Hey, 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 gonna keep the room cool. We have cool content on stage. It's gonna 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 in to the webcast, especially our colleagues. Many of them are tuning in, globally. So the last time we had an 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 was before we even had phase three 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 two KOL panels, one for Sjögren's and one for MMN. We have two 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 are 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.
You know, 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 Pre-clinical Product Development. She's been at the company 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 our three of our clinical scientists, Julie Jacobs for Sjögren'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. Jeffrey Guptill. Before he joined argenx, he was a practicing neurologist, treating MG, CIDP, and MMN. We also have two external speakers here who will join the panels, Dr.
Simon Bowman, who is from the University of Birmingham. He's a thought leader in Sjögren's, and Dr. Patrick Kwon from NYU. Pat, 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 wanna talk about, you know, today we're gonna get pretty technical on the science, on some of the clinical development, so I wanna 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's gonna 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 gonna 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, the—a platform of sweeping antibodies. You're gonna 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's gonna talk about how this is translating commercially. A little bit on CIDP, very early days, but a lot on MG. You know, we've talked about we think this is a bigger market than we initially thought. We're gonna give you a number around that, and we're gonna talk about how we're gonna reach those patients. One of the ways is through label expansions. You know about our AChR negative study, but we're also gonna 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 indications, so we're gonna talk about our Sjögren's data, the Ro 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 in the second half of the year. We're going to be building weight behind empasiprubart. This is no longer a molecule on the back burner. This is a phase three asset that has shown transformational data. We're gonna 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 wanna have two molecules.
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's 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 three 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 3 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 co-founded 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 startup 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 biotech 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, that's a risky endeavor. You know, 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're hunting for real important novel targets, not, you know, random targets, but master switches in the immune system of humans, foundational immune targets. We found them typically in academic labs, and I will talk about it in a second. While we embrace risk on the biology side, we're not taking a lot of risk on the drug format side. 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, a single target. That timeline is not compatible with a biotech company. We're good antibody engineers. We're not good in unraveling novel biology, so we team up through co-creation with these translation labs, and that's where the magic happens. When we seed 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 two parties meet and jointly create something which none of them could create standalone. It's a formula with a good track record. We have built 12 pipeline assets. 8 out of the 12 demonstrated pretty exciting data in humans. 9 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 listened 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 when I was 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. We're writing 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 in MG. 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 seronegative MG. Empasiprubart is now already in 4 indications. I'm very proud to say that we venture into a phase 3 registrational trial in CIDP for empasiprubart, 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 four 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 spanned three continents in less than 12 calendar months. Karen did even better. With 8 months, we reached patients in three continents with VYVGART Hytrulo. That is the commitment which we have made to patients. We stayed loyal to our scientific roots. Science is still the language of the company, from A to Z, from end to end. Of course, it's the language in the lab, but when we're in the marketplace, we talk about science, and we talk about data. No bullshit.
We are also sharing the science through an extensive patent portfolio and through our top-notch publications, which we typically co-author 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 3 by 2030, 10 labeled indications, and 50,000 patients. How are we gonna do that? Let's look at our innovation horizons.
Today, we only talk about 4 IND candidates on their way to the clinic, but boy, there's much more cooking in the IIP kitchen, and there are more molecules on their way to the clinic than we will be talking about today. So I'm confident we're gonna make 5 molecules in phase three 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 are 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 very high chance of success. So I'm confident in our ability to reach 10 label indications by 2030.
Last but not least, the 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 gonna 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. I would like to start again with a slide Tim already shared, our blueprint for innovation. Why is that? It's because it's so intimately in 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. 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 gonna show you how we lift that co-creation model for our clinical stage assets, ARGX- 113, or efgartigimod, ARGX- 117, or empasiprubart, and ARGX- 119. Let's start off with ARGX- 117. We worked together with disease experts in the University of Utrecht....
Who really helped us to understand that C2 is uniquely positioned within the complement cascades. We invested a lot in translational research, learning, for instance, that MMN is an IgM-mediated disease. We made a hell of a molecule, 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 proof 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 toolkit, which is allowing us to understand the pathway, understand the effect our molecule has on that pathway, and to use that toolkit to check whether disease biology is linked to that pathway. These insights we give back to the community by means of peer-reviewed, top-notch publications. Now, how does empasiprubart work? Let's have a look.
A critical component of the innate immune system, the complement system, is comprised of the classical, lectin, and alternative pathways, and are essential in the defense against different pathogens. All pathways lead to the activation of a final common terminal pathway, leading to inflammation and membrane damage. However, activation of the complement system can also contribute to tissue damage in various autoimmune disorders when dysregulated. Empasiprubart, ARGX-117, is a novel humanized monoclonal antibody, specific for complement C2, and engineered to achieve a prolonged half-life. Empasiprubart binds C2 with high affinity in circulation at physiological pH 7.4, and is taken up by pinocytosis into the cell. The empasiprubart C2 complex is internalized, and within the endosome, it binds to the neonatal Fc receptor, FcRn. Due to the enhanced mutation, FcRn prevents its degradation.
C2 is released from the antibody antigen complex due to low pH and calcium concentrations, and transferred into the lysosome for destruction. Empasiprubart remains bound to FcRn and can be recycled back into circulation and bind new C2, therefore continuously binding and targeting C2 for destruction. This proposed mechanism, with the prolonged half-life, is being studied in current clinical trials at different dosing intervals. By binding C2, empasiprubart's proposed unique mechanism of action targets upstream of complement C3, preventing its activation. It is then observed to block the downstream activation of the classical and lectin pathways, while leaving the alternative pathway intact. Empasiprubart may potentially offer a new approach to treating complement-mediated immune and inflammatory diseases.
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 a reduced 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. Now, how does all this relate, or translates to the clinic?
What you see here is a single ascending dose data from our phase 1 study, where you can appreciate that upon administration of empasiprubart, you have a very profound reduction in free 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 C2 blockade is sustained, for instance, with a dose of 30 milligrams per kilogram, you can sustain that 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 gonna explain that in a minute. 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 are building. A few elements which I would like to point out. We're working with Steve Burden, who has 30+ experience on MuSK biology, and by doing so, we were able to find the best epitope for a MuSK agonist. We are also working with disease 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 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, phosphorylating MuSK, phosphorylating downstream molecules, ultimately resulting in clustering of acetylcholine 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 ARGX-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 slides. So in the control group, you start with 80% innervated muscle, and you see that rapid denervation going on. And that denervation you can slow down by administering ARGX-119 or a MuSK agonist. Next to that, you can also improve the motor function output by adding ARGX-119 to the equation. So what you see, 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're taking the first step into patients with a phase 1b in congenital myasthenic syndrome and a phase 2a in ALS. And we're 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're 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 want to understand more the unmet need in that patient population and the impact on QMG score. In ALS, what we're using there is an electrophysiological measure called the MScan. What it's doing, 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 the typical endpoints in ALS research, the ALSFRS, but it's much more granular. So that's again, an innovative way to go for signal 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 modulating 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, but basically, 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 two 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 face down towards the membrane. 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 steric 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 toolkit, 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 efgartigimod or these full-length antibodies targeting FcRn. And what you can appreciate in blue is that efgartigimod is not affecting FcRn levels over time, while these full-length molecules are rapidly degrading FcRn, which you can see by the green signal 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 four times, again, efgartigimod or these full-length anti-FcRn antibodies.
Again, no impact of efgartigimod on these albumin levels, while 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 toolkit 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 edemas, these hyperlipidemias, or muscle cramps associated with that albumin reduction. We don't see severe headaches or that, or aseptic meningitis, which we believe is linked with that exposed Fc fragment, 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 efgartigimod, 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 insight to come up with a whole portfolio of FcRn antagonists, and ARGX- 213 is the first one which we can disclose today. But when you walk that path of thorough 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 antibody platform, of which ARGX- 121 is the first one we're going to disclose today.
I would like to call Karen Silence, Head of Preclinical Product Development, to the stage to introduce to you both ARGX- 213 and ARGX- 121.
Okay. 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, IgGs and albumin are recycled via FcRn, and because of that, they have a long half-life of three weeks. ARGX-213 binds to albumin, and because of that, we significantly increase the exposure of this, of 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 bound 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 two Fabs, you remove the two Fabs, and you replace them with two VHHs targeting albumin. We tested this antibody in cynomolgus 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-down conformation, with the Fabs pointing towards the membrane, in this case, the VHHs pointing towards the membrane. We had developed an assay that Peter was talking about.
We invested a lot in a toolbox of assays. 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 monkeys, 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 the 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. We have a very nice PK. The PK-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 1 studies in the second half of next year. Next, I would like to talk about ARGX-121. As people already mentioned, this antibody is targeting IgA.
It has the Fc-ABDEG 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 1-3 milligrams 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 need a few iterations. But we learned a lot along the process. We started with a normal antibody, as depicted at the left, with two Fabs binding to IgA in a pH-dependent fashion. The antibody does as we described in the cartoon in the previous slide. When we tested in cynomolgus monkeys, we saw indeed sweeping of IgA, but it was actually quite disappointing. Why is that? We believed 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 degrade all the IgA when we are in the endosome. So indeed, we further engineered the antibody in such a way that there was 0 binding at pH 6, and this helped a lot. When we tested it in cynomolgus monkeys, the sweeping of IgA was significantly better, but when there were cynos with high IgA levels, we were sweeping less good than cynos with lower IgA levels. And also in patients, we can expect quite some difference between IgA levels, so that was, for us, still not good enough. The real breakthrough came from making a one-armed antibody. Then we don't make those immune complexes anymore. We still have the pH dependency, but we don't make the immune complexes, not at neutral pH, not at acidic pH. So now we bind much better to FcRn.
