argenx SE (ARGX) Earnings Call Transcript & Summary

Good morning, and thank you to everyone for joining us today for our virtual R&D Day. I'm Beth DelGiacco, Vice President of Corporate Communications and Investor Relations at argenx. We're looking forward to a time soon when we can meet again in person. We decided to use the virtual forum to our advantage and invited several of our argenx scientists to speak today, likely team members that you haven't met before but who are the beating heart of the company. They work closely with our molecules, our collaborators and our clinical teams and drive the ongoing translational studies to better understand the results we're seeing clinically. On our agenda, you can see the depth of expertise of the speakers joining us today. Tim Van Hauwermeiren, our Chief Executive Officer and Co-Founder, will talk about where we are today as a company and how we are advancing towards argenx 2025. Hans de Haard, our Chief Scientific Officer and Co-Founder, will talk about efgartigimod and the translational work we've done more recently on our Fc fragment. We'll then move to our new indications where we'll have both of the scientific leads speak: Bas van der Woning for myositis; and Peter Verheesen for bullous pemphigoid. We have the pleasure of being joined by 2 top physicians to speak about the severity of these indications in a panel that is moderated by Albert Kovera from our global marketing team. Dr. Rohit Aggarwal joins the panel from the University of Pittsburgh to talk about myositis, and Dr. Russell Hall from Duke University to talk about bullous pemphigoid. Finally, we'll share data on our next immunology asset, ARGX-117. The lead physician on the team, Olivier Van de Steen and the lead scientist, Inge Van de Walle, will cover the potential of C2 as a target, data from our Phase I study in healthy volunteers and our path forward into multifocal motor neuropathy patients. We'll end the event with a Q&A session with our speakers and broader management team, including Wim Parys, Chief Medical Officer; Keith Woods, Chief Operating Officer; and Karl Gubitz, Chief Financial Officer. Our Q&A session will be audio only to allow you the opportunity to dial in and ask questions. We expect the event to wrap up shortly after 11:00 a.m. Eastern. Also to maximize the virtual format, we're hosting a microsite with several presentations from physicians and patients to support today's event. On this site, you can view disease overviews from both Drs. Aggarwal and Hall on myositis and bullous pemphigoid, respectively. We additionally asked 2 of our patient partners to talk about living with myositis and bullous pemphigoid. It's the patient perspective that motivates our team every day, and we encourage you to hear directly about the disease and treatment burden they face and how their lives changed after receiving their diagnosis. To provide more information on our global launch, we worked with Dr. Chongbo Zhao to talk about the MG opportunity in China, which we believe to be substantial. And finally, on the microsite, we included a second panel discussion with 2 vascular experts: Dr. John Kastelein and Dr. Daniel Rader. We continue to learn more about FcRn and its dual role in recycling IgGs and albumin. In this panel, we'll talk about the role of albumin as it pertains to our autoimmune patients. We also encourage you to visit the microsite to read relevant publications around the topics discussed today. All presentations will be available on the microsite for up to 1 year should you want to rewatch at a later date. And with that, let's start the event. Tim?

