core theme for today is going to be our leadership in MG. I think we're really setting a new standard in -- with our evidence generation in MG, and we expect to do the same in CIDP. Karen is going to talk about how this is translating commercially. A little bit on CIDP. Very early days, but a lot on MG. We've talked about we think this is a bigger market than we initially thought. We're going to give you a number around that, and we're going to talk about how we're going to reach those patients. One of the ways is through label expansions. You know about our CR-negative study. But we're also going to talk about our decision to go into ocular MG, which is the 15% of the MG market, and that really gives an opportunity for some near-term revenue. When we asked you about what you wanted to hear at the R&D Day, we talked about -- you mentioned a next wave of indication. So we're going to talk about our Sjogren's data, the Rho data. our MMN data, the ARDA data and also bring the biology rationale and the trial design for myositis back to life here and prepare everyone for that Go/No Go the second half of the year. We're going to be building weight behind [indiscernible]. This is no longer my molecule on the back burner. This is a Phase III asset that has shown transformational data. We're going to talk about MMN but also DGF, DM, and we're going to announce our fourth indication today, which is CIDP. We think that there's enough of an opportunity here that we want to have 2 molecules. And then all of this taken together, I mean, if you think about discovery, development, commercial, you fast forward progress across each that brings us to our Vision 2030, and that, Tim is going to roll out now. So please welcome our CEO to the stage. Tim Van Hauwermeiren.

Thank you, Beth, and a very warm welcome to all of you. It's good to be back together here face-to-face in New York. Our vision for 2030 is a bold vision. It basically stands on 3 legs. We want to reach globally 50,000 patients with argenx products; we want to reach them through at least 10 labeled indications for our products; and we want to create a continuum of innovation where we promise 5 new molecules in Phase III by 2030. It's a bold mission, but it goes back to the strong foundational DNA of this company. Let me take you back to 2008 when we cofounded the company, Hans, Torsten and myself out of an entrepreneurial spirit, all born out of the immunology innovation that the llama immune system is actually producing fully human antibodies with an incredible diversity, a very exciting start to build this company. But we were also in the storm of the Lehman Brothers' downfall. It was extremely difficult to raise money as a biotech start-up company out of Europe, and the only way we made it was through co-creation as a team and co-creation with our immediate environment around us, supporting this early venture. And boy, did we know the value of EUR 1 when we raised EUR 1 million to support a very aggressive business plan for the next 12 months. So the sharp focus on execution was born there and is still very much alive in the company. The way we go about building this company is we want to go for new biology. We think as biotech entrepreneurs, this is a very exciting time to live in. Our understanding of human immunology is growing exponentially. And we don't want to be a [indiscernible] of company, which is creating another tool -- another hammer to hit on the same old nails of CD3, CD20, CD19, HER2, HER3, we think this world badly needs novel targets. That's what we're going after. We're going to unpack an incredible opportunity, which consists of novel biology. Now I can hear you say, "Tim, it's a risky endeavor," going for novel biology that's very risky, but we have developed an innovation playbook on exactly how to do that. First of all, we are hunting for really important novel targets, not random targets but master switches in the immune system of humans, foundational immune targets. We found them typically in economic labs, and I will talk about it in a second. Once we embrace risk on the biology side, we're not taking a lot of risk on the drug format site. We work with the tried and trusted antibodies. And by the way, guys, antibodies continue to rejuvenate themselves. There's a ton of innovation going on in antibodies. And actually, what we can do today with antibodies is not even something we could dream of 10 or 20 years ago, and you will get a flavor of that today when Karen will be on the podium. And because we go after these master switches, these foundational targets, we eliminate binary risks. We do not like binary risks. We like targets, which can play across multiple indications such that if the molecule is a win, we can create real economies of scale. Let's unpack the co-creation formula. Novel biology, unraveling novel targets is hard, and the collaborators we work with sometimes spend 10, 15, 20 or more years of their life, just understanding a single pathway, the single target. That time line is not compatible with the biotech company. We're good antibody engineers. We're not good in unraveling novel biology. So we team up true co-creation with these translational labs, and that's where the magic happens. When we seek their academic research with our diverse antibody panels, when we jointly think about antibodies going after these novel targets and trying to make real exciting drug products, that's where the magic of co-creation happens. And the definition of co-creation is very simple. It goes back to the principle that 2 parties meet and jointly create something, which none of them could create stand-alone. It's a form with a good track record. We have built 12 pipeline assets, 8 out of the 12 demonstrated pretty exciting data in humans. Nine were first-in-class targets. Unfortunately, 5 had to be partnered on the journey to where we are today, not something we will repeat. And these 12 molecules actually can play across more than 35 indications. Co-creation is such a powerful formula that it found its way from the lab into every corner of the company. We co-create with physicians and patients when we design clinical trials. Who would ever think about individualizing the dosing of an MG patient in a registrational trial? That was the explicit request of patients, and we listen to patients. The CIDP trial design is now copied by so many people because it's setting a whole new standard, simply by working with the community and listening and learning from patients. We co-create with patients in these virtual universes like MG United, shining through CIDP. When we make new product presentations, new formulations, it's everywhere in this company. I'm confident that we're going to deliver on the 2030 vision, which is a bold one because whenever standing on this podium in 2019, declaring the vision for 2025, my team has delivered. We have delivered on every aspect of the 2025 vision. Let's take a look. First of all, the VYVGART launch is in good company, providing history in terms of launching a rare disease drug in the universe of autoimmunity. VYVGART acquired blockbuster status before it hit its second year of launch. It's already approved in 3 indications globally and it's already the market leader of all branded innovative biologics LNG. Now in order to stay up there in that class of outstanding drugs, we need to add more indications. Here are the 15 indications we promised for VYVGART. Ocular MG is the one I want to call out today. I'm very proud of the fact that we're going into Ocular MG next to [indiscernible] MG. Empasiprubart is now already in 4 indications. I'm very proud to say that we ventured into a Phase III registrational trial in CIDP for empa and -119 is coming on deck with 2 important clinical trials, the one in congenital myasthenic syndrome and one in ALS. And then we have 4 IND candidates we're talking about today, which are all racing towards the clinic, aiming to be in the clinic before the end of next year. I'm very proud of the way we reached patients. I know Keith is somewhere in the audience, but Keith, thank you, man, for reaching more than 10,000 patients globally. The launch of VYVGART span 3 continents in less than 12 calendar months. Can it be even better? With 8 months, we reached patients in 3 continents with VYVGART Hytrulo. That is the commitment, which we have made to patients. We stayed loyal to our scientific routes. Science is still the language of the company, from A to Z, from end to end. Of course, there's the language in the lab, but when we're in the marketplace, we talk about science and we talk about data. No bulls****. We're also sharing the science to an extensive patent portfolio and through our top-notch publications, which we typically go offer with our academic collaborators. For the shareholders, all of you here today. Since the Euronext IPO, which we celebrated a few days ago its tenth anniversary, since the IPO on Euronext in 2014, we generated a total shareholder return of 5,000%. And of the $5.6 billion we raised, we still have $3.1 billion in the bank. So back to the vision of 2030. Let's unpack this vision. 5 new molecules in Phase III by 2030, 10 labeled indications and 50,000 patients. How are we going to do that? Let's look at our innovation horizons. Today, we only talk about 4 IND candidates underway to the clinic, but boy, there's much more cooking in the IIP kitchen, and there are more molecules underway to the clinic than we will be talking about today. So I'm confident we're going to make 5 molecules in Phase III by 2030. 10 labeled indications. They will come from in-market expansion as well as a next wave of potential launches. In market expansion, we already have 3 indications approved with MG, ITP and CIDP. We're adding seronegative MG and ocular MG. That's a substantial addition to the label, and Karen will talk about it. And then we have a bunch of late-stage clinical trials and mid-stage clinical trials where I think we have a very high chance of success. So I'm confident in our ability to reach 10 label indications by 2030. But last but not least, to patients. Innovation has no meaning unless it's reaching patients globally and providing a real benefit. That's why the Vision 2030 is not about dollars. That's why it's about numbers of patients we try to reach, 50,000. Now when all of this is coming together, and we will be executing on our 2030 vision, this is the company we're going to build. It will be a continuum of innovation from early-stage pipeline to late-stage pipeline to commercial. Thank you for your attention in this introduction. I would now like to hand over the floor to my colleague, Chief Scientific Officer, Peter Ulrichts, who's going to talk to us about the blueprint for innovation. Thank you.

Thank you, Tim. And I would like to start again with a slide Tim already shared, our blueprint for innovation. And why is that? It's because it's so intimately related to how we bring new molecules into our portfolio, working shoulder to shoulder with academic experts to unravel new targets, new disease biology, combining that with our best in-field antibody engineering capabilities to come up with differentiated first-in-class antibodies. And by virtue of the foundational character of these new targets, we're able to develop these antibodies in a pipeline, in a product fashion. In the next couple of slides, I'm going to show you how we lift that co-creation model for our clinical stage assets, ARGX-113 or efgartigimod, ARGX-117 Empasiprubart and ARGX-119. And let's start off with ARGX-117. We work together with disease experts in the University of Utrecht who really helped us to understand that C2 is uniquely positioned within the complement cascade. We invest a lot in translational research learning, for instance, that MMN is an IgM-mediated disease. We made a hell of a molecule, a very potent sweeper of C2 with a very long half-life. And as Tim already mentioned, we are developing the molecule currently in 4 different indications, with the intention to do even more. We will talk a little bit more on the MMN of concept data later today. What we like to do with all of our assets is building something, which we call an innovation ecosystem. What does it mean? We heavily invest in an external network of experts. And that gives us the opportunity to develop an extensive tool kit, which is allowing us to understand the pathway, understands the effect that molecule has on that pathway and to use the tool kits to check where the disease biology is linked to that pathway. These insights, we give back to the community by means of peer-reviewed to much publications. Now how does empasiprubart work? Let's have a look. [Presentation]