When we tested this molecule in the cynos, we were blown away by the data. We see 90% reduction of IgA within a few days for a long time. When we saw this data, we knew we had a drug, but we also realized 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 out 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 one 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 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 one in the second half of next year. So I hope I convinced you that we have generated here a really great platform using the ABDEG in the Fc and the one-armed 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 gonna 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 20/30 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 this, all of these things go back into the toolbox and are going to be that beating heart of our IIP. We're gonna move on to clinical development, and Luc Truyen, our Chief Medical Officer, will come up.
Thank you. Thank you. Hard acts to follow. I'm gonna 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 re-engage with these patients. Every trial that we design has patient input, and that is to be, for us, an important way to make sure that what we do is relevant.
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 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 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, 8 in planning, is a remarkable achievement. 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 where 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. 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 when 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-ADL reductions that are sustained, and we also continue to explore those regimens because it is a strong belief there's no one-size-fits-all. Predictability of dosing is not really something that we see. What does this particular patient need? We continue to evaluate that. We also today have the broader safety database. In fact, including post-marketing, I'm sorry, I'm gonna use a number, Karen. We have over 6,000 patient-years of experience with efgartigimod in MG. Nobody's close. Another important aspect of what we try to make sure that the treatment environment for our patient gets better.
The use of steroids is of course, one of those that's classical, it's cheap, etc., 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 six months of use. Those are things that matter in the long term. This sort of approach, really closing data gaps, is what we're also gonna 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 the 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 their voice to make sure that we can actually run the trials, that it's bearable for them. And then, of course, and this is always of interest, particularly to me, how do we minimize white space or speed, shortening that path to patients? In what follows, I will go through a couple of trials where I 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... Oops. Okay. I start by our expansion in MG. So this is a case of build upon and extend.
We're building upon data we've already generated, both in ADAPT and ADAPT -SC, around seronegative patients, where we see that they do respond to efgartigimod 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 autoantibodies, so we should work.
There our thinking is, let's create a data set that we can meaningfully show benefit in ocular MG, patients typically excluded from the trials so far. So we're looking very much forward to getting that data sets together. Sjögren'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 two trial with our same mode of action.
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 gonna invest in a small study, deeply phenotyping patients, to get at that biological QED, bring the data together, look at them, and then make the decision to go to phase three. 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 autoantibodies 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 one. Innovation two is, let's do that in a seamless operationally seamless phase 2, 3, with an interim analysis of phase 2 informing this independent phase 3 cohort. The advantage of that is that you don't pay that much of an alpha penalty, therefore, your power stays up, and you can run a smaller study should you wish. 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 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 IVIG frequency of use was. Those patients were then randomized to empasiprubart or placebo, and on empasiprubart, the IVIG 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 3. 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, VYVGART Hytrulo, 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 gonna be moving to phase three 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, a very important, continue to innovate on patient engagement and recruitment. It's in 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, so there's that connectivity between the science and the patient. You know, taking the first-in-class antibodies that we have, developing them in the most relevant indications, taking the trend 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 and the study, we're going to hear from one of the myositis patients. Do I need to click? Okay.
My name is Melissa, and I have dermatomyositis. I woke up one morning, couldn't move, and it hasn't been the same since. I couldn't stand up in the shower. I just had this sharp pain go through both of my thighs. I didn't understand what it meant for someone to say they were fatigued. Daily activities, I just really thought brought on that tiredness that I was experiencing. After my diagnosis, my biggest concern was how I was gonna keep my independence. My daughter, Riley, she's very active. This disease has kind of taken a lot of that away from me, as far as the physical activities. Me and her play a lot of board games, sit-down games. ... My husband, he helps me a lot around home and with our daughter.
I personally believe that it's important for scientists and the whole healthcare community, even providers, to listen more to the patient. We're not a one-size-fits-all case, and that's what I feel like they try to box us into. Never give up. You envision your own quality of life, and that will make the biggest difference in your life.
Idiopathic inflammatory myopathies, also known as myositis, is a group of autoimmune diseases characterized by chronic muscle inflammation. As you could hear from Melissa'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, an 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 dressed. But depending on their antibody positivity, patients can also have additional clinical symptoms. On the right, you can see, for instance, how antisynthetase syndrome antibodies indicated in green and dermatomyositis antibodies indicated in red, are associated with interstitial lung disease and skin rashes. While certain IMNM antibodies indicated in blue can lead to, 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 in IMNM, antisynthetase syndrome, and DM. 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 an autoantibodies 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 in IMNM on the bottom. In patient muscle biopsies, it has been shown that DM antibodies can lead to interferon pathway 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 complement. In 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, and we 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 a 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 grip 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 experiment, 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, so show that efgartigimod treatment in red led to a reduction in the number of necrotic muscle fibers comparable to the control mice, and increased the number of regenerating muscle fibers compared to non-treated 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 muscle 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 antisynthetase syndrome and dermatomyositis. Together with the observed treatment effects of IVIG and rituximab, this creates a strong biological rationale that efgartigimod may bring therapeutic benefit across these three myositis subtypes.
So that's why we designed this innovative basket trial to evaluate the safety and efficacy of efgartigimod in these three myositis subsets. It's an operational seamless trial, which consists of a phase two stage of 90 patients with 24-week treatment, and a consecutive phase three stage of 150 patients with 52-week treatment. Both are separate cohorts, and the transition occurs without a halt between the two phases, which means that once the last patient was enrolled in phase two, the next patient was directly screened into phase three. 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 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 three subtypes based on the phase two analysis at the end of the phase two, which is performed while the phase three is already started at risk. The primary endpoint is the 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 3, and results on the phase 2 analysis and a decision on whether to continue in each of the 3 subtypes is expected by the end of this year. Thank you.
Good. 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 two, and then the next one goes into phase three. 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 it's a go forward on all three. So next up, we're going to move to the Sjögren's section, the RHO study results, and you'll hear from Julie Jacobs.
I am a mom of two grown children and have three little grandchildren. Love to be outdoors as much as I can, kayaking, camping, hiking, anything I can outside. My initial symptoms were blue toes, blue fingers, and I was very curious about that, so I mentioned it during a normal routine visit with my doctor, and he almost immediately diagnosed me with Raynaud's and recommended that I see a rheumatologist. It was a long, arduous journey. You know, a lot of self-doubt, a lot of questioning myself, wondering if I was crazy, hearing doctors tell me everything from, "Lupus, question mark," to, "Maybe you have fibromyalgia," "Maybe you're just tired.
You need more sleep." And in the meantime, not only were the original symptoms of the blue toes, blue fingers, but now I had muscle aches and pains, joint pain, swelling, digestive issues, exhaustion, debilitating exhaustion. And so here, these new symptoms were coming in and not understanding what was happening and having just doctor after doctor not knowing what to tell me, not knowing what to test me for. And it took 12 years and 5 rheumatologists and many other doctors and tests before I was diagnosed with Sjögren's in 2021. Right now, the only way we can treat Sjögren's is to treat each symptom. You go to the eye doctor for the dry eyes. You go to your dentist to make sure there's no impact on your mouth from the dry mouth.
You see a rheumatologist for your aches and pains, and for the disease itself. And then I see orthopedics for some of the joint issues. There isn't a way to make me feel better, and when my rheumatologist looked at me and said, "Well, we don't know a whole lot about Sjögren's, and we don't know a lot about autoimmune diseases, so I wish I could do more for you, but I can't," I, I left there in tears. I take my grandchildren overnight quite often, and if I do that, it's Friday night. It's unfortunate because if they have an activity or something I want to participate on Sundays, I either miss out or I go, and then I'm not feeling well come Monday morning. I hope that maybe I can go back to the way I used to live my life.
I'm possibly 12 years in, but 3 years into diagnosis, what is it gonna be like in 10 years? And so that's another reason that I hope that there will be a treatment, soon, sooner rather than later, because I don't know how quickly will this progress. What will I be like in 5 years, 10 years, 15 years? My eyesight has changed so much. I also worry about, my legs, the weakness in my legs, and will I be able to live by myself? So not being able to be independent is a, is a huge fear. Like, is that a year down the road? Is that 6 months down the road? The unknown is, is very scary, and I hope, hope someday we can have a treatment for-- that's meant for Sjögren's.
As you could hear from Lisa's story, Sjögren is a devastating disease, and unfortunately, it is not rare, 'cause 1 in 1,000 get the diagnosis of Sjögren. It goes well beyond the dryness, because one-third to even half of the patients suffer from extraglandular manifestations. As you can see from this figure, it can be very heterogeneous, 'cause Sjögren can affect multiple organs, ranging from interstitial lung disease to vasculitis, articular problems, neuropathy, and even 5% of the patients develop non-Hodgkin lymphoma. At this moment, there are no disease-modifying drugs available. Well, we have Professor Bowman here with us today, who will talk more about this unmet need. When we look into the disease pathology, you can see why we believe efgartigimod could play a role here.
'Cause 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 ones against Ro52, Ro60, and La. These autoantibodies will form immune complexes, and the immune complexes again activate the plasmacytoid dendritic cells to secrete even more type one 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 extraglandular 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 2 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 Sjögren'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 treatments, most of them on hydroxychloroquine or low-dose steroids. Half of the patients had hypergammaglobulinemia or IgG levels above 16 g/L.
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. 'Cause it consists of five items. It not just looks at the systemic disease by the ClinESSDAI, low disease activity, but it also takes into account the salivary function, the tear gland function, serology, as well as the patient-reported outcome.