Thank you, Beth, and thank you, everyone, for joining us today. We have very exciting content to share with you that we hope will outline important future programs at argenx. When we founded argenx, Hans, Torsten and myself, we chose the name argenx because it refers to the ancient myth of the Argonauts, a team on a mission to do the unthinkable. I still stand behind this choice because it underscores our purpose: we are a team, a quickly growing team that wants to bring a revolution to our patient communities in how we understand and perceive autoimmunity. You can see within this infinity symbol that we believe our opportunity is limitless when it comes to immunology innovation. We see nothing but an abundance of opportunity ahead. In order to embrace this opportunity, we lean equally on both the science and the patient. There's the critical unmet needs of the patient that drives us, but it is the breakthrough science that allows us to do something about it. There's no one without the other. Our Efgartigimod journey started in 2013. We had new modality thanks to our collaborator, Sally Ward, the opportunity to be first-in-class targeting FcRn and an innovative way to do so with our Fc fragment. We showed the first clinical proof of concept with an FcRn antagonist, demonstrating a clear correlation between the PD effect, i.e., total IgG reduction; and efficacy in MG with the improvements both on the MG-ADL and QMG disease scores. Once we validated the deep science, we turned to the patient. We relied on our patient partners in designing the innovative ADAPT trial, evaluating the potential of individualized dosing for the snowflake disease for patients each experience their own individual course. We have now committed our time to engaging with the MG community through our advocacy efforts, our patient marketing efforts and our real-world evidence study, MyReWorldMG, involving over 2,000 MG patients. We believe that we are standing on the precipice of a change in autoimmunity that reminds us of a monumental shift that has occurred in oncology. For decades, oncologists had only systemic blunt tools to treat tumors, classifying tumor types by the organ of origin, for example, lung or breast. There has been a shift in therapy to one of this tumor type-agnostic where we don't have therapies specific to lung or breast cancer but to a mutation that is present in many tumor types. We have also seen therapies like the PD-1 inhibitors approved in multiple tumor types with unifying biology. We believe that autoimmunity is set to undergo this revolution from traditional [ run ] tools like corticosteroids or chemotherapy to therapies like Efgartigimod, precision tools that reduce pathogenic IgGs regardless of the target antigen. The immune system holds the unifying biology that ties together diseases of the muscle, blood and skin. The power of a tool that is target antigen agnostic is twofold. One, it means the breadth of opportunity in terms of patients we can reach as fast were not limited to diseases of the muscle. We can look systematically at where the IgGs play. Two, we have a discovery tool in our hands. Best way to determine if a disease is IgG-mediated is to use a targeted approach like Efgartigimod. As we reach new patients, we will reach new frontiers of biology. With myositis, we have exactly this opportunity to use Efgartigimod as a precision tool to better understand the role of IgGs in the disease biology of each of the myositis subsets we will evaluate. You will recall that with MG, we had before us a very well-characterized autoimmune disease. We knew that 95% of patients had a form of disease that is driven by either acetylcholine receptor, mask or LRP4 targeting auto antibodies. CIDP, the disease is already more heterogeneous. We knew from the literature that about 40% of patients had characterized IgGs against the peripheral nerve. What we learned from our interim analysis is that more CIDP patients have an IgG mediated form of CIDP, where the auto antibodies are just not characterized, our go-no-go showed this. Now with myositis, we have an opportunity. We see a diverse group of autoantibodies, which are either known to drive disease or are associated with disease. This is about 70% of patients across subtypes, which means that about 30% are yet to be characterized. With efgartigimod, it's okay that we don't know the identity. If it's an IgG, we will clear it. It is this principle that we rely on as we continue to interrogate biology with new indications. With bullous pemphigoid, we have a different story to tell. This is the second indication within autoimmune skin blistering diseases and has some key similarities to pemphigus. In both the role of the specific autoantibodies is well characterized. In the case of pemphigus, they target DSG 1 and DSG 3, and in bullous pemphigoid, they target BP180 and BP230. We have equally as convincing data from therapies that are good proxies to efgartigimod, like IVIg, plasma exchange and, preferably, immunoabsorption. And we hear from patients it's similar high unmet medical needs for fast-acting safe therapies that allowed them to taper corticosteroids. In the more fragile BP population, this need to taper is even more critical. We will use similar principles from the pemphigus Phase III trial design to go straight into a registrational trial with BP. Our skin blistering franchise is quickly shaping up with these 2 serious autoimmune diseases. Efgartigimod emerged from the heart