So this slide was already -- or this pathway was already shown in the movie. But the reason why I want to show it again is to point you at the unique positioning of C2 in that complement cascades. Why do we think it's a differentiated molecule over a C5, a C3 or a C1 blocker? Well basically, we're not the type of company who is developing a third or a fourth generation of C5 blockers. But foremost, I think we want to inhibit the complement cascade, upstream of C3 and C5 to not only interfere with the membrane attack complex, but also other complement-mediated actions. We wanted to leave the alternative pathway open because it comes with the safety benefits. Basically, reduce the risk of infections. And then we wanted to inhibit both the classical pathway as well as the lectin pathway because that gives us more opportunity in terms of indications. So that's how C2 came in into the picture. On top of that, we also looked into genetic deficiencies in complement factor and understood that C2 deficiency, from a safety profile, has a much more benign profile as compared to a C1 blocker in terms of lupus risk. So that's why we believe that C2 is a uniquely positioned complement factor in that cascade. How does all this relate or translates to the clinic? What you see here is single ascending dose data from our Phase I study, where you can appreciate that upon administration of empasiprubart, you have a very profound reduction in three C2, and that effect is prolonged over time. What does it mean? I think in terms of C2 depletion, what it means we will show later in the MMN presentation. But the fact that, that C2 blockade is sustained, for instance, with the dose of 30 milligrams per kilogram, we can sustain at C2 levels by 95% over 100 days. That is allowing for a very convenient dosing scheme in patients. Now let's switch to ARGX-119, our MuSK agonist. MuSK was a protein or the importance of MuSK in the neuromuscular junction was already known for quite some time, but we are the first ones who are intervening therapeutically with that MuSK biology. We made an agonist, which is not so trivial and I'm going to explain it in a minute. And again, we are developing this molecule as Tim indicated, in congenital myasthenic syndrome in ALS, and are planning to add additional indications as we progress this program. Same innovation ecosystem we're building. A few elements, which I would like to point out. We're working with [ Steve Burden ], who has 30-plus experience on MuSK biology. And by doing so, we were able to find the best epitope for a MuSK agonist. We're also working with these experts, which gives us access to very unique disease models. And by now, we also have access to neuromuscular junction on a chip type of assays, which are allowing us to study ARGX-119 in degenerative -- neurodegenerative diseases like ALS. Now how is ARGX-119 working? What you see here is the neuromuscular junction, motor neuron on top muscle on the bottom. And MuSK is a very important molecule for proficient neuromuscular junction signaling. What is ARGX-119 doing? It's activating MuSK, dimerizing MuSK, phosphorating MuSK, phosphorylating downstream molecules, ultimately resulting in clustering of asset alcohol in receptors, which then are able to capture the signal from the motor neuron. What does this mean in a setting of congenital myasthenic syndrome? You basically can bypass genetic defects and as such, restimulate that neuromuscular junction signaling. Surprisingly, that clustering and that activation of MuSK is also resulting in a retrograde signaling in presynaptic differentiation. What does that mean? You keep the motor neuron attached longer to the neuromuscular junction. You keep it healthier for longer, which is, of course, an important element in ALS. Here, you see some animal data of a DOK7 model. These mice have the same mutation as the most prevalent DOK7 mutations in humans. And what you see in these animals is that MuSK phosphorylation is inhibited. That's leading to muscle weakness, which is lethal in these animals. Now we can basically rescue that phenotype by administering -119, as you can see on the graph. And when the effect winds off, you can basically revert that relapse by a second shot of ARGX-119. So very compelling data that we can bypass that genetic defects in DOK7 congenital myasthenic syndrome. Next slide is showing some biological evidence that ARGX-119 might have a beneficial role in ALS. What you see here is data from a [ SOD1 ] ALS model. And that's characterized just like in humans by very rapid denervation of the muscle, and that's what you see on the left-hand side of the slide. So in the control group, you start with 80% innovated muscle, and you see that rapid denervation going on. And that's the denervation you can slow down by administering ARGX-119 or MuSK agonist. Next to that, you can also improve the motor function outputs by adding ARGX-119 to the equation. So what you see, if you take -- if you stimulate the phrenic nerve on the diaphragm, you see a very rapid decline in compound muscle action potential. And that phenotype, you can revert by stimulating MuSK with a MuSK agonist. What does it mean in the clinic? Basically, you are keeping that neuromuscular junction healthier, stronger for a longer time, resulting in delayed disease onset in these models and improved survival. Where are we with -119? We just finished the healthy volunteer study. We understand now fully the PK profile of the molecule. The study also was clean from a safety point of view. And now we are taking the first step into patients with a Phase Ib in congenital myasthenic syndrome and a Phase IIa in ALS. And we are innovating also in these settings. CMS is the cleanest proof of biology setting you can imagine. And what we're doing there in that ultra-rare population is we are dose-escalating intra patiently and we're using QMG to measure the effect. Next to that, we also have a natural study ongoing where we will want to understand more the unmet need in a patient population and the impact of -- on QMG score. In ALS, what we're using there is an electrophysiological measure called the MScan. What it's doing is it's basically calculating the functional number or the number of functional motor units, and we know from literature that that's nicely correlated with atypical endpoints in ALS research, the ALSFRS, but it's much more [ granular ].So that's again an innovative way to go for single hunting in ALS. Now let's focus on the molecule where that whole co-creation model basically started, ARGX-113 efgartigimod in FcRn. We've -- over the years, learned so much about FcRn. We now also know how efgartigimod is unique in its way, it's moderating FcRn. And of course, we're very honored that at this moment, we can serve more than 10,000 patients using this molecule. I'm very proud of this innovation ecosystem, which we built, because basically, what we can do now is predict the human behavior of our FcRn-targeting molecules using the toolkit, which we developed. This cartoon here shows on the left-hand side, the normal interaction between an IgG and FcRn. You see an IgG being trapped by 2 FcRN molecules. And what is very surprising and something which we learned over the years is that counterintuitively, the IgG is binding to FcRn with arms facing the membrane. Next to that, you see the albumin binding on the opposite side. Over the years, we basically found the crystal structure of efgartigimod. And we know that efgartigimod is binding exactly the same way to FcRn as a normal IgG. Also, faced down towards the membrane. And that is the reason beyond the ABDEG mutations to increase the affinity for FcRn. But the fact that it's facing downwards, and you don't have that [indiscernible] hindrance that an Fc fragment is the best entity to block FcRn. This way of interacting with FcRn is completely different as compared to full-length monoclonal antibodies targeting FcRn. They bind with their arms to FcRn, leaving the Fc tail open for the immune system. And we know that these molecules are impacting with albumin recycling and also coming with a differentiated safety profile. Using our tool kit, we now understand how this is coming. Not only are these molecules directly interfering with albumin binding but what we know is that they're also [ inducing ] FcRn degradation. What you see on this figure here is FcRn in green. We incubate these cells with either efgartigimods or these [ full-length ] antibodies targeting FcRn. And what you can appreciate in blue is that efgartigimod is not affecting FcRn levels over time as is these full-length molecules are rapidly degrading FcRn, which you can see by the green [indiscernible] disappearing. Great from an IgG perspective, no FcRn around, but it comes with collateral damage which is that albumin reduction. This is also something,, which we can replicate in vivo. This is a very unique animal model, expressing human FcRn, expressing or at least, where you have constant levels of human albumin. And in that setting, we administered 4x, again, efgartigimod or these full-length anti-FcRn antibodies. Again, no impact of efgartigimod on these albumin levels as for these full-length molecules, you do see the impact on albumin recycling. You do see that albumin reduction. So that's a proof that we can use our tool kits to predict human behavior. And that is also demonstrating why efgartigimod is uniquely modulating FcRn. We do not see these albumin reductions. We do not see these edema, these hyperlipidemias or muscles -- grams associated with that albumin reduction. We don't see severe headaches or aseptic meningitis, which we believe is linked with that exposed Fc fragments. And we also do not observe clearance of anti-drug antibodies. Now this slide here brings it all together. We have invested a lot of time and a lot of energy in understanding FcRn. We built efgartigimod, which is a unique way of blocking FcRn and we are now developing that in 15 indications. By doing so, we also understood that the opportunity in FcRN world is so big that we would need new FcRn antagonists. And we leveraged that insights to come up with a whole portfolio of FcRn antagonist, and RGX-213 is the first one, which we [ can ] disclose today. But when you walk that part of total biology understanding, something -- sometimes, magic is happening. And that's -- I would like to point your attention to the right-hand side of the slide. We were able to use FcRn biology knowledge together with efgartigimod as a building block to come up with a unique sweeping antibiotic platform of which ARGX-121 is the first one we're going to disclose today. And I would like to call Karen Silence, Head of Product -- Head of Preclinical Product Development to the stage to introduce to you both ARGX-213 and ARGX-121.