The main objective of our study was to demonstrate more CRESS responders at week 24 after efgartigimod treatment. Here are our results. So with efgartigimod, 45% of the patients were responder to the CRESS, and only 11% in placebo, giving it 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 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 rare, not that weird, because what we see from historical trials is that the ESSPRI is not so sensitive to change. This can be due to the two-week recall periods, and this again confirms that there is a need for new PROs in further development. Next to the CRES, we also looked at STAR. STAR is another composite endpoint, also in need for validation, and the STAR is very similar to the CRES, 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 ClinESSDAI is a bit different. It doesn't go for low disease activity, but for the three 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 with the CREST, and the difference here is not in the active treatment, but that we have more placebo responders in the STAR measurement. 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 two different ways, using responder analysis. On the one hand, we used an MCII of three points. So if you have a decrease of three points in the ESSDAI, you're a responder. And on the other hand, we raised the bar a bit and used the four points. Now, what you see is, again, a treatment effect with efgartigimod, which is even more pronounced when we raise 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 autoantibodies, here represented by the Ro52, 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 the pathophysiology in the beginning slides, where we had that loop of immune activation? Well, it seems that we are breaking that loop with efgartigimod.
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. I wanted to close with one more patient narrative of a patient that was on efgartigimod treatment. This was a patient with very high IgGs at baseline of 17 grams per liter. We can see that the IgGs nicely go down very fast. We see the effect on the autoantibodies, here represented by the Ro60, as well as La. We see a nice reduction in the 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 had glandular swelling at start, as well as lymphadenopathy and articular disease. Well, all of that went away with efgartigimod treatment.
Finally, we saw that there was an improved salivary function, because the patient started in hyposalivation and now at levels above this threshold. Overall, we established our proof of concept in Sjögren's disease. We saw the 60% reduction in IgG and the benefit on the biomarkers. We had an increased response rate looking at the composite endpoints, not just in one domain, but in four out of the five domains, and we saw that stepwise improvement over time in multiple measures. Finally, of course, efgartigimod was again safe and well-tolerated. Our data, together with a bigger fixed phase two trial, also with an FcRn blockade, really justify that advancement towards a new phase three study. That is something that is already ongoing. We had our end of phase two meeting, and we are planning to start the phase three by the end of this year. Thank you.
... Thanks, Julie. And actually, I'm gonna ask you to stay up here, and we're gonna get the panel set up. It's great. We could really feel 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 Sjögren'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. What we're going to do is we're going to have the panel questions. That'll take, you know, 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.
Good morning.
Morning.
Welcome.
Thank you.
Simon. I can call you Simon?
Of course.
Thank you. So, Simon, to situate maybe your expertise in the field of Sjögren's, could you tell us a bit more about your practice, your years, or, and-
So I'm a general rheumatologist, but I've been involved in looking after patients with Sjögren's over 25 years in Birmingham, in the U.K. I set up the clinic there. I've been involved in research in Sjögren's over that period. So, for example, I led the development of the Profile of Fatigue and Discomfort Sicca Symptoms Inventory, which was one of the first tools to measure patient symptoms in Sjögren'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. Sjögren'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 endpoint, I think it did demonstrate the ability to deliver clinical trials effectively in large numbers in Sjögren's.
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 have been a long journey into now, hopefully seeing the pharma industry take up the baton and hopefully bring drugs into clinical use.
Yeah, it seems certainly that you led the way in in some seminal work here. Thank you so much. Now, if you think about the patients you see, for which patients do you think is the unmet need greatest?
... So we have no, as Julie said in her talk, we have no effective licensed disease-modifying drug in Sjögren'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, severe Sjögren's is desperate for a, a drug that works. So I don't know if you'd like me to run through some of the features. There are basically three domains in Sjögren's. You heard from Lisa, the patient, about the debilitating fatigue and the impact that that can have on patients' 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 gonna 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, on Sjögren's. If you've got severe dry eyes, if you're having to put eye drops in every 30 minutes, I'm looking around at the number of people on laptops today, you're not gonna be able to do a job with a laptop if you're having to stop, you can't concentrate, you're having to put eye drops 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.
You've heard that about the multiple systems that can be involved: the lungs, the joints, the skin, the muscles, et cetera, et cetera. We are really desperate for medication for all of those three domains.
Yeah. So what struck me in Lisa's 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? Because I found that remarkable in this case. What do you think?
Well, it's not unique to Sjögren'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.
Yeah. Julie, coming to you. As you've designed this trial, what were the key considerations that you made saying, "This is how we're gonna get to the data we need?
Yeah, I think first of all, why we went into Sjögren's. So, it was actually there was a definite medical need, that we were approached by Dr. Isabelle Peene from the Ghent University Hospital, 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 fit, that 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 2 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.
Mm-hmm. So, Simon, you've, you spoke about how you did some of the seminal work with rituximab trials, and that your trial is today. What, from your point of view, are the key challenges that we need to think about fielding trials in Sjögren's today?
So, let me start with a 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, you know, would I have predicted that five years ago? Probably not. So that's a huge step forward. I think where the challenge is, that Julie's also alluded to, is demonstrating patient improvement. Now, part of that may be that the ESSPRI needs to be refined, and certainly a lot 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 trials 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.
Mm-hmm. And these endpoints, I mean, how would you translate them to clinical practice, or composites like STAR or CRISP, more relevant for clinical practice than an SDAI? How about 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.
Yeah. Thanks. Julie, you quite enthusiastically presented the data. What did you find particularly exciting?
Well, 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, 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 autoantibodies 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 stepwise improvement upon efgartigimod treatment.
... Yeah. 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, you know, 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 three. We gonna execute on that plan, Julie. Maybe just for the audience, just line up your thinking, what warranted really going to this phase three 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 three.
Mm-hmm. Yes. And would you agree with that progression to phase 3?
So obviously, I'm heavily biased here because I want to see effective drugs come to market. Obviously, people will be aware there are a number of different companies pursuing this. I think what they all have in common in my simplistic approach is they're all, in inverted commas, B-cell driven. So of course, I'd like to see this particular mechanistic drug develop and come to market. It, you know, I've been looking after patients for a long time. We've been waiting a long time to get to this point. You know, it is very exciting for me as a clinician to 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.
Mm-hmm. 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 I really look forward to getting efgartigimod signature in a phase three environment to show the risk benefit. So... But thanks for answering these questions, and I believe we now open the floor to some es-
We're just gonna take a couple of questions. I got a pre-request from Derek, so we're gonna start with him, and then we'll call on one other as well. Great.
Great. Good morning, and thanks for holding the event today. And yeah, Derek from Wells Fargo. So first question actually is for you, Luc. Just in terms of... You know, you described during the earlier presentation, your clinical strategy in Sjögren'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 and phenotype these patients was literally, can we show what Julie showed, that interruption of that vicious cycle? That's really what we wanted to get to and show. I'm not ashamed to say that then getting data in a bigger SC trial with the same MOA that gives us, significance is 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 gonna speculate on. We need to do the study.
But I feel from a safety point of view, that's why I said 6,000 patient years already, feel confident that we could be very competitive there, but it's all gonna be about the efficacy, ultimately.
Thank you.
Yaron Werber from TD Cowen. I have two interrelated questions. You did not give us the clean ESSDAI. You gave us the responder analysis. Can you give us a sense, what was the delta that you saw, just so we can kinda look at the nipocalimab data? And then secondly, as you think about phase 3, is ClinESSDAI gonna be the primary, or is it gonna be CRES? Thanks.
Yeah, so maybe on your first question, at the change from baseline, I assume you mean. So we did a very small study, as was already mentioned. It was not powered for significance. We only had seven 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 three-point difference, which nicely aligns actually with the nipocalimab data. And on the trial design, for the primary endpoint, now, Luc, if you want to comment.
Yeah. So we have had our end-of-phase 2 meeting, where we discussed this endpoint, and the ClinESSDAI is the endpoint that we would be moving forward with, in an appropriately sized for that measure trial, evidently.
So we'll take one last question for the panel, and then we're gonna... Yatin. Then we're gonna bring up the rest of management to cover the whole first half of the event.
Thank, 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 mechanism 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 unlocked with FcRn versus the B cell and the T cell that are being developed in Sjögren's? Thank you.
Chris Bowman, you want to give your opinion?
... I mean, the issue with Sjögren'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 Sjögren'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 a hundred percent this is the bit that's gonna work.
Because actually what has come about so far is there have been a number of different mechanisms, all broadly in this, this B-cell side, that look as though they, they may well be effective.
Mm-hmm.
So, I think probably-
Yeah. Maybe, maybe on the immune complexes, it could be vasculitis, for example. That's an example where we know immune complexes play a role, so that could be of interest. But what we saw in our small trial is that we really had multiple domains of the SDAI, where we saw an effect with efgartigimod. So I think it's too soon to say whether there was a specific feature.
Good. Thank you, Julie and Professor Bowman. I'm gonna have you guys step down, and then we're gonna have Tim and Peter and Karen Silence come up and sit in the stools, and we're gonna 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, you know, keep the event moving along, and then we'll do a second Q&A after the rest of the topics.
Okay. Thank you so much.
We do also have Karl available and, Arjen, our head of corporate development. We won't give you a clinical development question, Arjen. Tazeen, can we grab a mic up here?
Hi, good morning. Thanks for hosting, Tazeen Ahmad from Bank of America. When you talk about EMPA for CIDP, Tim, I just wanna get a sense of how you're thinking about, how the market's gonna 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, that's our mission. Our mission is to push to perform the efficacy envelope, so to speak, in severe debilitating diseases like CIDP. So having 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, Luc, than MMN. We know that next to IgG autoantibodies in a subset of patients, IgM autoantibodies are in play.
We know what IgM autoantibodies do, right? Very important recruiters of complement. We have shown in MMN how important actually EMPA can be. So we think that MMN is CIDP is a type of a disease where actually multiple innovative molecules can play shoulder to shoulder. So we're going to do the experiment and analyze the data retrospectively. We're not going to limit the patient population in any means or measure 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 gonna 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.
Just for the webcast, the second question was how the trial would be dosed for CIDP.
Yep.
Hi, hi. Charles Pitman-King 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 competitive landscape as we see further development from competitors.