of our science, which is our immunology innovation program. As I said earlier, unique way in which efgartigimod interacts with FcRn as an Fc fragment, we're making the natural interaction of a wild-type IgG with FcRn, this is all due to collaboration. ARGX-117, our second immunology asset, which we also talk about today, emerged from a productive collaboration with Utrecht University and Professor Erik Hack. As we look at data from the Phase I healthy volunteer trial, we'd be hard-pressed to find a better way to interrogate C2. If this is your target of choice, we believe ARGX-117 to be the best way to address it in terms of complement knockdown and durability of PD effect. Both efgartigimod and ARGX-117 are children of the IIP mold. We know that to identify first-in-class targets, we need collaboration. We know that to build the best molecules, we need collaboration. We are also realizing that to interpret why we see the clinic results that we see, we need to go back to collaborative science and to run the translational studies. This seamless knowledge transfer is the power of the IIP program. Going forward, we plan to shift our priorities to those assets that fit our growing franchises of neuroinflammation, hematology, skin and kidney. The most proliferative of our therapeutic franchises is within neuroinflammation. We will talk about both efgartigimod and ARGX-117 in detail today, our 2 lead candidates. But we also want to talk briefly about our investment into the candidates that will follow. There is a wealth of opportunity within neuroinflammation alone. In its way, the franchise is shaping up to be a company within a company. The unmet need across MG, CIDP, myositis MMN is serious. We see this need extends to diseases like SMA, ALS, congenital MG, various muscular dystrophies and rare neuropathies. ARGX-119 will be a very exciting part of the story, but there is a lot of more work to do. As we look forward to the cadence of launches ahead within the neuro franchise, the importance of building infrastructure now becomes abundantly clear. We can leverage what we've built for MG into CIDP, MMN and myositis, as well as ARGX-119 over the next 5 years. Focusing our energy and resources into a franchise not only creates the economies of scale but also allows us to attract top talent and deep in-house expertise. I would like to end my presentation with a peek into the future. Today, we are in the middle of 2021, and by the end of this year, we expect an approval of efgartigimod by the FDA for our first indication myasthenia gravis. We have been grateful for all of you who have joined us on the journey of bringing efgartigimod to this point. We're always thinking to the future and want to share some of the expectations we have for an argenx 2025. While much will change as we reach more patients living with autoimmune disease, we are committed to keeping true to the roots of argenx. We were built out of an antibody engineering discovery platform and entrepreneurial spirit, and we believe that collaboration drives innovation. We see these traits, innovation, entrepreneurship, collaboration as core to our culture and core to our growing pipeline. These are priorities as we grow and as we bring forward a new asset each year. We have capitalized on our innovation in various ways, including through partnerships and company creation opportunities. This is the forest you see on the slide. We plan to prioritize programs that fall within our therapeutic franchises going forward, but we also know good science when we see it. Value can come in many forms. Now in moving up the tree, the IIP feeds our immunology pipeline. Today, we are in 6 efgartigimod indications, and we have committed to get to 10 indications as quickly as possible. And the work doesn't stop there. Thanks to our Zai collaboration and our commitment to externally sponsored research, we expect to be well beyond 10 indications by 2025. ARGX-117 is on the heels of efgartigimod. We are starting with NMM but have laid out exciting opportunities within our current and future therapeutic franchises to capture the breadth of potential of C2 as a target. 2025, we expect to see multiple late-stage ARGX-117 trials. We also spoke about ARGX-119 today, which, while early, could be an important part of our story by 2025. Finally, shifting to the patients, the leaves of our tree. Our patients and their communities will remain a core priority for us. The autoimmune market is growing. And as I said earlier, we hope to be standing at the precipice of a revolution within it. In the market we expect to surpass USD 150 billion by 2025, we want to make efgartigimod as broadly available as possible. We want to be available in many markets across 6 of the 7 continents, whether through our own commercial capabilities or through partnership. We will be active in indications across 5 therapeutic franchises. This comes with significant team growth. We plan for our team to double in 2021 from 400 to 800 and for that growth to continue to accommodate to global commercial and robust R&D business. Let me end by expressing my gratitude to all my colleague, Argonauts. It is thanks to their relentless enthusiasm and unconditional commitment that we are where we stand today. The journey has been an intense one, and the hope of our patients is a deep source of inspiration to all of us. I would now like to hand over to my colleague and Co-Founder, Hans de Haard, who is our Chief Scientific Officer. Hans?