Thank you, Peter, and good morning, everybody. I'm so glad that I can finally present to you ARGX-213 and ARGX-121. But let's start with ARGX-213, which is basically efgartigimod, where we added VHH-targeting albumin to prolong the half-life. So as you know, IgG is an albumin recycled via FcRn. And because of that, they have a long half-life of 3 weeks. ARGX-213 binds to albumin and because of that, we significantly increased the exposure of this -- efgartigimod in circulation. But once the antibody is taken up into the cells, it behaves exactly the same as efgartigimod. So it will block FcRn, thereby, it will block the binding of IgGs to FcRn. The IgGs are shuttled into the lysosome and degraded, whereas ARGX-213 remains banned to FcRn and can be recycled, either by FcRn binding or by albumin binding. Now initially, we thought this was going to be a very easy exercise. So we started from a conventional antibody, where indeed, you have efgartigimod in the Fc, you have 2 Fabs, you remove the 2 Fabs, you replace them with 2 VHHs-targeting albumin. We tested this antibody in [indiscernible] monkey and the PK was really great, super happy, but the PD was completely lost. We did not see any IgG reduction. By that time, we understood how IgGs are binding to FcRn, indeed with the upside confirmation, with the Fabs pointing towards the membrane. In this case, the VHH is pointing towards the membrane. We had to develop an assay that Peter was talking about. We invested a lot in a toolbox of assay. We had an assay to look at FcRn occupancy in-vitro. And what we saw is that the antibody was binding perfectly well to FcRn. Unless we added albumin, then all of a sudden, the antibody could not bind anymore. And if you look at that picture, it actually makes sense. So we said, okay, then we need to put the VHHs at the other side, pointing away from the membrane. This should solve the issue. And indeed, in the FcRn occupancy, assay both in the presence and absence of albumin, we now have great binding. But when we tested this antibody in cynomolgus monkey, we came to another surprise. So this antibody had great PK. Now it's nicely reducing the IgGs. But in some of the monkeys, we saw reduction of albumin levels. Now we want to develop a molecule that is as safe as efgartigimod, so we don't want to have any albumin reduction. So we understood that some more engineering is required. Again, we developed some assays, in vitro, in vivo and our FcRn degradation assay became quite instrumental here because it's indeed the FcRn degradation that is causing the albumin reduction. So we played around with the antibody. We removed one of the VHHs, so we kept only one of the VHHs, and the FcRn degradation was already significantly less. But we had to further engineer the antibody. We had to reduce the affinity of VHH. We had to play with the length of the linkers so that every piece could be positioned in the ideal formation to allow excellent occupancy of FcRn and no FcRn degradation. And here we are. ARGX-213 is now tested in cynomolgus monkeys. In a dose response, you have a very nice PK, the PD is as expected, and we do not see albumin reduction. So with this long-half-life version of efgartigimod, we believe that we can replace the weekly dosing of efgartigimod with a monthly dosing with ARGX-213. So now we are adding here another molecule in our FcRn antagonist portfolio to treat our patients. Where are we in development? Currently, we are fully busy with the tox studies, and we are on track to do a CTA submission in the first half of next year and start Phase I studies in the second half of next year. And next, I would like to talk about ARGX-121. As people already mentioned, this antibody is targeting IgA. It has the Fc update or efgartigimod as a building block and a Fab-targeting IgA. So how does it work? ARGX-121 binds to IgA in circulation. And this complex is taken up in the cells via FcRn. Once the complex enters the endosome where the pH is acidic, the antibody will release IgA, the IgA goes in the lysosome and is degraded, whereas the antibody can recycle via FcRn and repeat the cycle of IgA degradation. We call this a sweeping antibody. The antibody also blocks the binding of IgA and its immune complexes to its receptor, CD89. But also here, we were up for some challenges. I need to tell you that IgA is a very abundant target. It's present in 1- to 3-milligram per milliliter. That's really a lot. Also, the half-life of IgA is short and the production rate is high. So we knew if we want to sweep such an abundant target that we would probably meet a few iterations. But we learned a lot along the process. We started with a normal antibody as depicted at the left with 2 Fabs binding to IgA in a pH-dependent vessel. The antibody does, as we described in the cartoon in the previous slide, where we tested in cynomolgus monkeys, we saw indeed sweeping of IgA, but it was actually quite disappointing. Why is that? We believe that the pH dependency of the antibody was not good enough. I need to remind you of the cartoon at the left, where the fabs are pointing downwards. This is a free antibody, but imagine this antibody is now also in complex with IgA, you create these big immune complexes and it becomes really difficult for these immune complexes to bind to FcRn. So we really need to dismiss all the IgA when we are in the endosome. So indeed, we further engineered the antibody in such a way that there was zero binding at pH6. And this helped a lot when we tested it in cynomolgus monkeys, the sweeping of IgA was significantly better, but when there were sinus with high IgA levels, we were sweeping less goods than sinus with lower IgA levels. And also in patients, we can expect quite some difference between IgA levels. So that's what for us, still not good enough. The real breakthrough came from making a one-arm antibody then we don't make those immune complexes anymore. We had still have the pH dependency, but we don't make the immune complex. It's not a neutral pH, not that acidic pH. So now we bind much better to FcRn. When we tested this molecule in the sinus, we were blown away by the data. We see 90% reduction of IgA within a few days for multiple -- for a long time. When we saw this data, we knew we had a drug, but we also realize that we have a very powerful platform here for sweeping of targets. And that's indeed what we will be applying now for some future products, and you will hear of that in the future. So also the dosing for this molecule is quite remarkable. Indeed, also in humans. We expect that we can sweep more than 90% of IgA within 1 week. And we see also a broad therapeutic potential because the biology for IgA is not very well understood. It's really understudied, but we know that there are multiple indications where pathogenic IgAs play a major role. So also here, ARGX-121 is, again, a pipeline in a product. Where are we in the development? The CTA submission also for this molecule is planned for the first half of next year, with start of Phase I in the second half of next year. So I hope I convinced you that we have generated here a really great platform using the update in DFC and the one-arm concept to sweep targets for future products. Thank you for your attention.

Peter and Karen are very humble. They're flemish but I'm American. So I'm going to stand up here and brag a little bit. That is really leading edge antibody engineering. And I think when you put this into the context of our 2030 vision, 121 and 213 are late-stage molecules. You see already that we have some sweepers that exist that are earlier stage, but all of these things go back into the toolbox and are going to be that beating heart of our IIP. We're going to move on to clinical development. And Luc Truyen, our Chief Medical Officer, will come up.

Thank you. Thank you. Hard act to follow. I'm going to go over here fairness for this audience. So patients you've already heard are our alpha and omega. And we enthusiastically are supported by KOLs, academics that are facing these patients in their daily business, and they say, what innovation can you bring. They then collaborate with Peter and Karen addressing new targets, and then we are on our way to bring these beautifully designed molecules into clinic to try to answer the questions that matter for patients. And that's where we reengage with these patients. Every trial that we design has patient inputs. And that is to be, for us, an important way to make sure that what we do is relevant. And of course, we then generate the data, and we hope that the data, of course, are of that nature that we can file and then we want to make sure we can create access. But that's only one direction. There's also a back direction, a back translation of what we see in the clinic back into our basic science and discovery to continue to optimize. And that's why you see this figure coming back where this is a continuum. But again, patient at the center. Now I joined argenx in 2021, which you can see about in the middle of this graph. And I'm very proud of the argenx teams that if you look at this incredible increase in activity, that, I mean, just stand still with that to carry 48 studies today, 40 running, 18 planning, is a remarkable achievement. And the infrastructure scaling, the thought that has to go in, in delivering this cannot be underestimated. So I'm very proud. Now we created our own Kanagawa wave here, as you can see, for those familiar with that image. And that generates a lot of data. And again, we look at this data, we feed them back with appropriate and we're hopefully again, feeding them forward into submissions, which most recently led to the approval of VYVGART Hytrulo in CIDP, the first new innovation in 3 decades. And I would be remiss not to thank the patients that are actually part of this journey. You see here the number. We have really, really been fortunate to have such an engaged patient community and evidently also, the investigators to make these journeys possible. Beth already alluded to this, is that once we enter a space, we really want to make sure that we fully understand it, maximize the data sets, which is exactly what we've been doing with ongoing work in myasthenia and that has become a playbook. And for example, when we entered this space, the concept of minimum symptom expression really wasn't in the forefront of anybody's mind. But in the conversations then with the patient organizations, the ability to say you have this probability that you can actually be symptom-free becomes a very important conversation piece when initiating treatment. And we have shown consistently across studies that over half patients can achieve that. Think about that before we started, physicians said, and I'm a neurologist, so I can blame myself. These patients are very well taken care of. No, they were not. We generated the data convincing that we can really make a material difference. By virtue of the features of our compound, we also have the highest MG-AGDL reductions that are sustained. And we hope to continue to explore those regimens because it is a strong belief, there's no one size fits all. And so predictability of dosing is not really something that we see. What does this particular patient need? So we continue to evaluate that. We also, today, have the broader safety database. In fact, including post-marketing, I'm sorry, I'm going to use a number, Karen. We have over 6,000 patient year of experience with efgartigimod and MG. Nobody is close. Another important aspect of what we try to make sure that the treatment environment for our patient gets better. And the use of steroids is, of course, one of those that's classical and cheap, et cetera. But it's only cheap in cost of the drug. It's not cheap in cost of side effects. And therefore, we were very happy to be able to show that we can significantly reduce steroid use from real-world data. We have in a significant portion of patients after 6 months of use. Those are things that matter in the long term. This sort of approach really closing data caps that we're also going to deploy for CIDP. Now how do we think about innovation in clinical development? Of course, it's all about the data. We have to generate a data that are conducive to: a, convince regulators; and b, convince payers that what we are doing is meaningful for these patients. We have the needs of the patients because they have to tell us what is relevant for them in their daily life because that allows us to choose the endpoints. And we also need to have voice to make sure that we can actually run the trials, that is bearable for them. And then, of course, and this is always of interest, particularly to me. How do we minimize white space? Our speed, shortening that path to patients. In what follows, I will go through a couple of trials where we will try to illustrate these points. I will try not to steal too much of the thunder of those that come behind me, but some things I do have to already highlight. And I'll start. Okay, I'll start by our expansion in MG. So this is a case of built upon an extent. We're building upon data we've already generated, both in ADAPT and ADAPT subcu around seronegative patients, where we see that they do respond to efgart across multiple cycles. And of course, as you know, we are only currently approved in acetylcholine receptor-positive patients. So we went to the agency and said, "Listen, we already have some data here. We understand you want a dedicated study to really get this to the label. Can we build on existing knowledge?" And so the agency agreed, and we will be able to run a quite efficient study with what is called a relaxed P value to get that evidence. Ocular MG was also already mentioned, a significant portion of patients. And the biology tells their symptomatology is driven by auto antibodies. So we should work. And there, our thinking is, let's create a data set that we can meaningfully show benefit. In ocular MG, patients typically excluded from the trial so far. And so we're looking very much forward to getting that data sets together. Sjogren's disease. To me, this is a case of situational awareness, smart borrowing and getting biological QED. What do I mean? When we were thinking about this study, we, of course, were well aware that there was a competitive study that was running a large Phase II trial with our same mode of action. Then we have to say, "Okay, what's the added value of repeating that, especially if you want to speed up?" And so we said, "We are going to invest in a small study, deeply phenotyping patients together that biological QED, bring the data together, look at them and then make the decision to go to Phase III." We had some learning on the measures in the meantime, and we will adapt that. But the main thing that can happen is we caught up, if not, maybe even get faster with our competitor. Immune myopathies. You'll hear more of this later. For me, this is a case of double innovation. The first innovation is we recognize that a number of these phenotypes are driven by auto antibodies and have different symptomatology but also overlap in symptomatology namely, muscle weakness. So we thought we can test multiple together with a single endpoint in a basket trial, Innovation 1. Innovation 2 is, let's do that in operationally seamless Phase II/III with an analysis of Phase II informing this independent Phase III cohort. The advantage of that is, is that you don't pay that much of an alpha penalty. Therefore, your power stays up and you can run a smaller study as you do it. MMN. Phenomenal data. This is pioneering in triplicate. And Inge and Jeff will talk about this. It's a novel mode of action, first-in-class, that is built on first-rate academic research saying, "This could really interrupt what is going on in MMN." We are learned about this disease. We are investing in learning more about this disease with a natural history study. And we designed a POC that I call that "go slow to go fast", which is we wanted to make sure we: a, had the right patients; that we knew that they were IVIg-dependent; and also what their agrin frequency of use was. Those patients were then randomized to efgart or placebo. And on efgart, the agrin frequency disappeared. Almost no patient needed rescue. Sorry, Jeff, I'm stealing your thunder. On placebo, we saw very quickly patients reverting to their prior IVIg frequency. So very exciting data, and we're leveraging all of this to move fast to Phase III. And then exciting, you already heard about this. CIDP is the fourth determined indication for empasiprubart. Why? One, the data we got on empa characterize it so well from our MMN trial. Emerging science, of course, we have to remain aware. And then third, humility. Efgartigimod [indiscernible], the first new innovation, is a great addition to the armamentarium but it is not perfect. Some patients did not respond. Some patients did relapse. So I think when we have a handle on another innovative MOA, we should be responsible and be willing to put that next to it, and we're going to be moving to Phase III as fast as we can. In closing. These are great innovations, but we also have to innovate at every level of our development efforts, including basics, which is how do we capture data, digital endpoints? Do we use AI in generating regulatory answers? And so much more. Also very important, continue to innovate on patient engagement and recruitment. It's a competitive world. But the driver for all of this is that patients are waiting. Thank you.