I think I will start with answering this question, and then I will invite Karen to add on. 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 1 clinical trial, we had an IgG reduction of more than 75%, and that percentage is relatively lower in a phase 3 clinical trial because patients which are already on immunosuppressants happen to have lower IgG levels. So don't forget that in phase 1, we have put forward almost 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 a VYVGART effect has 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 it 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 one molecule, and there is a time clock in the back, be it, you know, 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 one molecule.
So think of 213 as a molecule which is substantially differentiated from 113, from efgartigimod, 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're saying. 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 program, the ambition was to make a molecule with where we need less frequent dosing. And 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.
Hi, it's Rajan Sharma from Goldman Sachs. Thanks for taking my question. Just a follow-up on 213. As we think about the indications that you could target and kinda 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 mode 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?
Yeah, we're paying a lot of attention when we develop molecules like 213 to formulability , 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 gonna do, guys, is go into phase 1 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, you know, a very powerful IV product, a very powerful sub-Q-- a powerful sub-Q product with VYVGART Hytrulo, soon a prefilled syringe, and then afterwards an auto-injector.
So we want a portfolio of options to maximally tap the opportunity in front of us.
Hi, great. Alex Thompson from Stifel. On 121, I'm just curious if you could talk a little about the IgA program and how you're thinking about a product profile versus the BAFF/APRIL and IgAN, how you might be able to play in that space. Thanks.
Karen, do you want to talk about the speed, depth, and durability of the molecule?
Yes, I like this question a lot because indeed, I mean, there is indeed some antibodies targeting the APRIL and the BAFF in the clinic. But with these antibodies, you lower IgA maximally 65%, and they need between 3-6 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, you know, approaches where you cool off an entire B-cell population, or even worse, deplete an entire B-cell population. We want to go with a precision tool after 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 mention that, Tim, because indeed, with our program, we leave, for example, the IgM intact, while with the anti-APRIL and anti-BAFF, you do also significantly lower the IgM levels. We leave IgM intact. That's an important one.
Hi, 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 Sjögren's, if you can clarify. Maybe I missed it, but the phase three will that enroll patients with anti-Ro autoantibodies or also anti-La antibodies, or is it an all-comer study? Thank you.
Hey, thanks, Suzanne, and thank you for flying over the pond for this R&D Day. I appreciate it. Peter, do you want to take the two questions, please?
Yeah, I think in terms of half-life, we have a half-life in healthy volunteers of approximately 70 days. 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 in 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 Sjögren's, Peter-
Well, basically, it's...
Antibody status
... Yeah, we will not zoom in to a specific antibody status, so we will include... Basically, it's an all-comer study.
... Karen, as our sweeper 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 variants again, which we tested in cynos, and we compared it to an antibody targeting C1, which had really a horrible PK, and it was adding those enhanced mutations and making it a 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.
We're gonna take two final questions. I think we have Gavin and then Jun.
Hey, Gavin Clark-Gartner from Evercore. So just one question on dermatomyositis. You had a little bit of Sjögren's data on reducing the C1q immune complexes. I'm wondering if this has any read-through to DM, since the immune complexes can drive some type one interferon signaling and maybe some of the cutaneous symptoms. So I'm wondering if this kind of de-risks that side of the disease or if you have any preclinical data to get at this component.
Yeah, it's, 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.
Mm-hmm.
There's a lot of focus and attention to the interferon biology and whether actually we can preempt it at biology upstream, right, Pieter?
Yeah, correct. I think this is incorporated in our clinical study in myositis, so we'll give you the answer a little bit later. I think what you do see, and it was also evident from the talks from Julie and Leentje, is that there is quite some similarity between Sjögren's and myositis. That is indeed to your point definitely the case.
Thanks.
Joon Lee from Truist. Thanks for hosting the event. 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 threshold effect, and is that threshold, you know, similar across different autoimmune diseases? Thank you.
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 that type of data. Pieter, is there anything specifically you would like to mention to help us?
Yeah, I think the disease which we understand best is MG, where that 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, that level in different indications, that's a difficult question, and data should speak to that, yeah.
Thanks for the question.
Thank you. So we're gonna take about a 10-minute break, and I mentioned before, there's posters up and around if you wanna 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. Cool. Great. Welcome back. We have an exciting second half ahead. We're gonna 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.
Living with MMN for me is interesting because I'm only affected in my legs. So I have to think about everything before I start my day that's gonna involve steps. Do I need my walker? Am I gonna be able to get to point A or point B by myself? So it's just always having to plan ahead, and I'm always very fatigued, so that's another thing that comes into play. So it's picking and choosing what is important, what can hold off, what I can get done in one day. It's emotional as well because I have a family, and I know this affects them, too. You know, there's some things I can't do and I have to say no to, which kind of break my heart. I noticed things were starting when it just... I just started tripping.
I did, you know. So we call it, you know, tripping on air. But I think in 2012 was when things kinda sped up. That's when I started to struggle to walk more than 50 feet, and my balance felt really off. And it wasn't until I was in Nashville with my husband, and we were going to a cocktail party, and I was in heels, and we were walking across the hotel lobby, and I started feeling tingling in my left foot. And then I couldn't feel my foot at all, and I fell really hard. I think that was the moment for me that I realized that I need to get in and get checked. I was diagnosed with MMN in 2013. Unfortunately, for a lot of us, we're misdiagnosed with ALS, and that was about six months for me, and it's very scary.
When I was told that I had multifocal motor neuropathy and not ALS, I was very relieved. But I was also very scared 'cause I didn't know what this meant for the rest of my life. I'm a survivor of abuse, and so it really affected me after diagnosis, right? So I was very depressed. I was very anxious. I felt very guilty. I told my husband he could leave me because if I didn't believe I was worthy of what I had, why would a broken me be worthy of that, right? So I did start on IVIG, which, unfortunately, I was one of those that got very sick on it. So, I would have flu-like symptoms for three days after every infusion. Switching to subcutaneous for me was a game changer. I did not have any reactions from it. I felt fine afterwards.
I've never had any issues traveling anywhere with it, which is great. ... You know, when you get something like this, you lose a lot of yourself, and just gaining some of that independence back is huge. I still really struggle with a lot of walking. You know, I love to go visit my son in New York, but it's tough. He lives in Brooklyn, and there's, you know, you can't grab cabs like, you know, you used to, and he likes to go out and do things. So it's just that limitations of trying to figure out how to make this work and not miss out on life.
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 a subset of patients. In MMN, mainly hands and forearms are affected, and therefore, patients struggle with daily activities, but also legs 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 the lectin pathway 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 the target GM1, which is located at the motor neuron, at the node of Ranvier or on the Schwann cells. Those IgM autoantibodies, they bind, and they activate the classical pathway of the complement system, leading to complement deposition at the motor neurons and the Schwann cells, ultimately leading to destruction and axonal damage, leading to the conduction blocks.
Together with, in University of Utrecht, we also have some new learnings, meaning that IgM autoantibodies, which target GM1, located on the Schwann cells, also play an important role in a subset of MMN patients. So together with the collaboration of Utrecht, 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 a Schwann cell, is you see the nice structure of the cell with no complement deposition and a nice marker of structural of the structure. However, when you add anti-GM1 autoantibodies to the mice, you clearly see 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 the Schwann cells, which is also one of the hallmarks of MMN patients.
When anti-C2 is added, so when EMPA is administered to these 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 these 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 breathe. After administration or addition of the autoantibodies in the mice, which then underwent a complement attack, you can see that the mice start to breathe very fast and superficial. When EMPA was added to these 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 empasiprubart to these mice, reduced the structural injury and also, significantly improved the functional respiratory rate in these mice. So actually, we have really unraveled the role of complement in MMN, and therefore, we went for MMN as our first indication. And now I will guide you through the phase II design. So ARDA is our phase II double-blind, placebo-controlled trial in which we test empasiprubart in patients with MMN. So during the screening, the MMN diagnosis and the IVIG dependency is assessed by an MMN confirmation committee. When their dependence on IVIG was uncertain, patients entered an optional IVIG dependency period. All eligible patients, after being dependent on IVIG, entered an IVIG monitoring period. During that period, patients received three 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-to-1 randomization, and they were treated for 16 weeks. After the 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 plus or long-term extension study. In ARDA, we have tested two cohorts, so and after in DSMB , so meaning two different doses. After DSMB, it was decided to lower the dose for cohort 2. Now we will invite Dr. Jeff Guptill to guide you through the data of both cohorts.
Thank you, Inge. So on behalf of the ARDA study team, I have the pleasure to reveal the results today for both cohorts of the ARDA study, so cohort one and two. 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 wanna touch on that since this was a phase two 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 three. 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 a scientific congress the results of of the cohort one. So what we saw across the two cohorts was that treatment with EMPA reduced the risk of retreatment with IVIG between 84%-91%. So in blue depicted on the graphs are the patients that were treated with EMPA, and we can see that in cohort one, only three patients required retreatment with IVIG, and one patient in cohort two. 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 were fewer retreatments in cohort two.
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 two, 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 one, 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, that when patients get their IVIG treatment, we see an improvement in their grip 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 received 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 to 1 to either start receiving placebo or they start receiving EMPA. In the placebo group in red, we see that basically the patients continue on a relatively flat line. And of course, mixed in here are 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 patients, 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 was also, you know, obviously, very remarkable data from our standpoint. What I'd like to do is actually drive it home with looking at an individual patient profile and the journey of one 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 inability 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 grip strength, with none of the cycling that was evident before with IVIG. In the more severely affected hand, which we presume, you know, could also have axonal damage associated with it, 'cause 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 MRC score, where this is a bedside exam of muscle strength, there are two different scores that were measured, the MRC 10, which looks at 10 muscle groups, and the 14, which, as the name implies, measures 14 muscle groups.
The difference between them is that the 14 has more measurements of hand function, which tends to be the most relevant for most MMN patients. And we basically here 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, the questions that are depicted here. And in this study, during the double-blind period, across both cohorts, we see a significant improvement in the MMN-RODS scores in the patients that were treated with 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.