Thank you, Tim. I'm very excited to be here today to talk about the FC fragment of efgartigimod, the unique design properties that emerge from our collaboration with our partner, professor Sally Ward, and why we believe these properties are directly connected to the differentiated clinical outcomes we have seen. You will recall that Sally Ward work on FcRn contributed to an immunology breakthrough. She found that the FcRn is not only responsible for the transfer of IgGs from the mother to the baby but also responsible for IgG homeostasis, in other words, for the long CM half-life of IgG. This picture shows the function of X1 and explains how this receptor gives IgG along FcRn molecule. Small volumes of blood, including the CM proteins are taken up into endothelial cells. Due to the pH-dependent binding of IgGs to FcRn, these immunoglobulins bind to the receptor at the low pH of the [ lysosome ]. Auto CM proteins and excess IgGs that are not bound to FcRn will disappear into the lysosome and be degraded. The FcRn IgG complexes will recycle back. And at the neutral pH of the blood, IgG will be released, and they'll go back into circulation. It is important to realize that albumin is the only other protein next to IgG, which binds in a pH-dependent way to FcRn and is also recycled resulting in a long FcRn half-life of this molecule. As is shown in the yellow square, albumin binds to a different site of FcRn as opposed to IgG. And therefore, both molecules can interact simultaneously with a single FcRn molecule. We are learning that not all FcRn antagonist molecules act the same and that there are different ways to antagonize this receptor. We choose the design of the Fc fragment as it is a natural ligand of FcRn and induces a highly potent and specific antagonism. The picture shown here illustrates the differences between the various anti-FcRn molecules. On the left-hand side, you can see how one IgG molecule in a very specific way fires detail in the X with 2 FcRn molecules. In the middle, you can see efgartigimod, which is the Fc fragment derived from human IDDI. And that has been engineered to have a higher affinity binding for its receptor while maintaining the pH dependency. It is clear that efgartigimod binds exactly in the same way to FcRn as IgG is doing. Anti-FcRn monoclonal antibodies have been selected to recognize an epitope close to or overlapping with the side to which IgG binds. However, it is approximate binding and not an exact fit. Our hypothesis and what we address is our translational studies is that these different ways of binding to FcRn will lead to different sub-cell traffic pathways so that efgartigimod can mimic the pattern of endogenous IgG, while a monoclonal antibody that targets FcRn that is through fab arms will not. To learn more about the differentiation of efgartigimod, we launched a series of translational experiments with efgartigimod and a monoclonal antibody targeting FcRn. Remember that we already published our microscopy experiments in the JCI paper from 2018, where efgartigimod and an anti-FcRn monoclonal antibody were presently labeled. These experiments revealed that efgartigimod was recycling whereas the positive control on the FcRn monoclonal antibody rapidly disappeared into the lysosome. The experiments, which I will discuss here are making use of fluorescently labeled FcRn and unlabeled efgartigimod and an anti-FcRn monoclonal antibodies. In these movies, you can see that efgartigimod does not affect the fate of FcRn since over time, it gives a similar picture as the untreated cells. However, in the movie of the control on the FcRn monoclonal antibody, FcRn seems to have rapidly disappear. And by co-staining of lysosomal markets, we found out that FcRn ends up in the lysosome. I'm going to play the movie again so you can carefully watch this effect of efgartigimod and the monoclonal antibody and see how this compares with the untreated cells. When plotting the FcRn volume, as done on the graph on the right, you can clearly see that untreated cells and efgartigimod-treated cells have similar amounts of FcRn, which do not change over time. Whereas for the positive control on the FcRn monoclonal antibody, the FcRn signal rapidly goes down. Since FcRn disappears from the positive control on the FcRn monoclonal antibody, a decrease in IGG can be expected upon treatment. Since albumin is recycled by FcRn as well, this serum protein is expected to be reduced in circulation also. In contrast, efgartigimod does not reduce FcRn levels, so the lower IgG levels observed in treated patients and healthy volunteers can be explained by the fact that efgartigimod is occupying the IgG binding site of FcRn. Therefore, the drug should not reduce albumin levels. We are continuing to educate ourselves on albumin because this is an important player of the FcRn story. In the literature, it is clear that