Thanks, Luc. Amazing amount of work from your organization. Also importantly, for Luc's team is they really sit at the intersection. There's that connectivity between the science and the patient, taking the first-in-class antibodies that we have, developing them in the most relevant indications, taking the insights from the field, generating evidence through additional studies and all of this goes back into our engine. At argenx, we know that everything does start with the patient. So we are going to shift to myositis. And as Leentje comes up, to talk about myositis and the biology rationale in the study, we're going to hear from one of the myositis patients. [Presentation]

Idiopathic inflammatory myopathies, also known as myositis, is a group of autoimmune diseases characterized by chronic muscle inflammation. As you could hear from Alisa's story, patients typically experience muscle weakness, but the disease can also affect the skin, lungs, heart and joints, and can even be associated with malignancies, interstitial lung disease and inflammation of the heart muscle. Patients are typically treated with steroids in combination with immunosuppressants but they can also have off-label use of IVIg, which is currently only approved for dermatomyositis as well as rituximab. So there remains a need for targeted therapies, which can reduce the muscle and other symptoms in these patients as well as the quality of life across myositis patients. Autoantibodies play an important role, not only for diagnosis but also as drivers of the disease. On the left, you can see that there are many different myositis-specific antibodies, these are subtype-specific, and they target autoantigens involved in transcription and translation, lipid metabolism or interferon production. Patients experience muscle weakness of the upper arms and legs and typically have difficulties raising themselves up from a chair, climbing stairs or lifting an object above their head, such as simply combing their hair or getting themselves thrust. But depending on their antibody positivity, patients can also have additional clinical symptoms. On the right, you can see, for instance, how anti-synthetase syndrome antibodies indicated in green and dermatomyositis antibodies indicated in red are associated with interstitial lung disease and skin rashes. While certain IMM antibodies indicated in blue, can lead to a difficulty swallowing and infection of the heart or inflammation, sorry, of the heart muscle. There is growing clinical and preclinical evidence that antibodies are actually driving disease and IMNM anti-synthetase syndrome, NDM. On the left, it has been recently shown that antibodies can enter muscle fibers. They can colocalize with their antigen in the cytoplasm and even in the nucleus of these cells and that they drive the disease by disrupting the normal function of their antigen. On the right, you can see that if you transfer auto antibodies or antigens into mice, these mice develop symptoms that are similar to what is seen in patients. We focus on some observations in DM on top and IMNM on the bottom. And patient muscle biopsies, it has been shown that DM antibodies can lead to interferon power activation. On the other hand, if you transfer DM antigen and antibodies into mice, these mice develop a severe lung injury with expression of IgG antibodies and active complements. And patient muscle biopsies, certain IMNM antibodies lead to lipid accumulation, while if you transfer IMNM antibodies from a patient into mice, these mice develop severe muscle weakness and necrosis. We will focus on the pathogenic role of antibodies in IMNM. I will share some preclinical efficacy data on how efgartigimod was able to reduce the muscle weakness in this IMNM mouse model. In IMNM antibodies on one hand, cause muscle damage by binding to the muscle fibers, activating the complement system, leading to formation of the membrane attack complex, which induces muscle necrosis. On the other hand, antibodies have also been shown to directly impair muscle regeneration by inhibiting the fusion of myoblasts into myotubes, which generates new muscle fibers. So we hypothesized by inhibiting autoantibodies, efgartigimod could bring therapeutic benefit to IMNM. And this was tested in the IMNM mouse model. Mice were injected with autoantibodies of an IMNM patient and they were either left untreated or treated with efgartigimod starting on Day 8, which is once the disease is established in these mice. On the left, you can see that on Day 7, these mice have high antibody levels in the blood. In the middle figure, you see that these mice have a reduced grip strength compared to control mice that were injected with antibodies isolated from a healthy donor indicated in gray. Efgartigimod treatment starting on Day 8 led to drop in autoantibody levels, as you can see in red, compared to non-treated mice indicated in blue. Efgartigimod treatment also induced a significant restoration of the group's strength and the muscle strength compared to non-treated mice in blue, and even to levels comparable to control mice. At the end of the experience, muscles were isolated from these mice and were evaluated for muscle damage. On the top, you can see that mice injected with autoantibodies, they express these necrotic muscle fibers indicated by the triangles. Efgartigimod treatment reduced the number of necrotic muscle fibers and generated these clusters of regenerating muscle fibers, which are indicated by the white stars, and which you can recognize by having the nucleus in the center of the cell or even sometimes two nuclei in the center of the cell. Quantification on the lower panels show that efgartigimod treatment in red led to a reduction in the number of necrotic muscle fibers comparable to the control mice, and increase the number of regenerating muscle fibers compared to nontreated mice. Our preclinical results indicated that efgartigimod can prevent muscle damage, which is a process that is antibody and complement-dependent. And on the other hand, can also lead to a restoration of bustle regeneration, which is antibody-dependent but complement independent, together leading to a full regain of muscle function in these mice. Our preclinical data, together -- actually reinforce the evidence that autoantibodies are driving disease in IMNM, anti-synthetase syndrome and dermatomyositis. And together with the observed treatment effects of IVIg and rituximab, this creates a strong biological rationale that efgartigimod may bring therapeutic benefits across these 3 myositis subtypes. So that's why we designed this innovative basket trial to evaluate the safety and efficacy of efgartigimod in these 3 myositis subsets. It's an operational seamless trial, which consists of a Phase II stage of 90 patients with 24-week treatment, and a consecutive Phase III stage of 150 patients with 52-week treatment. Both are separate cohorts and the transition without -- occurs without a hold between the 2 phases, which means that once the last patient was enrolled in Phase II, the next patient was directly screened into Phase III. Patients are treated with a weekly subcutaneous formulation of efgartigimod or placebo on top of background treatments. And importantly, this background treatment should be stable and patients should be -- have active disease and muscle weakness, despite treatment. It is also an adaptive trial, which means that there will be a GO/NO GO decision on each of the 3 subtypes based on the Phase II analysis at the end of the Phase II, which is performed while the Phase III is already started at risk. The primary endpoint is TIS, or total improvement score, which can capture therapeutic effects of the drug on the common muscle component, the muscle weakness, but as well as on other important features of the disease, such as the muscle enzymes functioning and extra muscular assessments and physical patient and physician assessments. The trial is currently ongoing with active recruitment in Phase III, and results on the Phase II analysis and a decision on whether to continue in each of the 3 subtypes is expected by the end of this year. Thank you.

Thanks, Leentje. We are looking forward to the GO/NO GO later this year. And it's a really important point that she mentioned that the last patient gets enrolled into Phase II, and then the next one goes into Phase III. That's really the beauty of that operationally seamless design. So when we make that GO/NO GO by the end of the year, it's actually more of a stop decision on any one of the subsets or to go for it on all 3. So next up, we're going to move to the Sjogren's, the RHO study results, and you'll hear from Julie Jacobs.