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. Across the two cohorts, when you ask a patient, ask the patients how your condition has improved compared to the baseline, basically coming into the trial, 83%-94% of the patients thought that they are improved, and that's indicated in the, in the green here, while on empasiprubart. Furthermore, over half to two-thirds 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 empasiprubart, is that this is something that is gonna be very meaningful for patients and clearly, leads us in the direction of working, to phase 3 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 3 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 the overall patient experience, as well as giving us important information on outcome measure performance that can help us with the design of phase 3 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 gonna give us some more exciting news for the next steps and other indications for EMPA.
Thank you, Jeff.
Mm-hmm.
So next to MMN, we also have two 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 two slides. So delayed graft function after kidney transplant occurs approximately in 40% of cold 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 get activated due to the damaged cells of the donor kidney. We have shown that blocking C2 improved the kidney function in transplanted rats.
So therefore, we think it's a very nice indication, tackling both the pathways of the complement system we can inhibit. Currently, our phase two trial, VARVARA, is ongoing. The third indication we have selected for EMPA is dermatomyositis. So dermatomyositis is a multifactorial idiopathic inflammatory myopathy. But what about the pathophysiology? It's multifactorial, and next to the presence of autoantibodies, 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 or of C1q to necrotic cells, which activates the classical pathway of the complement system, leading to inflammation. As you can see, C4, the deposition on biopsies of both the muscle and the skin. So here, our study is about... Our empasiprubart study will be a proof-of-concept phase two study and is about to start.
So empasiprubart is our next pipeline and a product asset, as we have currently selected four indications and much more to come in the future. So thank you.
Thank you, Inge. Thank you, Jeff. So we're gonna 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 gonna hear a little bit about the unmet need in MMN and, you know, potential positioning of empasiprubart. Interestingly, this is the indication where actually we get the most inbound inquiry, 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 wanna mention is we are gonna 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?
Patrick's fine.
Okay. To again, to situate you for the audience, could you just explain, you know, your practice, who you see, what's your connection to MMN?
Sure. So I am a neuromuscular physician at NYU. I see patients with both acquired and hereditary nerve and muscle diseases. So MMN falls into my practice.
Yeah. And so how many do you see, MMN patients?
Well, MMN is pretty rare. I think over the last 8 years that I've been in practice, probably on the order of maybe 1 a year, so somewhere between 6 to 8.
Mm-hmm. Yeah, and do you have a kind of a patient in your head that you would say, "This is one that I would describe to tell people like this audience what MMN is like?
Yeah, so my sort of concept of MMN, it's usually more male. Usually the patient is 40s, 50s years old, and usually it's the upper extremity that gets affected first. Usually, it's hand weakness. I think of one of my patients who was in his late 30s, and he was a construction worker who he came in to see me with painless right upper extremity weakness. And so that sort of concept of a younger male is kinda what I think of.
Mm-hmm. Now, we heard from our patient here that one of the frustrations is that there's often misdiagnosis. What do you think is the reason for that? How can we do something about that? Because I'm sure getting a diagnosis of ALS when you don't have it is pretty stressful.
Yeah, it's tough because the diagnosis oftentimes depends on EMG findings, and the patients don't always present like textbooks. So that issue of misdiagnosis of ALS comes up all the time.
Yeah. Yeah. So, okay, limitations in treatment were already described. What are your own frustrations with the current state of affairs?
Well, so the biggest issue is that IVIG is really the only treatment that we know works. And it doesn't always fully work, and there are plenty of patients that are refractory. There are plenty of patients that don't have a complete response. And you know, once IVIG is tried, and if it fails or if there's some other contraindication, really, steroids or plasma exchange, which we usually use for other immune neuropathies, those therapies really don't work. So you're sort of stuck with either immunosuppressants, which obviously have a host of problems, and ultimately, you know, it's just trying one thing after the other, and it's one failure after another. So it becomes very, very frustrating for the patients, obviously, but also for the treating physician.
Yeah. Thank you. So, Jeff, you were doing this, too, in a not too distant past?
Mm-hmm.
Although probably there was gonna be an expiry date on that. Does this suit follow your experiences with this? What was-
Yeah, it's very much so. So I think the diagnostic challenges are certainly there. When I was in practice, yeah, we would get a lot of referrals for patients diagnosed with ALS and other muscle conditions that turned out to have MMN, or patients that were diagnosed with MMN that actually didn't have that and had some other problem. In terms of the treatment, I'd say my experience is very similar to Dr. Kwon's, is that IVIG, you know, obviously is the first-line treatment and works for a lot of patients. Like, and patients are typically very thankful to have, you know, something to treat them when, particularly when they've been previously diagnosed with ALS. But the problem tends to be, as Dr.
Kwon mentioned, not everyone responds, and oftentimes there's an incomplete response. And then just to add a little bit to this is that my other experience is that over time, the IVIG effect tended to wane, and that patients that initially responded to IVIG slowly got worse over the course of several years. And as you mentioned, at that point, then there aren't a lot of options for those patients, and you're basically just you know trying to do the least amount of harm to the patient with unproven immunosuppressants.
Yeah. Thanks, Jeff. So Patrick, we showed some new data today on the trial. As you look at this, as somebody standing in the field, what's your impression of what you've seen on the data so far?
Well, you know, it's important to note that oftentimes when we think about therapies for our patients, it's really stabilization of disease. And you know, obviously, that data showed that aspect, but what was really impressive to me was that the patients actually improved, and significantly, and there was a sustained response. Particularly, you know, the grip strength, which is very important, but also even the functional scales, you know, the MMN-RODS, for me, that is pretty impactful because, you know, these patients, the biggest issue is their disability in their daily lives and their inability to function. You know, for instance, my patient that was a construction worker, he was unable to work, and knowing that there is a functional improvement for me is very important.
Mm-hmm. Yeah, thanks for that. Now, Jeff, in the trial design, as you presented it, what do you think were some key factors for success?
Yeah, so I would point to, I guess, two factors. I think you may have alluded to these earlier in the morning session, is the confirmation committee that helped to ensure that we were enrolling the right patients in the study, patients that actually had MMN and that had the potential to benefit from the therapy, given the problems with misdiagnosis. And then I think the other part was the IVIG dependency and monitoring period. I think we learned a lot from that, to really understand the patient's experience while on IVIG and to clearly demonstrate the cyclical nature of standard treatment at this point. So yeah, I think that really helped us.
Yeah. So, Jeff, just putting you on the spot before asking the last question to Patrick.
Okay.
You're confident going to phase III?
Yes. Yeah, yeah. So I hope I made that clear from the presentation. I think we have a lot of confidence in the safety profile, in the efficacy data that we've demonstrated to date across multiple endpoints that are all very consistent and clearly clinically meaningful.
Yeah. By the way, I agree with you. Patrick, then bigger picture, what are you looking for for a new therapy in MMN? What, what would really make a difference for you?
So, you know, kinda going back to what I said before, you know, the therapies that we use right now are all very sort of general and generic. And you know, one thing that I really look for is something that's more targeted. So the fact that we've thought through, or you've thought through the science and sort of made specific targets for this disease, I think, that's very, very important. The other thing is, obviously, safety and efficacy is important, but ease of administration and, you know, making it easy for the patient to access the drug is very important. IVIG can be very difficult. It's a 4- to 6-hour infusion, oftentimes 2 days every 3 weeks...
It's very time-consuming, and for a young worker or a young man, somebody in the sort of the prime of their sort of career, it becomes very debilitating.
Yeah. Thanks so much for this, and this is the end of the prepared questions. Beth?
Yeah. So we're gonna open up to the audience for a couple of questions to the MMN panel.
Hi, this is Vikram Purohit, Morgan Stanley Research. Thanks for taking our questions. So we had two for both doctors, based on your current experience and your prior experience. What portion of your patients, if you had to put a rough estimate on it, at any given time, are on IVIGs versus immunosuppressants? And any context you could provide around how long patients stay on IVIG typically would be helpful on kind of an annual duration basis. And then secondly, understanding it's still early days for empasiprubart heading into phase III, but based on the data you see right now, do you see it positioned kind of more like a standalone first-line treatment, or would you hope to use it as something that can make IVIG kind of less used throughout the year?
Kind of push apart the frequency and the windows between using IVIG.
Want to start?
So in terms of patients on IVIG for MMN, generally speaking, you know, of the patients that I have, probably a little over half are still on IVIG. There are maybe two or three that we've unfortunately had to try other things, and it's been very, very challenging. The second part of your question was about what you know, how it would fit into the landscape. I mean, honestly, if we could avoid having to use IVIG in a lot of these patients, I would absolutely go for it. And you know, kind of just even looking at VYVGART and Hytrulo, you know, that's been pretty impactful for me for my myasthenia patients. We've been able to get a lot of patients off of IVIG, off of steroids, off of a lot of immunosuppressants.
I mean, it would obviously, if we were able to just use a monotherapy, that would be the goal.
Yeah. And so, for me, I mean, basically my practice, every single patient got IVIG, unless there was a contraindication that prevented them from receiving it. And then the duration of it, I think the expectation when I was counseling patients is this is gonna be a lifelong treatment for you. Yeah. Do you wanna elaborate any further on or the positioning here moving forward?
No.
Yeah. Okay. I figured I'd defer that to him.
We'll come back to that one. Leland?
Hey, good morning. Yeah, Leland Gershell with Oppenheimer. A couple of questions, first for Luc, if you could just address on the phase II for delayed graft function. So presumably, you're looking at time to dialysis, dialysis delay in terms of the endpoints. Just to maybe describe what you're looking at there.
Yeah. No, no, we're looking at, because it's a proof of concept, we're looking at a bit more proximate endpoints that could be surrogates, like change in eGFR rate and so forth. So not, not a delayed for the pre POC.