in the severe autoimmune population we are aiming to treat, maintenance of albumin levels is of crucial importance. Albumin has different functions as depicted on this slide, but I would like to highlight the role it has in lipid homeostasis. I encourage you to visit the Events website where you can hear more from a panel of experts on the importance of albumin and lipid microembolism. These are data from our Phase III ADAPT trial in 167 MG patients. The patients were treated in cycles, where in each cycle, efgartigimod was given by weekly administrations followed by an observation period. Depending on clinical deterioration, a new cycle was given, so patients were treated in a personalized way. On the left, the PD effect is shown for all patients during the first cycle. A deep reduction in IgG was observed, which resulted in an unprecedented clinical benefit, as has been described in the Lancet Neurology Publication, which came out earlier this month. On the right hand side, in the top panel, you can see the albumin levels of efgartigimod-treated patients shown with blue symbols and for the placebo patients shown in red. Clearly, no reduction in albumin levels was found in efgartigimod-treated patients as illustrated for the first and the second treatment cycle. In the lower panel, the LDL levels have been plotted. And again, no difference was observed for efgartigimod-treated patients as compared to placebo. We already published before that no albumin reductions were observed in our Phase I [indiscernible] study and the Phase II studies in MG and ITP patients. Also in the Phase II Pemphigus trial, where patients have been treated with 125-milligram per kilogram efgartigimod for a period of 34 weeks, we did not observe albumin reduction or an increase in LDL levels. These clinical results make sense based on the translational work that I shared with you today. This is a perfect example of the interplay between clinical and science at argenx. We use breakthrough signs to build a differentiated molecule. We have achieved very strong clinical results. And now we go back to the science to learn about our molecules potential in the most complete way possible. In conclusion, we are rapidly expanding our safety database with the trials we have run to date and the ongoing global registrational trials. We have gathered PD data, efficacy data and albumin data from each indication and have seen consistent results on safety and tolerability. And we have also now dosed over 125 patients with efgartigimod for over 12 months. To date, we have not incurred any toxicity limitations in healthy volunteers or patients, which, therefore, enables us to dose and to achieve our maximum clinical response and a maximum PD effect. These outcomes are very important as we look ahead to bring efgartigimod to as many patients as possible who are living with severe autoimmune disease. I now like to introduce my colleague, Bas. Bas is a research fellow at argenx and also the scientific lead for our myositis program. Bas, the floor is yours.

Thank you, Hans. Hello, my name is Bas van der Woning, and I'm the lead scientist on this myositis program. During this presentation, I'll explain our rationale to target idiopathic inflammatory myopathy with efgartigimod. I'd also like to encourage you to learn more about myositis from the presentation by Dr. Aggarwal, which you can find on this website. Idiopathic inflammatory myopathy, or myositis, is a very severe and disabling immune disorder that has a devastating impact on the quality of life. There are no FDA-approved therapies for myositis. We believe that some of the subtypes of myositis are also antibody-mediated and can, therefore, be treated with efgartigimod. These subtypes are: Immune-mediated necrotizing myopathy, antisynthetase syndrome and dermatomyositis. The classification of the subtypes within myositis can be done on the basis of myositis-specific autoantibodies. Those of you who have already seen the presentation by Dr. Aggarwal will recognize this chart. It shows that in dermatomyositis, there are 5 different targets of autoantibodies. Then there is polymyositis, which can be sub-divided into antisynthetase syndrome and immune-mediated necrotizing myopathy. In antisynthetase syndrome, there are autoantibodies against many different tRNA synthetases. The far most of these autoantibodies in antisynthetase syndrome are directed against tR1. In necrotizing myopathy, patients have either antibodies against necrotizing myopathy or against HM-TCR. Job classification can also be done on the basis of clinical symptoms using the classification criteria from ECR Europe. Either way, surpluses can be formed where autoantibodies associated with clinical symptoms. The involvement of autoantibodies in the pathology of myositis is best understood in immunomediated necrotizing myopathy. Here, we can distinguish