[Presentation]

As you could hear from Lisa's story, Sjogren's is a devastating disease. And unfortunately, it is not rare because one in 1,000 get the diagnosis of Sjogren's, and it goes well beyond the dryness because 1/3 to even half of the patients suffer from extra glandular manifestations. And as you can see from this figure, it can be very heterogeneous because Sjogren's can affect multiple organs, ranging from interstitial lung disease to vasculitis, articular problems, neuropathy and even 5% of the patients develop non-Hodgkin's lymphoma. And at this moment, there are no disease-modifying drugs available. Now we have Professor Bowman here with us today, who will talk more about this unmet needs. When we look into the disease pathology, you can see why we believe efgartigimod could play a role here. Because in the salivary glands, the salivary gland epithelial cells become activated, and they start to behave like an innate immune response, making sure that immune cells are attracted to the salivary glands. Plasma cells are generated and autoantibodies are formed of which the most well known are the once against Ro52, Ro60 and La. These auto antibodies will form immune complexes. And the immune complexes again activate the plasmacytoid dendritic cells to secrete even more type 1 interferon, making sure there are more immune cells attracted to the salivary glands. And this causes this loop of immune activation that eventually leads to tissue damage and causes the glandular but also extra glandular manifestations. With efgartigimod, we hope that we can break that loop of immune activation, and thereby reduce the symptoms and disease activity. Now how did we unravel the biology into a clinical trial? We did a small Phase II proof-of-concept study, where we enrolled approximately 30 patients, 22 on efgartigimod, 9 on placebo. And we gave them weekly infusions for 24 weeks. Patients could be included in our trial, if they had Sjogren's disease, of course; they had to have at least systemic manifestations which was measured by an ESSDAI of at least 5; and needed to be positive for anti-Ro. When we look into the demographics and the baseline characteristics, 68% of our patients actually had an ESSDAI of at least 10, and all of them were on stable treatment. Most of them on hydroxychloroquine or low-dose steroids, and half of the patients had hypergammaglobulinemia or IgG levels above 16-gram per liter. After patients finished the main study, they could roll over in the open-label extension. And actually, all but one patient really did that. And that patient did not continue due to logistical reasons. When we look into the primary endpoint of our main study, that was the CRESS or the composite of relevant endpoints. The limitation of the CRESS is that it is very new. So this endpoint is still in process of validation. And that's actually also why we used it, to help the community validate this important endpoint that really captures the heterogeneity of the disease because it consists of 5 items. It not just looks at the systemic disease by the ClinESSDAI, low disease activity, it also takes into account the salivary function. The tear gland function, serology as well as the patient reported outcome. And the main objective of our study was to demonstrate more CRESS responders at week 24 after efgartigimod treatment. And here are our results. So with efgartigimod, 45% of the patients were responder to the CRESS and only 11% in placebo, giving [ at ] a treatment response of 34%. When we look more into the different domains, we could actually see improved treatment effect in 4 out of the 5 domains. Let's start with the ClinESSDAi. So remember, 68% of our patients had an ESSDAI of at least 10 when they started the treatment. Well, with efgartigimod, almost 60% are now in low disease activity with a ClinESSDAI of less than 5. Also looking at salivary gland function and tear gland function, we saw an improved treatment response with efgartigimod and of course, also in serology. The only thing that didn't work was the ESSPRI or the patient-reported outcome. And this is actually not that [indiscernible] because what we see from historical trials is that the ESSPRI is not so sensitive to change. This can be due to the 2-week recall periods. And this, again, confirms that there is a need for new PROs in further development. Next to the CRESS, we also looked at STAR. STAR is another composite endpoint also in need for validation. And the STAR is very similar to the CRESS, only it puts more emphasis on the systemic measurements and the ESSPRI. So if you're not a responder on either one of those items, you cannot be a responder on STAR. And the measurement for clear assay is a bit different. It doesn't go for low disease activity, but for the 3 points. Now when we look at the data, again, we see an increased treatment response upon efgartigimod treatment. It's a little bit lower than what the CRESS. And the difference here is not in the active treatment, but that we have more placebo responders in the STAR measurements. Of course, we could not ignore the ESSDAI because the ESSDAI is still the key tool to use -- to capture the systemic disease measurement. And we looked at the ESSDAI in 2 different ways using responder analysis. On the one hand, we used an MCII of 3 points. So if you have a decrease of 3 points in the ESSDAI, you're a responder. And on the other hand, we raised the bar a bit and use the 4 points. What you see is, again, a treatment effect with efgartigimod, which is even more pronounced when we hire that bar. Now how is efgartigimod doing that? We looked into the biology a bit more. And first of all, we looked at IgGs. We see a very nice rapid reduction in the IgGs of 60%, which is consistent with what we see in other indications. And when we look at the auto antibodies here presented by the Ro-52, you can see it nicely aligns that effect with the IgGs. In addition -- this is the first trial where we show that we also have a reduction in rheumatoid factor. And we again see a very nice reduction in the C1Q immune complexes. Remember when we talked about pathophysiology in the beginning slides, where we had that loop of immune activation? Well, it seems that we are breaking that loop with efgartigimod. And we can also see that this is improving the salivary gland function because in the salivary gland ultrasound, we see a STEPWISE reduction in the active arm. Now I wanted to close with one more patient narrative of a patient that was on efgartigimod treatments. This was a patient with very high IgGs at baseline of 17-gram per liter. We can see that the IgGs nicely go down very fast. We see the effect on the auto antibodies, here represented by the Ro-60 as well as La. We see a nice reduction in C1Q immune complexes and the rheumatoid factor levels fall below the lower limit of quantification. When we look at the systemic disease activity in this patient, the patient at glandular swelling at start as well as lymphadenopathy and articular disease. Well, all of that went away with efgartigimod treatment. And finally, we saw that there was an improved salivary function because the patient started in hyposalivation and now at levels above these thresholds. So overall, we established our proof-of-concept in Sjogren's disease. We saw a 60% reduction in IgG and the benefit on the biomarkers. We had an increased response rate, looking at the composite endpoints, not just in 1 domain, but in 4 out of the 5 domains. And we saw that step-wise improvement over time in multiple measures. Finally, of course, efgartigimod was again safe and well-tolerated. Our data, together with our bigger fixed Phase II trial, also with an FcRn blockade really justify that advancement towards a new Phase III study. And that is something that is already ongoing. We had our end of Phase II meeting, and we are planning to start the Phase III by the end of this year. Thank you.

I'm going to ask you to stay up here, and we're going to get the panel set up. It's great we could really fill your excitement. And the team, I know, is working really hard to get that trial up and running by the end of the year. So on our panel now for Sjogren's, we're going to have Julie; we're going to have Luc, our CMO; and then also Dr. Simon Bowman from the University of Birmingham. This Is what we're going to do is we're going to have the panel questions that will take 10, 15 minutes, and then we're going to open up for Q&A. A couple of questions specific to the panel from the audience. And then we'll move on to the broader management Q&A, just to give everyone a lay of the land.

Welcome. Simon, I can call you Simon.

Of course.

So Simon, to situate maybe your expertise in the field of Sjogren's, could you tell us a bit more about your practice, your years or...

So I'm a general rheumatologist that I've been involved in looking after patients with Sjogren's over 25 years in Birmingham in the U.K. I set up the clinic there. I've been involved in research and Sjogren's over that period. So for example, I led the development of the profile of fatigue and discomfort [indiscernible] symptoms inventory, which was one of the first tools to measure patient symptoms in Sjogren's. And that led into some European collaborations where we developed the ESSDAI and the ESSPRI. And then that led on to the U.K. Sjogren's Registry, which led on to the trial of rituximab that I was the Chief Investigator for, an academic-led trial that although it didn't meet its primary end point, I think it demonstrates the ability to deliver clinical trials effectively in large numbers in Sjogren's. And in fact, the samples, the blood samples that we collected along with the data is still delivering new papers even now. So it sort of -- it's been a long journey into now hopefully, seeing the pharma industry take up the baton and hopefully bring drugs into clinical use.

Yes. It seems certainly that you led the way in some seminal work here. Now if you think about the patients you see, for which patients do you think is the unmet need greater?

So we have no -- as Julie said in her talk, we have no effective licensed disease-modifying drug in Sjogren's. We have some stimulants that will produce extra saliva and tears, but we have no drug that targets the underlying disease. So really, anybody with moderate [ sphere ] Sjogren's is desperate for a drug that works. So I don't know if you'd like me to run through some of the features. There are basically 3 domains in Sjogren's. You heard from Lisa, the patient, about the debilitating fatigue and the impact that, that can have on patient's lives. The other domain, obviously, is the dryness. And I think it's worth just reflecting that if you've got a severely dry mouth, you're not going to be able to do your job as a teacher or a lecturer or stand up in front of today's panel and deliver an effective talk on Sjogren's. If you've got severe dry eyes, if you're having to put eyedrops in every 30 minutes, I'm looking around at the number of people on laptops today, you're not going to be able to do a job with a laptop. If you're having to stop, you can't concentrate, you happen to put eyedrops in. So these are not trivial symptoms. And then the third element that Julie's already mentioned, and we've been talking about is the systemic disease in about 40% of patients. And you've heard about the multiple systems that can be involved, the lungs, the joints, the skin, the muscles, et cetera, et cetera. So we are really desperate for medication for all of those 3 domains.

Yes. So what struck me in Lisa is how long her journey was to getting a final diagnosis. Is that you think because of the unavailability of treatments or just unfamiliarity with the disease? Or could -- I find that remarkable in this case, what do you think?

Well, it's not unique to Sjogren's, to be fair. I think that you see it in other rheumatic diseases, and it's probably a combination of health care systems, lack of knowledge, perhaps patients not knowing to seek advice, et cetera, et cetera.

Yes. Julie, coming to you. As you've designed this trial, what were the key considerations that you made saying, this is how we're going to get to the data we need?

I think, first of all, why we went into Sjogren's. So it was actually -- there was a definite medical needs there. We were approached by Dr. [ Isabel Peña ] from the University of -- Hospital of Ghent, who really said that there is a need for new treatments in these patients and that we have to go there with efgartigimod. And then secondly, it was also from a biological perspective that it fits. You have the high IgGs, the autoantibodies, the immune complexes. It definitely made sense to go there with efgartigimod. And then finally, looking at the design. So we leveraged insights from the field. And then we decided to do a small Phase II proof-of-concept study, really focusing on the biology and getting a signal as well as helping the community with these new endpoints that are in need for validation.