Got it. Okay. And then for the physicians, dermatomyositis, obviously a tough indication, other complement-based approaches to some extent have been looked at. I guess I wanted to ask, you know, if there's any particular confidence in C2 as a target for DM? I guess, Dr. Guptill.
Yes, I think as was laid out earlier in the discussion, talking about the mechanism of C2, I think we have confidence in through some of the preclinical data that this is an appropriate target to look at in a proof of concept study. And again, you know, I think the complement studies to date have really focused on kind of the end of the complement cascade, and here with C2, we have the opportunity to intervene at a more proximal stage, which hopefully will lead to better outcomes than prior studies.
Do we have one final? Okay, Yaron.
Yaron Werber from TD Cowen. A question about the MMN trial design, in phase III, maybe based on your phase II learnings. So is the thought to take patients who are doing well on IVIG, do they need to be unstable, sort of not terribly symptomatic, or they need to break through, and then do you wash them out and then put them on empa versus placebo, and it's time to relapse or time to IVIG therapy? I'm trying to get a sense of exactly-
Yeah
... this is essentially a switch study.
I'll take that one.
Yeah.
We're gonna engage with the FDA and get an agreement on what the trial design will be or will have to be to meet the needs, and we will disclose at another date that's appropriate.
But that was the phase II trial design, right? What I described was phase II.
Oh, in the phase II?
Yeah. Just so we even have the phase II.
Well, that, that's... Yeah.
Yeah. So, the phase II design was everyone was on IVIG coming into the study, on their established regimens that they had been on, according to their treating physician, and I guess, optimizing their IVIG frequency. And then we had the monitoring period where we observed them during their regular IVIG treatment, and then after the third cycle of their monitoring, they were then randomized to active treatment with empa or placebo. And again, I think the key feature there is that they were randomized at the point that they were experiencing their maximum effect from IVIG.
... Good. Thank you. Thank you to our panelists. We're gonna now shift over to commercial, and maybe we can have Karen circle back on that MMN question about where we would hope to be positioned in line of treatment based on some of the market dynamics.
Yeah, it's the fingers up there. Perfect. Okay. Well, well, thank you. It's great to see everyone this morning. I hope you're all as excited as I am and impressed with what's been a few hours of absolutely incredible science. And I guess I just wanted to start before getting into talking about our commercial engine and our impact for patients, with taking a moment to say thank you and express my gratitude to my colleagues in discovery and development that are here, that have presented this science this morning, but also those back in Ghent and around the world that are working tirelessly and consistently to develop this groundbreaking science and make this impact for patients.
I can tell you, it's truly a privilege to be working alongside you and your teams to bring this medicine, these medicines and this science to 50,000 patients by the end of the decade. I think it's a bold mission, but and I'm proud to be part of it. So what I wanna talk about a little bit today is how do we get to that 50,000 patients? What does that look like? And what I can tell you, and what you can see from this slide, is that it looks like a consistent cadence of indication launches year on year, between now and 2030, and with the potential for two additional molecule launches before 2030. So it looks like a lot of launches.
To quote Keith, my predecessor, "It's another example of launches upon launches upon launches." So it's a really exciting time for the, for the commercial organization and for our argenx. So when we think about the commercial engine that we need to build, what we're focused on is how are we disciplined about our scaling, while at the same time ensuring that we're maximizing the impact for patients and for shareholders. So we think about it in three waves. We think about Wave One today. How do we maximize MG and CIDP? Think about Wave Two, where we really start to expand our impact in neuro, including potentially an approval in MMN for empasiprubart. And then Wave Three, where we really start to expand beyond neuro into additional autoimmune indications.
I'll talk a little bit, and just touch a little bit on TED and Sjögren's towards the end of the presentation. So with those three waves of growth, what we can expect is a continued cadence and momentum of revenue growth through the end of the decade. So to get into Wave One and start with that, where are we with MG? Well, MG really set the standard on commercial excellence and really painted the picture of what our playbook for launch will be for future indications. And there are three components that I think drive the success of what we've seen in MG, and that we continue to see in MG. The first is a continued commitment to generating evidence post-approval that makes efgartigimod, whether it's VYVGART or VYVGART Hytrulo, relevant to clinicians and to patients.
So whether that's the 50 setting the standard of the new efficacy, the new efficacy standard of MSE that Luc talked about, over 50% demonstrated across our trials and actually, up to 9 cycles, 80% of those patients sustain that MSE. That's unmatched. Luc already mentioned the 6,000 patient years of safety data. We have meaningful steroid reduction. We also have invested in both cyclic dosing as well as sustained dosing to give more options in terms of real-world dosing to get the efficacy that patients need. So that's part of the playbook, continuing to generate relevant evidence to continue to entrench and lead the market. The second is around empowering patients. We want to empower patients to believe they deserve more and that they can ask for more and expect more from their treatments.
And we've heard throughout this morning from individual patients across various diseases, talking about their want and their need for more for their autoimmune diseases. We're delivering that with MG. We made the innovative decision to invest in DTC at launch. Innovative for a rare disease, certainly a big step for a company like argenx that hasn't commercialized before. And what we're seeing is that innovation certainly has impact and has paid off. We continue to see return on investment on the... And will continue to invest in that direct-to-consumer. We have 92% brand awareness among patients, and what that translates into is patients going into their neuros and asking for more, asking for VYVGART, and over half the time, those patients are granted those requests.
What's really important to know around that, that grant is that we have a broad base of neurologists that are prescribing VYVGART, and that's part of our strategy, and that's part of our playbook. We have over 2,700 prescribers in the U.S. We're the number one prescribed biologic amongst advanced biologics, and that's thanks to the speed of execution and the focus of execution of our teams in the field. It's really important to note that whilst all of these examples here are U.S. examples. We see the same thing playing out across the globe. We were approved in three continents within one calendar year.
With VYVGART Hytrulo, it was within 9 months, and what you'll hear about in a moment is that we're gonna continue that geographic expansion, and most importantly, and close to my heart as an Australian, we'll be in our 4th continent in just a short period of time since we have submitted in Australia. But this playbook, evidence generation, co-creation with patients, and executing with speed, is what's delivered VYVGART to be over $1 billion before the second year of launch, 9 quarters of growth, and over 10,000 patients globally. And that's the playbook that you can expect for all of those indications and molecule launches through the end of the decade, and that's what gives us confidence that we can maximize the impact for patients and for shareholders.
So what it looks like in the future as we think about MG, taking that same playbook and doubling down. We're continuing to generate evidence, and you heard earlier from Luc, in seronegative as well as ocular. By expanding our-- That'll expand our addressable market significantly and entrench our leadership in MG. We're continuing to empower patients. We've shared previously that we're developing a prefilled syringe as well as an auto-injector. We've filed the prefilled syringe before the end of June this year, and we're with the goal of self-administration, and we're continuing to execute with speed, with our global expansion, as I mentioned earlier. That's a key to accelerating our time to peak.
So if those are the future drives of growth in MG, and we've said a few times now that actually, we think the MG opportunity is larger than what we, than what we thought at, at launch, what does that look like? We've done a lot of work internally, and looked at the data in a lot of different ways, and so here, this is the updated TAM, or Addressable Market, for MG. So let me walk you through this chart, to, to talk about how we got to up to 60,000 patients, total addressable market in MG. We started at 17,000 potential patients at launch. That's the AChR positive patients.
You'll remember we, that's our current label, and we've, we've, we were looking at the current use of biologics, which is in late, well, at that time, was in later lines of MG. We add to that 17,000, 11,000, with the seronegative, potential seronegative approval, and another 7,000 with ocular. In addition, based on what we're seeing with the uptake of VYVGART in the market, and VYVGART Hytrulo, and actually, you heard from one of our neurologists today around how, around the experience with VYVGART, we believe that VYVGART will be used and is able to be used in earlier lines than we thought at launch. In fact, we're seeing over 50% of new patient starts for VYVGART and Hytrulo are directly after the orals.
So with that, we add 25,000 patients to our addressable market to get to a total addressable market of up to 60,000 patients by the end of the decade. So that's a significant amount of growth in the addressable market 3.5 times, and I'll tell you, when we first saw these numbers, I think each and every one of us on the management team that saw them said: "Is that real?" "Is that true?" And so we've looked at these numbers from multiple different angles, both within MG, and also taken a data-driven approach to look at other analogues in other rare disease markets. And what I can tell you is that consistently, across rare disease markets, you can see the same thing.
When there's new treatments and new innovation that comes to the market, what you see is an expansion in diagnosis, an expansion in treatment rates, and an expansion in the addressable market. We see it very consistently. I think I've shared in the past, my experiences in MS, and we've certainly seen it in MS, and we think that that's a good analogue to use, and just to share what that looks like in MS, between the period of 2012 and 2023, the percentage of the market that was taken up by advanced therapies in MS grew from 11% to almost 70%. So that's actually six times the addressable...
The advanced therapeutic use in MS during that period, and what it was driven by was new mechanisms of action, multiple launched assets, and in fact, because as the treatment rate grew, as the diagnosis rate grew, when they redid the analysis of prevalence, it had also had grown. Why this is important is because I think we are in a leadership position where the first-in-class FcRn, we're the number one prescribed in terms of the advanced biologics in MG, and we see that there are more innovations coming to market. We see that as a good thing because it will grow the market, it will improve outcomes for patients, and we believe we'll continue our leadership in that market.
So moving on from MG to what I know from when I've spoken to a few of you out in the hallways on top of everyone's mind, which is CIDP, which is the other leg of our portion of our growth in wave one. We're about 16 days into the launch or post-approval, 16 working days from June 21, when we got the CIDP approval. So I won't have a significant update for you today, but I do wanna share some of the exciting early signals that we're seeing around a successful launch in CIDP, and I can tell you, it is a really exciting time.
What we've seen in the last 16 working days, although I can tell you, the argenx team has worked more than 16 days, is we are seeing rapid execution and early and good signs of early adoption. In terms of rapid execution, we got the approval on June 21. On June 22, we were at the Peripheral Nerve Society up in Montreal. We already had approved materials, approved talking points, and we were out engaging with customers, and one week later at EAN in Helsinki. I can tell you from those engagements with neurologists, there is a palpable sense of excitement for the first innovation in three decades, first new MOA in three decades. They're really people are really excited about the 61% relapse reduction, no question about it.
But what really stands out is the improvement in function data, and that is truly motivating for neurologists. In addition to being out at those congresses in the first couple of weeks, our team has reached 25% of our key targets within 14 days of launch. You'll recall from the approval, we've expanded our target audience of neurologists in the U.S. to 10,000, and that reflects actually the bigger opportunity in MG, as well as the additional opportunity in CIDP. So we've reached 25% of the key targets within that in the first 14 days, and we're making great progress on our payer policies. That's a key to unlocking the launch. We have payer policies in principle.
I think over the next few weeks, we'll be able to announce some payer policies in place. We are seeing early adoption already, and what we're seeing, as enrollments come into My VYVGART Path, which is the patient support program, is both prescriber breadth and depth. So we have prescribers or neurologists that have written VYVGART Hytrulo for a number of their CIDP patients, so more than one patient, and we're also seeing that 20% of prescribers are new to VYVGART or VYVGART Hytrulo, so new to the franchise. So we're seeing that broadening in our prescriber base with CIDP. So really positive early signals, and I'm incredibly excited to share that we also have our first patients on treatment.
We've already had two patients injected last week, both coming from IVIG, one, a fee-for-service Medicare, the other a commercial patient. So we're able to navigate the dynamics of payer approvals even in the short term before policies are in place. So I would say I'm really confident, I'm really happy with where we are with the CIDP launch. There is early excitement internally as well as externally, and we're exactly on track. So with that, I wanna move on to the wave two of growth that I mentioned as we think about the vision of getting to 2030. And with wave two, what we start to think about is the potential for a second molecule approval and launch in MMN, in empasiprubart.
I hope you'll all agree when you see that data from the trial; it's incredibly impressive data, and that's hence the confidence as we move into MMN in phase three. What we have with MMN is the opportunity again to build a market. So we see this as very similar to what I was talking about earlier, MG, CIDP, all those other rare disease markets where there's been limited treatment options. You've heard about how long the diagnosis takes. We believe there's an opportunity to accelerate diagnosis, and for empasiprubart to become the standard of care, to become the first line of care in MMN.
There are around 10,000 patients in this market, and the approach that we will take to building this market is the same playbook that we've taken for MG and that we're taking with CIDP. It's demonstrated success. We'll focus on innovative evidence generation. We talked about the natural history study already to understand the real-world experience. We're gonna engage with patients not just on clinical trial design, but similar to how we have with MG and CIDP. Certainly, we'll be working with the patient advocacy organizations as well as patients themselves, to think about how we wanna, how to engage in the market. And on execution, we have the advantage of leveraging our existing neurology relationships. This is really an expansion of our leadership in neuromuscular.
So that's an incredibly exciting moment for us to think about and to prepare for, with a potential second molecule in an additional indication in neuromuscular. Last thing that I want to touch on before we end the day today is to touch on our third wave of growth, which gets us to 2030, which is as we expand outside of autoimmune, so outside of neuro into other autoimmune diseases. So I'm touching right here on Thyroid Eye Disease and Sjögren's disease. Those are the thyroid eye disease, we've already kicked off the phase 3 study. That's with the PFS. We shared that that has kicked off early this year. Sjögren's, we've shared today, that our plan to kick off before the end of the year.
There are a lot more indications that I could be covering if I had more time, that I would. But just to touch on these and why I'm really excited about these two indications, it's another example where we have the opportunity to transform outcomes for patients. So in Thyroid Eye Disease, we have seen the unmet need that exists with the TEPEZZA launch. It's clear that there is an unmet need, and we believe bringing another, potentially bringing another mechanism of action, with a different, risk-benefit profile, will add benefit to those patients and will continue to grow that market. So we see a real opportunity, to start, to continue, to have an impact for patients and grow that market.
In Sjögren's disease, I don't think I can say it any better than what was said earlier today from the patient. This is a devastating disease. It's not just about mild, dry eye, dry mouth. This has real significant impact on patients' quality of life. The systemic manifestations are serious, and these patients deserve an advanced and targeted therapy. And we're excited with the opportunity to bring that to potentially up to 100,000 moderate to severe patients in the future. So those are just some of the highlights of where we're focused in that wave 3 of growth that get us to the 50,000 patients by the end of the decade. So with that being said, I wanna come back to where Tim started the day, Vision 2030.
... Hopefully, what you've seen through the last few hours is how we build towards this incredibly ambitious and incredibly bold mission for and vision for 2030. 5 new molecules in phase III by the end of the decade, 10 labeled indications, and together, that getting us to 50,000 patients on treatment. And what that is built on is a foundation of entrepreneurial spirit that brings together innovation, true innovative approaches, along with a focus on disciplined execution as we scale this organization. And the only way we can do this and deliver on this is if we truly deliver on our promise of becoming an of being an integrated global biotech company built for the future that's transforming the lives of autoimmune patients. And I, I'm incredibly excited to be part of that. With that, I will hand it back to Beth. I think we have a Q&A.
Yeah.
Um-
We're going to... You stay up, please.
Okay.
Then we're going to invite Tim, Peter, Luc to join, and then you can also ask questions. We do have Karl, Arjen, and our scientists available for any questions that came up in the second half. While we're getting set up here, so the plan is we'll do the Q&A, then Tim's gonna close. Then we have lunch available out there and happy to stay around and answer any further questions in a more informal setting. The one question I have been getting is when the slides will be up. They'll be up within, you know, 20, 30 minutes of the end of the program on our microsite, which you can access on our website.
This is for when you-
Tazeen. Oh, okay. Yep, go back there first. That's fine. We'll come up after. Yep, go ahead.
Yep. Okay. Hi, Amy Li, Jefferies. Thanks so much for taking our question. So just going back to Sjögren's, what percentage of the patients were on background therapy, and did you see any impact from background therapy to efficacy? I guess another way of wording it is, how difficult is it to show a benefit on top of background therapy?
So I'm going to give the word in a second to Julie, but in general, background therapy in Sjögren's is pretty limited. So we had the usual suspects in terms of, for example, hydroxychloroquine, et cetera. These patients had to be on a stable dose for a significant amount of time, which was pre-specified and still be symptomatic despite being on the background therapy. But Julie, we had the traditional background medications present in the study, right? Why don't you come on the podium, please? Yeah.
That's not necessary.
Okay.
So yes, indeed, we had only stable doses of hydroxychloroquine, actually, in the patients that we selected, which seems to be the majority of them that are on that treatment. I think what is important that is even with the hydroxychloroquine or the low-dose steroids, 50% of the patients in our study had levels so high from IgG that they were above 16 grams per liter. Even with our first assay that we used to detect autoantibodies, they all exceeded the upper limit of quantification, so definitely still a lot of improvement there.
Yep. Thank you for the question.
Thank you. Tazeen?
Yeah.
Okay. Hi, first question for Karen. Thanks for that quick update about how the launch is going. I'm sure all of us appreciate that. I wanted to get your thoughts about... I think you said there's two patients that have now been converted to actually receiving treatment. Now, I think people have been laser focused on the commentary that your team has been providing about being cautious about initial uptake as it relates to the speed with which- ... payers are gonna start to reimburse. You know, our doctor checks are indicating high demand, of course, but you've talked about the 16 days on the market. Can you just talk about... I know it's an N of 2, but-
Yeah
... how is this early, early, launch metric reflecting internally on your expectations about the speed with which you're gonna get reimbursed?
Mm-hmm.
And then I have a question for Tim, a separate question for Tim.
Yeah, I can touch on that. So the patients that have been injected last week, the approval process for that is a sort of an exception process, let's call it that. So that doesn't mean that we have payer policies in place, but we're really pleased that we were able to, for those patients, get those exceptions in place. And of course, we'll be working really hard to continue to get those exceptions for where the patient enrollments have come in. That's similar to the approval to MG and to Hytrulo.
I can say what matters most for the trajectory is getting those payer policies in place because that just streamlines the whole process of getting patients started, and importantly, getting a critical mass of those payer policies in place. I would say where we are with that is definitely on track. The payer conversations are progressing very well, and I would say in line with our, with our expectations. We're, we're really confident, and we're really pleased with how the launch is going.
Okay. And then, Tim, a question about competitive landscape. We've talked about the gMG launch now for several quarters. Again, you've also have talked about the potential for the space to get crowded. As far as competitors in the pipeline go, it's kind of been disappointing in terms of what everyone's been able to produce, but there are questions coming up about the potential attractiveness of cell-based therapies. I know in particular, as of now, there's questions about CD19-targeted therapies. Can you just talk about, theoretically, how you view that particular class relative to the advantages that have been demonstrated for VYVGART and VYVGART Hytrulo so far? Thanks.
My God, I knew there was a difficult question coming. The first thing I would like to say is that in the space of myasthenia, we have put the bar very high. Just to give you some perspective, for patients on VYVGART, 78% of these patients achieve an ADL below 5. Remember, an ADL of 5 is an inclusion criterion to be eligible for a clinical trial. So it gets more and more difficult actually to find patients to participate to an MG trial, because when you're in VYVGART, I mean, it's basically an outstanding result. The second thing I would like to say is we're not only setting the bar high from an efficacy and a safety point of view and a convenience point of view, we are also working very hard to move upstream into the treatment paradigm.