So Simon, you spoke about how you did some of the seminal or rituximab trials and that your trialists today. What did -- from your point of view are the key challenges that we need to think about fielding trials in Sjogren's today?

So let me start with the positive, which is it's amazing that we have a number of really big trials from several different pharma companies that have demonstrated improvement in systemic disease. So would I have predicted that 5 years ago? Probably not. So that's a huge step forward. I think where the challenge is that Julie has also alluded to is demonstrating patient improvement. Now part of that may be that the [indiscernible] needs to be refined. And certainly, a lots of companies are now developing daily diary approaches, but they're still tackling the same core disease elements. And I think the challenge will be to design the trial so that you've got alignment between the entry criteria, the measure and the outcome so that you can demonstrate that patient improvement. But that -- I'm confident that will come, but it does need a little bit of thinking about.

And these endpoints, I mean, how would you translate to clinical practice or composites like STAR or CREST, more relevant for clinical practice and [ Sjogren ]? How -- what's your view on that?

I think I'm supportive of composite endpoints. I mean, again, they need to be demonstrated to be effective in clinical trials, but they do enable to capture both the systemic disease the other elements, the patient reported outcome in a single tool. And I think that has benefits. And I think, again, the critical thing is to make sure you align the entry criteria and the outcome measures so that actually you optimize your ability to demonstrate improvement. And these are really related very closely to what patients want, how they describe their disease and what they want out of an effective medication.

So Julie, you've quite enthusiastically presented the data. What did you find particularly exciting?

I -- I think, first of all, it was a very small study, and when we were developing it and talking to KOLs. We said if we see 20% treatment response on our primary endpoint, that would really be a positive signal. And well that you saw the data, we had 34%. So that was definitely a surprise. And also, what I find very encouraging is the biology. We see nicely that reduction in the auto antibodies and the immune complexes and that, that really affects the disease activity. So I think that was all a very positive data. And then overall, just that we see that consistency about -- on multiple measures, we always see that step-wise improvement upon efgartigimod treatments.

Yes. So Simon, how did you look at the data?

So similarly, I mean, it's a small study. You wouldn't expect in a study of 30 people to be able to have statistically significant improvement in clinical measures. But you do have the [ nipo ] data that did and you've got a similar mechanism. And the fact that you saw really quite a nice difference between the active and the placebo group, I think, is very encouraging.

So we're now taking the step to move to Phase III. We're going to execute on that plan, Julie. Maybe just for the audience, just line up your thinking what warranted really going to this Phase III progression now?

Well, the biology worked. We saw what we wanted to see. We had a clear signal in the clinical measures. And then we have that data from a confirmatory trial. That also helps. So I think all of that together really made it obvious to go to Phase III.

Yes. And would you agree with that progression to Phase III?

So obviously, I'm heavily biased here because I want to see effective drugs come to market. And obviously, people will be aware, there are a number of different companies pursuing this. I think what they will have in common in my simplistic approach is they're all in a [indiscernible] is B-cell driven. So of course, I'd like to see this particular mechanistic drug develop and come to market. I've been looking after patients for a long time. We've been waiting a long time to get to this point. It is very exciting for me as a clinician, see the potential to have a drug approved and come to market. You heard from Lisa, a similar, I think, very well expressed view. I share that view.

Thanks so much for that. From my perspective, what I look forward to is indeed, the B-cell approaches are being taken. They, by nature, are a bit less precise than taking the autoantibodies out of the equation. So we look forward to getting efgartigimod signature in a Phase III environment to show the risk benefit. So -- well, thanks for answering these questions. And I believe we now open the floor to some...

So we're just going to take a couple of questions. I got a pre-request from Derek. So we're going to start with him, and then we'll call on one other as well. Great.

Derek from Wells Fargo. So first question actually is for you, Luc. Just in terms of -- you described during the earlier presentation, your clinical strategy in Sjogren's, looking deeper at patient phenotyping versus your competitor. So I guess how do you think about that in terms of VYVGART's overall market opportunity and potential labeling in the future relative to that competitor?

Well, I mean, our approach to look deeper in phenotype these patients was literally can we show what Julie showed that's interruption of that vicious cycle. That's really what we wanted to get to a show. I'm not ashamed to say that then getting data in a biggest trial with the same MOE -- MOA that gives us significance, it's a great asset to us. The inverse has happened also where people looked at our CIDP data said, "Oh, they're so strong. We can change our trial design". So we do the same. It's a mutual learning in the class. The ultimate profile, I'm not going to speculate on. We need to do the study. But I feel from a safety point of view, pretty -- that's why I said 6,000 patient years already feel confident that we could be very competitive there. But it's all going to be about the efficacy ultimately.

Yaron Werber from TD Cowen. I have 2 interrelated questions. You did not give us the clean [indiscernible]. You gave us the responder analysis. Can you give us a sense what was the delta that you saw just so we can kind of look at the [ Nipo data ]. And then secondly, as you think about Phase III, is [indiscernible] that's not going to be the primary or is it going to be CREST?

Yes. So maybe on your first question, the change from baseline, I assume you mean -- so we did a very small study, as was already mentioned. It was not borrowed for significance. We only had 7 patients in the placebo arm that completed the trial. So looking at the change from baseline, it's obviously a bit risky. But when we look at the median, we do see a 3-point difference, which nicely aligns actually with the nipocalimab data. And on the trial design for the primary endpoint, I don't know Luc, if you want to comment.

Yes. So we have had our end of Phase II meeting where we discussed this endpoints. And the cleanest [indiscernible] is the endpoint that we would be moving forward with in an appropriately sized for that measure trial evidently.

So we will take one last question for the panel and then we're going to Yaron. Then we're going to bring up the rest of management to cover the whole first half of the event.

Thank you. Thank you everyone. Thank you, Beth. Yatin Suneja from Guggenheim. I think, Luc and Dr. Bowman, we were just talking or touching on the different mechanisms that are in play. So could you maybe just talk a little bit about, is there a particular unique biology or a disease symptom that can be sort of better unlock with FcRn versus the B-cell and the T-cells that are being developed in Sjogren's?

I mean the issue with Sjogren's is that there are no shortage of targets for drugs. You can pick pretty much any bit of immunology that you wish and produce a rationale for why that might be a good target in Sjogren's. I mean I've alluded earlier to the sort of B-cell elements in a broader sense. I mean, clearly, immune complexes, antibodies, cell-cell interactions, all of these things may be effective. And I think the clinical trials to date have broadly supported that analysis. I think, if you want to talk about immune complexes specifically, I may hand over to Julie, but I think it's quite difficult actually from basic biology to say 100%, this is the bit that's going to work because actually, what has come about so far as there have been a number of different mechanisms or broadly in this B-cell side that look as though they may well be effective. So I think probably...

Yes. Maybe on the immune complexes, it could be vasculitis, for example. That's an example where we know immune complexes play role, so that could be of interest. But what we saw in our small trial is that we really had multiple domains of the [indiscernible] where we saw an effect with efgartigimod. So I think it's too soon to say whether there is a specific feature.

Good. Thank you, Julie and Professor Bowman. I'm going to have you guys step down, and then we're going to have Tim and Peter and Karen Silence come up and sit in the stools. And we're going to open up to Q&A on anything from the first part, and we would ask that you keep the content to those topics just to keep the event moving along, and then we'll do a second Q&A after the rest of the topics. We do also have Karl available and Arjen, our Head of Clinical -- Corporate Development. We won't give you a clinical development question, Arjen. Tazeen, can we grab a mic up here.

Tazeen Ahmad from Bank of America. When you talk about empa for CIDP, Tim, I just want to get a sense of how you're thinking about how the market is going to look? So you are, of course, starting the much anticipated launch for Hytrulo there. What proportion of the patient population do you think would be better served hypothetically with empa? And how are you thinking about both molecules coexisting.

Thank you, Tazeen, for the great question. I think if you analyze the VYVGART Hytrulo data in CIDP, they're unparalleled. I think no one has shown a better efficacy in CIDP, but still you see significant room for improvement. And remember, it's our mission. Our mission is to push to perform the efficacy envelope, so to speak, in severe debilitating diseases like CIDP. So have you seen the MMN data, further understanding the biology of the disease. We think that in a subset of patients, maybe a complement inhibition could add something to the picture, and that's exactly what we're going to test in the clinical trial. CIDP is a little bit more heterogeneous right look than MMN. We know that next 2 IgG autoantibodies in a subset of patients, IgM autoantibodies are in play. We know what IgM autoantibodies do write, very important recruiters of complement. We have shown an MMN how important actually empa can be. So we think that MMN is a -- CIDP is a type of disease, where actually multiple innovative molecules can play shoulder to shoulder. So we're going to do the experiments and analyze the data retrospectively. We're not going to limit the patient population in any means or measures for empa in CIDP. We will disclose the details of the study protocol later on when it gets live on clinicaltrials.gov. I think we're going to show you some data later in today's talk. I'm very excited about. These are the MMN data. They will start to give you a flavor about how to dose.

And just for the webcast, the second question was how the trial would be dosed for CIDP.

Charles Pitman from Barclays. Just a quick question on ARGX-213 and the anti-FcRn space and next-generation development. So you're looking at obviously trying to improve the convenience with a monthly treatment. But Karen, I'd love your opinion just in terms of how you differentiate within the treatment of MG with an anti-FcRn and thinking about how you would think about improved IgG reduction in terms of differentiation and how that might play into the kind of competitive landscape as we see further development from competitors?

I will start with answering this question, and then I will invite Karen to add on. And the first thing I would like to say about this whole theory of deeper IgG reduction is that we would like to remind the people of the data. In our Phase I clinical trial, we had an IgG reduction of more than 75%. And that percentage is relatively lower in the Phase III clinical trial because patients which are already on immunosuppressants, happen to have lower IgG levels. So don't forget it in Phase I, we have put forward 78% IgG reduction, which is already, I think, best-in-class. The second thing I would like to add to it is there is no evidence that going deeper above and beyond VYVGART effect as any additional clinical benefit. If anything, I think the Pemphigus data have shown the opposite where actually we did go deeper in IgGs compared to steroids, but they didn't really add a lot on top of steroid efficacy because it looks like once you pass a certain threshold, it no longer matters whether you go deeper. The second thing I would like to say about ARGX-213 specifically is we're not trying to solve for any issue with VYVGART, I think that's a hell of a molecule. What we face is that actually there is too much opportunity for 1 molecule. There is a time clock in the back, be it a patent clock, be it an IRA clock and we just run out of time to embrace all the opportunity. It's already 15 indications, but we have bigger plans with just 1 molecule. So think of 213 as a molecule which is substantially differentiated from 113 from VYVGART but not necessarily fixing a problem. Now we're pretty excited about, for example, the dosing potential right, Karen?

Yes. Indeed, it's absolutely correct what you said, we're not trying to fix a problem. We don't need to go deeper, and that was never the ambition of this program. The ambition was to make a molecule where we need less frequent dosing with the limited modeling -- limited data that we have available today, we believe we can go to a monthly dosing schedule. Thank you for the question.

It's Rajan Sharma from Goldman Sachs. Just a follow-up on 213. As we think about the indications that you could target and kind of to the point on the IRA clock potentially ticking, should we think about indications beyond where you are with VYVGART? And then second, on that one, how should we think about motor of administration? So obviously, with VYVGART, you have the IV, the subcut and potentially a prefilled syringe. Is that a similar playbook that you'd be utilizing with 213?

Yes. We're paying a lot of attention when we develop molecules like 213 too, formulatability, how high we can concentrate the molecule. We're very excited about the ability actually to concentrate the molecule and actually play with different product presentations. The first thing we're going to do guys is going to Phase I and basically validate the PK/PD profile in healthy volunteers before we're going to make a choice going either into new additional indications or maybe entering existing indications where we want to continue to raise the bar. So let's be a little bit patient. It gives us fantastic optionality above and beyond the options we already have today for VYVGART, which is a very powerful IV product, a very powerful subcu product with VYVGART Hytrulo. Soon a prefilled syringe and then afterwards an auto-injectors. So we want a portfolio of options to maximally tap the opportunity in front of us.

Alex Thompson from Stifel. On 121, I'm just curious if you could talk a little bit about the IgA program and how you're thinking about a product profile versus the [indiscernible] and how you might be able to play in that space?

Karen, do you want to talk about the speed depth and durability of the [ VYVGART ]?

Yes. I like this question a lot because indeed, I mean, there is indeed some antibodies targeting the [ April ] and the [indiscernible] in the clinic. But with these antibodies, you lower IgA maximally 65%, and they need between 3 to 6 months to get to that depth of depletion of IgA, whilst we can do 90% reduction of IgA within a week. So I think that's quite a big difference.

In addition, remember we're on a mission to develop precision tools. We don't really like approaches where you cool off an entire B-cell population or even worse deplete an entire B-cell population. We want to go with the precision to [ left ] the real cause of the disease. And that's also how we're going to select indications. We need to have conviction. Pathogenic IgAs are true drivers of the disease biology.

I think it's important that you mentioned that Tim, because indeed, with our program, we leave, for example, the IgM intact was with the anti-acetylcholine [indiscernible] also significantly lowered IgM levels. We leave IgM intact. That's an important one.

This is Suzanne from Kempen. One question on empa. The half-life stands out compared to other sweeping antibodies out there. Can you share some thoughts on what could explain the super long half-life of this molecule and allow me to also squeeze one in on Sjogren's, if you can clarify maybe I missed it, but the Phase III, will that enroll patients with Anti-Ro autoantibodies or also Anti-La antibodies or is it an [indiscernible] study?

Thanks Suzanne. Thank you for flying over to Pontos for this R&D day. I appreciate it. Peter, do you want to take the 2 questions, please?

Yes. I think in terms of half-life, we have a half-life in healthy volunteers of approximately 70 days. And as I showed you, I think the half-life is linked to affinity for FcRn. That's where the half-life extension mutations come into play, which we incorporated in empasiprubart. But what is also evident is that the fab arms are important as well in that half-life. Remember the cartoon showing the arms, facing the membrane, there is some interaction there. I think we have optimized empasiprubart on that context as well, which results in that long half-life as compared to other recycling molecules.

And then on the inclusion/exclusion criteria for Sjogren's, Peter? [indiscernible] our status.

Yes. We will not zoom into a specific antibody status, so it will include -- basically, it's an Alzheimer's study.

Karen, as our people expert, is there anything you would like to add to this?

Well, indeed, when we developed the ARGX-117 antibody or empasiprubart. We made some variance again, which we tested in [ sinus ] and we compared it to an antibody targeting C1, which had really a horrible PK. And it was adding dose enhanced mutations and making it the pH-dependent and calcium-dependent antibody that made it such a long half-life molecule. Sometimes engineering takes time, but on the long run, you really benefit from it. So we have now really a beautiful molecule.

So we're going to take 2 final questions. I think we have Gavin and then Joon.

Gavin Clark-Gartner from Evercore. So just one question on dermatomyositis. You had a little bit of Sjogren's data on reducing the C1q immune complexes. Wondering if this has any read through to DM since the immune complexes can drive some type 1 interferon signaling and maybe some of the cutaneous symptoms. So I'm wondering if this kind of derisks that side of the disease or if you have any preclinical data to get at this component?

It's a great question, and we don't have Bas here today, our lead scientist on the program. I think he would wholeheartedly agree with you. There's a lot of focus and attention to the interferon biology, and whether actually we can preempt that biology upstream, right, Peter?

Yes, correct. I think this is incorporated in our clinical study in myositis. So we'll give you the answers a little bit later. I think what you do see and it's also was evident from the talks from Julie and Leentje is that there is quite some similarity between Sjogren's and myositis. So that is, indeed, to your point, definitely the case.

Joon Lee from Truist. So you maintain that there is no dose relationship between IgG reduction and clinical efficacy and invoke a threshold effect. So what's the biological rationale around such a threatful defect? And is that threshold similar across different autoimmune diseases?

That's a great question, Joon and we need to stick to data, right? In absence of data, it's very difficult to speculate. I'm referring to data, which we have in-house. I don't think we can give a general answer across all autoimmune diseases because we simply do not have the type of data. Peter, is there anything specifically you would like to mention to help us?

Yes. I think the disease, which we understand best is MG, where the neuromuscular junction has a safety factor. So by reducing the antibodies to 60%, you're restoring that safety factor leading to complete restorement of that signaling. And I think that's the way you should see it. You need to have a certain threshold of IgG reduction to revert that phenotype, whether that's similar to that level in different indications. That's a difficult question, and data should speak to that.

Thank you. So we're going to take about a 10-minute break. And I mentioned before, there's posters up and around, if you want to talk to anyone from the team on the content on those posters or get yourself a coffee, but we'll be back here in 10 minutes. Thank you. [Break]

Great. Welcome back. We have an exciting second half ahead. We're going to do -- talk about MMN, talk about the ARDA data. We'll have a panel on MMN and then we'll have a section on commercial. So to start, we're going to invite Inge up to the stage. And while she's coming up, we'll hear again from another patient who is living with MMN. [Presentation]

So thank you, Brenda, for telling her story about what it is about living with MMN. To quickly summarize, the diagnosis for MMN can take long and is frustrating for patients as it's often misdiagnosed as being ALS first. MMN is a severe debilitating autoimmune disease which leads to severe disability in subsets of patients. In MMN, mainly hands and forearms are affected, and therefore, patients struggle with daily activities but also lags can be affected, which is the case for Brenda and there she experienced difficulties in walking. Currently, IVIg is the only approved therapy for MMN. However, patients do still deteriorate when being on IVIg. As a quick reminder, empasiprubart is a monoclonal antibody that targets C2 and thereby inhibiting both the classical and lectin partway of the complement system. It is engineered to sweep C2 from circulation and has mutations that extend the half-life as you have seen in the section of Peter, it has a long half-life. So what about the pathophysiology of MMN? In MMN autoantibodies of IgM targeting GM1 play an important role. So you have IgM autoantibodies that bind to their target GM1, which is located at a motor neuron at a node of Ranvier or on the Schwann cells. Dose IgM autoantibodies, they bind and they activate the classical pathway of the complement system, leading to complement deposition at motor neurons and the Schwann cells, ultimately leading to destruction external destruction and external damage leading to the conduction blocks. Together with a University of [indiscernible], we also have some new learnings meaning that IgM autoantibodies, which target GM2 located on the Schwann cells also play an important role in the subset of MMN patients. So together with the collaboration of [indiscernible], we have previously generated in vitro data showing that empa can block complement deposition on motor neurons in vivo -- in vitro. So today, I would like to show you some proof-of-concept data from an in vivo mouse model for which we collaborated with the University of Glasgow. So what is the model about? So in this model, anti-GM1 autoantibodies are injected together with serum, which is a source of complement and either an isotype control or empa is administered to the mice. So here you see, which is a normal situation of a motor neuron and Schwann cell as you see the nice structure of the cell, with no complementary position and a nice marker of structural -- of the structure. However, when you -- at anti-GM1 autoantibodies to the mice, you clearly see a bright complement activation, as seen by the C3c staining. So really, they have a complement attack and this leads to structural damage at the Schwann cells because you have loss of the pink staining. So meaning there is structural damage to Schwann cells, which is also one of the hallmarks of MMN patients. When anti [indiscernible] is administered, when empa is administered to this mice, you nicely see that complement is completely blocked and there is no structural damage to the Schwann cells anymore. So meaning that there is a reduction in the structural injury or almost no injury at all. When we further look at what that functional means in this mice, we have to look at the respiratory rate of these mice. So in a normal situation, this is a normal graph of how mice breaths. After administration or addition of the autoantibodies in the mice, which then underwent a complement attack, you can see that the mice start to breath very fast and superficial. When empa was added to this mice, you could see a nice breathing of the mice, meaning that they can breathe normally. So to conclude, we can say that administration of empa to this mice reduce the structural injury and also significantly improved the functional respiratory rates in these mice. So actually, we have really unraveled the role of complements in MMN and therefore, we went for MMN as our first indication. And now I will guide through the Phase II design. So ARDA is our Phase II double-blinded, placebo-controlled trial in which we test empasiprubart in patients with MMN. So during the screening, the MMN diagnosis and IVIg dependency is assessed by an MMN confirmation committee. A vendor dependence on IVIg was uncertain, patients entered an optional IVIg dependency periods. All eligible patients after being dependent on IVIg entered an IVIg monitoring period. During that period, patients received 3 cycles of IVIg at their normal frequency and dose. After the third cycle, after 7 days after the last cycle, so patients were randomized to either empa or placebo in a 2:1 randomization, and they were treated for 16 weeks. After 16 weeks double-blind treatment period, patients could enter the 15-month treatment-free safety follow-up period or they could roll over to ARDA+ or long-term extension study. In ARDA, we have tested 2 cohorts. So -- and after DSMB, so meaning 2 different doses after DSMB, it was decided to lower the dose for cohort 2. Now we will invite Dr. Jeff Guptill to guide you to the data of both cohorts.