That's where we want to play. We want to actually, in analogy with my—with MS, not reserve innovation for those patients, you know, who had to really deteriorate and be last line and refractory. No, we want to make that innovation available as close as possible to first line, and that's why we are investing in getting drug available in patients, you know, which are just going off Mestinon. So there will always be a small subset of patients which are refractory to many drugs, and maybe that is the place where CAR-Ts ultimately will play, given the complexity and the cost associated with such therapy. But that's not where we want to play. We think our job is to prevent as many people as possible from sliding down into that refractory status, and move upstream into the treatment paradigm.
Thank you for the question.
Hi, thanks for taking my question, George Farmer from Scotiabank. I was wondering if you maybe could talk a little bit about the growth of VYVGART in MG. And, you know, you set this 60,000 patient kind of number. That's pretty significant relative to where we are today. And now that you have a lot more quarters of growth, you know, how are you thinking about retreatment, and how does that also fits into your assumptions?
Yeah, I can talk about that from a commercial perspective. What we're seeing and how we're seeing the MG market, I would say, play out, is that based on the efficacy and safety and tolerability profile of VYVGART, along with, of course, VYVGART Hytrulo, the 30- to 90-second injection, it's being used earlier line. And patients are staying on therapy on VYVGART. So rather than thinking about a where we were with the 17,000, where maybe the patients were being treated with biologics were more refractory and there was some cycling and potentially retreatment, what we're seeing is that patients are being treated earlier with VYVGART. They're staying on therapy. They're getting their cyclic dosing, whatever their number of cycles needs to be.
We're quite pleased with the retention that we're seeing. For us, retreatment with VYVGART is not a big driver. It's rather using it earlier line and keeping those patients in control with that minimum symptom expression.
Hi, Douglas Tsao from H.C. Wainwright. Tim, just a question. We've still continued to hear largely the focus on orphan disease. We've seen some of your competitors start to move into development into sort of more prevalent conditions with their FcRns, as well as even some of the other cell therapies like CD19. I'm just curious, since you did talk today about your vision in 2030, does there come a point with either VYVGART or potentially some of the other molecules, where you start to look at more prevalent indications for the company?
I think that is a great question. And the way we work, and I hope you could see that from the R&D day again, is that, you know, we typically make indication decisions based on a deep understanding of biology and let the data guide us, you know, where that biology is best in place. So we're never going to force fit the molecule into a franchise or a marketplace because we happen to play there. Now, it is true when you look at our sequence of indications, right, that the prevalence numbers are steadily going up. So I think it's fair to say that once you leave MG, CIDP, and you go into areas like, for example, Sjögren's, you're probably gonna leave the orphan marketplace.
Although, I think the subsets of patients we will effectively be treating from a numbers point of view, actually would look like a, an orphan indication. So expect a continuum of indications from orphan to maybe specialty, or I don't know how you would call it, but I think that's a natural evolution, taking this molecule where it should play. And I don't know, Luc, whether you want to add further perspective to that.
Sure. The confounding factor, though, with more prevalent indications is that probably the autoimmunity part with other mechanism may become a subpart of the driving force. And then you have to start thinking, "Okay, we take this intervention, what do we add?" And we already see this happening actually today-
Mm-hmm, mm-hmm
... that where people are thinking combinations, which personally I find exciting, but yeah.
Yeah. Thank you, Luc, and thank you for the question.
Just a quick follow-up. Do you think that the biology for some of these more prevalent conditions is starting to be better understood and something that you would be able to exploit?
At least I think that's what we try to make is a small contribution to the science and the understanding of these diseases. As our expert called out in the panel, we are moving into Sjögren's, which, you know, targeted B-cell therapies. We try to be even more targeted. So I think it's a matter of time, and we will understand some of these bigger indications, you know, with a much better level of understanding than we had before. And that opens the gate to the precision tools, which we would like to make. So that takes us all the way back to my opening. The more we understand about human immunology, the better we're equipped to make precision tools with transformational benefit risk profiles, being able then actually to give people's lives back.
... Myles, I think I see you with a microphone.
Yeah, Myles Minter from William Blair up the back here. Just two questions from us. The first one is, I'm sure you're well aware that one of your peers in CIDP is running a couple of trials, and one includes trying to demonstrate superiority over IVIG. I mean, how important is that for you to maybe generate a data set along those lines for either VYVGART or maybe more importantly, for empasiprubart down the line? That's the first one. And then the second one is just: what is the FDA's definition of a relaxed P value as it applies to ADAPT in the ocular and seronegative patients?
I'm going to give that second question to Luc. I think with pioneering in CIDP, I mean, the first innovative medication in 30 years, when you enter such a space, you have a different approach and a different clinical trial design in mind. If you're a follower and you anticipate that VYVGART will be on the market for 2, 3, 4 years, the question is: how are you going to position yourselves in such a playing field? So I think we understand that strategic choice to try and go for superiority over IVIG because they're just coming so many years behind. On the relaxed P value, a question, Luc, maybe we want to give a bit more context.
Sure, sure. And this was actually a great dialogue we had with the agency. So, of course, we are, over the number of years, trying to get seronegatives based on what we already in hand. You may recall from the ADAPT subQ study that we have data there that they show response, and so we proposed a number of designs to them with different varying reliance on the preexisting data in seronegatives. And so where we ultimately landed was that they agreed that it would make sense in the presence of preexisting evidence that our alpha control could be set at 10% instead of the normal 5%.
So it's a small, elegant trial where we have been leveraging the historical data. I just want to call out that we have been approved in Japan for seronegatives. We're selling very well in Japan for seronegatives, and these patients doing equally well as the seropositive. So I think there's an accumulating body of evidence, which I think helped in the conversation.
Absolutely.
Joel?
Joel Beatty from Baird. For MMN, which dose of empasiprubart do you plan to move ahead in phase III, and were there any differences in safety between the two doses?
There was no difference in safety between the two doses. Remember, there's a very strong rationale to go for C2 from a safety point of view, and so far, I think that's really materializing in the study. We're not going to be public today about the design of the phase III trial in terms of dose, dosing regimen, or endpoint because we don't want to pre-alert competition.
Great, thanks. Gavin, do-
Yeah. Hey, it's Gavin again. You actually just answered my question, but I'll ask it in a slightly different way for Empa dosing in MMN. Where does the cohort 2 put you in terms of dosing target? Is it around the 95% free C2 level or a different threshold?
Allow me to stay silent on the answer, because if we give that type of information, actually you can reverse engineer the dose. But it was a significant step down in dose. And actually, we're playing with two variables, right, Luk?
Yep.
We're playing with dose and dosing cadence. Maybe you want to explain it conceptually?
Yeah, so and the way both cohorts were set up is not only did we study different doses, but also increasing intervals between doses and seeing where we got breakthrough, so that we could kind of, in one study, figure out what dose, but also the, the cadence. And given that we don't have... Well, there are several reasons not to disclose it now, but one of them is we also have to have the agency agree to it.
Yeah, and the spacing Luc described is happening in the open-label extension portion of the study. And remember, we always said this actually serves to populate the PK/PD model. We now have a pretty sophisticated PK/PD model, which can actually predict the dose and the dosing regimen we need to use in phase III to optimize efficacy versus dose. Yeah. Thanks for the question.
Rajan?
Hi, it's Rajan Sharma from Goldman Sachs. Firstly, just on the auto-injector for VYVGART, what's your base case for launch time on that? And then follow-up on Sjögren's. So you identified the kinda two autoantibodies. From what you have internally in terms of the data, is there anything that suggests that one of those may be more dominant in driving pathogenesis or indeed specific symptoms associated with Sjögren's?
Thank you for the question. From an auto-injector point of view, let's be patient for a while. This project is going full blast. It is still somewhat away from the marketplace. We're prioritizing the prefilled syringe, which will be the first stepping stone away from the current generation of VYVGART Hytrulo. The auto-injector is coming as a next generation, and we will be informing the market about it, you know, in due time. In terms of pathogenicity and driving symptoms in Sjögren's, I think it's fair to say, Julie, right, that they do drive symptoms, as you explained on the podium. The different autoantibodies drive different types of symptoms. There has been a debate in the literature about their pathogenicity, but I think there is growing evidence, right, Julie, about their role in driving disease biology.
Is there anything you would like to add to that?
Yeah. Yes, and then I can stop talking, right? So I think concerning the autoantibodies, I think Ro and, and Professor Bowman can explain it better, but the Ro 60 is most linked to the Sjögren's disease, and it's also known that if you're positive for Ro 60 and Ro 52, then you have more extraglandular manifestations and more severe disease. There also have been some passive transfer models where they show that with the anti-Ro 52 or the anti-Ro 60, you really get disease, so that confirms the pathogenicity. But concerning the autoantibodies, I think Ro is, Ro positivity is most important.
La on its own is not linked directly to Sjögren's. The Ro is the principal antibody, and the La in the context of Sjögren's is probably a bit secondary.
Thank you.
Looks like-
Thank you for the question.
Yeah. Thank you all for the Q&A engagement. Looks like we're all set. We don't have any more questions, so thank you to the Q&A panelists, and I am going to leave it to Tim to close out the event.
Yeah. Thank you, Beth. But I'll keep it very short because I'm between the audience and the lunch. And I think we had a very full menu explaining actually the new vision, Vision 2030. We're leaving Vision 2025 behind us. We think that's mission accomplished. We are now into the 2030 game plan. Full confidence in the team and its ability to execute. But what I really want to say before we break out for lunch is, I would like to say thank you. We're on the journey together. This is an ambitious plan. It requires time. It requires patience. Sometimes there is success, sometimes there is attrition, but I would really like to thank all our long-term shareholders, giving us the chance and the opportunity to build such a company we're currently building.
We, as a team, are extremely grateful for that, and you have our commitment that we will continue to execute the way we have been executing so far. So thank you very much for being here today in full summertime, and let's now enjoy the lunch. Thank you.