Thank you, Inge. So on behalf of the ARDA's study team, I have the pleasure to reveal the results today for both cohorts of the ARDA's study. So cohort 1 and 2. The discussion today will focus on the efficacy of the first and second cohorts. We will not talk much about safety for the purposes of this presentation. But I do want to touch on that since this was a Phase II proof-of-concept study that the safety profile in this study looks great and has no concerns to hold us back from moving to Phase III. So for this study, in terms of the efficacy, we will look at time to retreatment with IVIg as one of the key measures. We have previously reported at the Scientific Congress, the results of the Cohort 1. And so what we saw across the 2 cohorts was that treatment with empa reduced the risk of retreatment with IVIg between 84% to 91%. So in blue, depicted on the graphs are the patients that were treated with empa, and we can see that in cohort 1, only 3 patients required retreatment with IVIg and 1 patient in cohort 2. We do see some differences across the cohorts in terms of the retreatment needs in the placebo group as well, where we observed that there are fewer retreatments in Cohort 2. Of course, this is a small proof-of-concept study. But I think the thing that is extremely encouraging to us is the consistency of the result even on a lower dose in Cohort 2, the significant impact on need for IVIg retreatment. So next, I'll talk you through the grip strength results for the study. And here, we will be showing both cohorts combined. And so this is a complicated slide. But as Inge already introduced, we had an IVIg monitoring period built into the study, where we observed the patients on their natural IVIg dosing prior to study entry. And so in the different colors, these each represent the different IVIg doses that the patients came in on. So the first block here is cycle 1. And so we see in green, those are patients that were receiving every 2-week IVIg cycles, and similarly, every 3 weeks, 4 weeks and 5 weeks, et cetera. And what we can see across the different cycles is the same pattern is that when patients get their IVIg treatment, we see an improvement in their group strength. But then over a period of time, we see a waning of that effect, and this is pretty consistent. So the grip strength measurement is helpful for us because it's also a surrogate for kind of hand function. And it's something that is easily assessed on a daily basis and is one of the innovative aspects incorporated into this clinical trial. So when we get to the third cycle, after -- a week after they receive the third cycle of treatment, they then -- the patients entered into the double-blind treatment period. And as Inge mentioned, at this point, patients were randomized 2:1 to either start receiving placebo or they start receiving empa. In the placebo group in red, we see basically the patients continue on a relatively flat line. And of course, mixing here also the fact that the patients are getting retreated with IVIg as needed if they experienced a clinical deterioration and need for retreatment. Whereas in blue on the empa-treated patents and again, we're starting treatment at basically what we would expect to be the maximum effect of what IVIg can deliver for this patient cohort. We see a rapid improvement in their grip strength that's evident within 14 days, and that continues consistently for the duration of the double-blind treatment period. So this is -- was also obviously very remarkable data from our standpoint. And what I'd like to do is actually drive it home with looking at an individual patient profile and the journey of 1 particular patient that's representative of the group. And so what I'm showing here, this is the treatments. And so here, we have the IVIg cycles during the IVIg dependency period for this patient as well as the IVIG monitoring period. And that -- those are the green triangles. And then we see the start of the ARDA trial, where patients are -- where this patient, in particular, was started on empa. And then below that, we have a couple endpoints for the study, clinical endpoints. So again, the grip strength, which we showed before, and the different colors are the different hands. So in this particular patient, the blue is the patient's right hand and the red is the left hand. And we can see that during the IVIg dependency and monitoring period, the right-hand is severely affected with basically an ability to even squeeze the grip strength monitor. And the other hand, what we see is this cycling effect on the IVIg. So we see during the IVIg dependency period, it's clear that this patient is very dependent on IVIg. We see an improvement, but then we see the waning of improvement over time. And then once the patient starts on empasiprubart, we see this immediate improvement in the grip strength and this rock solid steady -- steadiness to their grips with none of the cycling that was evident before with IVIg. In the more severely affected hand, which we presume could also have axonal damage associated with it because we don't see it really moving very much with IVIg treatment, even there, we see some improvement in this particular patient. When we go down to the MMRC score, where this is a bedside exam of muscle strength, there are 2 different scores that were measured, the MRC-10 which looks at 10 muscle groups, and the MRC-14, which as the name implies measures 14 muscle groups. The difference between them is that the MRC-14 has more measurements of hand function, which tends to be the most relevant for most MMN patients. And we basically hear or see the same consistent story. We see minimal effect on -- with treatment with IVIg. And then once the patient starts on treatment, in the ARDA study, we see an improvement that's very rapid and sustained in both of these MMRC scores. In the study, we also looked at disease-specific activity limitations on a scale called the MMN RODS. Some of you may be familiar with the I-RODS, which is a similar scale that was developed for CIDP. This scale is less well validated than the I-RODS scale is, but it has been developed more to look at specific functions that tend to be a problem for MMN patients. So there's a lot more emphasis on upper extremity function. You can see some of the questions that are depicted here. And in this study during the double-blind period, across both cohorts, we see a significant improvement in MMN RODS scores in the patients that were treated within empasiprubart and essentially no change in the patients who were treated with placebo. So we have both grip strength and muscle strength as well as disease-specific outcome measures that demonstrated the potential of empa in MMN. And then, so the final element to this, that I think was also very remarkable when we turned the data card, was looking at what the patients actually thought of their experience in the study. And so across the 2 cohorts, when you ask a patient -- ask the patients how your condition has improved compared to the baseline basically coming into the trial, 83% to 94% of the patients thought that they are improved. And that's indicated in the green here, while on empasiprubart. And furthermore, over 1/2 to 2/3 of the patients thought they were either much improved or very much improved. So I think this also tells us this is not a small effect that we're seeing with empa, is that this is something that is going to be very meaningful for patients, and clearly leads us in the direction of working to Phase III as fast as possible. So where are we now? So we have, I think, clearly demonstrated proof of biology for C2 inhibition in multifocal motor neuropathy. We've also clearly demonstrated proof of concept with empasiprubart for the treatment of these patients across multiple disease-specific measures and patient-reported outcomes, that give us great confidence moving forward. And again, a clean safety profile to this point. So we are embarking on discussions with the regulators at this point with a goal to start the Phase III study in the fourth quarter of this year. In the background, we also have the iMMersioN study, which is a natural history study, which is adding to our understanding of the disease burden and treatment and overall patient experience, as well as giving us important information on outcome measure performance that can help us with the design of Phase III study. If you'd like more information on the iMMersioN study, there is a poster on that, that our team would be happy to tell you more about. And so with that, I'll turn it back over to Inge, and she's going to give us some more exciting news for the next steps and other indications for empa.

Thank you, Jeff. So next to MMN, we also have 2 other indications which are in clinical development. And these include delayed graft function after kidney transplant and dermatomyositis. I will guide you through the biology on the next 2 slides. So delayed graft function after kidney transplant occurs approximately in 40% of [ occult ] kidney donor transplants. And it ultimately can lead to graft loss. There is a high unmet need as currently there is no approved treatment to prevent DGF. So, but why have we selected DGF? Because the biology is spot-on as both the classical and the lectin pathway are activated in this indication because complements gets activated due to the damaged cells of the donor kidney. We have shown that blocking C2 improved the kidney function and transplant threats. So therefore, we think it's a very nice indication tackling both the pathways of the complement system we can inhibit. Currently, our Phase II trial of [ VYVGART ] is ongoing. The third indication we have selected for empa is dermatomyositis. So dermatomyositis is a multifactorial idiopathic inflammatory myopathy. But what about pathophysiology? It's multifactorial. And next to the presence of auto-antibodies also complement plays a pivotal role. How is complement activated or thought to be activated here? So actually, you have a direct activation of -- direct binding of C1Q to necrotic cells, which activates the classical pathway of the complement system, leading to inflammation. As you can see, C4 deposition on biopsies of both the muscle and the skin. So here, our study is empasi study will be a proof-of-concept Phase II study and is about to start. So empasiprubart is our next pipeline and product asset as we have currently selected 4 indications and much more to come in the future. So thank you.

Thank you, Inge. Thank you, Jeff. So we're going to get set up for the panel, and I'm going to invite Jeff and Dr. Kwon and Luc back up to the stage. We're going to hear a little bit about the unmet need in MMN and need of potential positioning of empasiprubart. Interestingly, this is the indication where actually we get the most inbound inquiries from patients on participating in this study. So we know that they're waiting, and I'm eager to hear the discussion. The other thing I want to mention is we are going to do the same thing with the panel. We'll open it up to a couple of questions from the audience on the MMN panel specifically, then Karen will come up and talk about commercial, and then we'll open up for the broader Q&A.

Thanks, Beth, for the introduction. Dr. Kwon, or can I call you, Patrick?