complement dependent and complement independent processes. In necrotizing myopathy intra-SRP and intra-HGCR can bind muscle fibers thereby activating the complement system and the formation of the membrane attack complex. This leads to a process that we call myolysis. The membrane attack complex actually holds into the cells of these muscle fibers, and this leads to an increase of muscle enzyme levels that can be measured in the blood samples of these patients. The affected tissue becomes necrotic and the recruitment of macrophages leads to microphagocytosis and the release of pro-inflammatory cytokines such as IL-1, IL-6 and TNF alpha. And there's to complement independent process. Normal muscle regeneration occurs by the activation of resident satellite cells, namely myoblasts, that fight and engage in the fusion process forming myotubes to generate mature muscle fibers. Muscle regeneration is directly impaired by autoantibodies to ectopically express auto antigens on the regenerating fibers. What is not on this figure is that autoantibodies also can directly upregulate markers of atrophy. As compared to necrotizing myopathy, the role of auto antibodies in the pathogenesis of dermatomyositis and antisynthetase syndrome is less well understood. But there are 2 mechanisms that are clearly involved in dermatomyositis and antisynthetase syndrome that are likely triggered by autoantibodies. These are complement activation and type-1 interferon production. First, the activated complement targets muscle tissue directly leading to myolosis and necrosis. Second, the complement system targets the micro fascilature of the muscle tissue, leading to the destruction of capillaries and the hypoperfusion of the muscle tissue. Independent of the complement system, immune complexes can also induce the production of type I interferon by specialized dendritic cells. Interferon impairs myotube formation and muscle angiogenesis, leading to the hypoperfusion of muscle tissue. Type 1 interference also stimulate the adaptive immune system to produce even more autoantibodies, resulting in a positive feedback log. In case these pathogenic processes are not controlled well, this will eventually lead to atrophy. In summary, autoantibodies are involved in the pathophysiology of myositis by activation of the complement system that targets the muscle tissue directly, or by the activation of the complement system that targets the microvasculature in these muscle tissues. Immune complexes trigger specialized dendritic cells to produce type 1 interferon, and then there's the direct inhibition of myotube formation, either by direct binding to ectopically expressed auto-antigens or via type 1 interference. Now I have explained the role of autoantibodies in the pathophysiology. Let's take a look at the identity of these autoantibodies. There are many different myocyte-specific antibodies. These antibodies are specific for myositis and can even be used for the sub classification of the different subtypes of myositis. There are also patients that have myositis-associated antibodies. These autoantibodies can also occur in other autoimmune diseases. And lastly, there are patients that have autoantibodies against yet unidentified targets. Regardless of the target antigen, efgartigimod will clear all these autoantibodies as these are predominantly IgGs. Preclinical experiments have demonstrated that the passive transfer of IgGs from patients generate all disease features of the recipient mice. Although there are no approved targets for the treatment of myositis, common immune therapies, like rituximab and IVIg, have demonstrated that the antibodies are foundational drivers of the disease. In patients, there is also a correlation between autoantibodies and muscle damage across all of these subtypes of myositis. There's also a direct link between autoantibody levels and the disease activity. So let's take a deeper look at the clinical data, showing the correlation between autoantibody titers and disease characteristics. CK is commercial enzyme in the market for active myolysis in blood samples. This figure shows a perfect correlation between auto antibody titers and CK levels. In this era of these 8 patients, the CK levels exactly follow the trend of the entire SRP levels. Similarly, anti-HMGCR year 1 and MI2 titers have been demonstrated to correlate with CK levels and commercial strengths. Furthermore, anti-MDA5, year 1 and anti-I2 titers have been reported to correlates extramuscular disease activity like interstitial lung disease and skin disease. Many years ago, the efficacy of rituximab was tested in the large myositis trial involving 200 patients. That trial failed for several reasons. But what we learned from this trial is that autoantibodies are predicted biomarkers for the efficacy of rituximab. Retrospective analysis demonstrated that those patients positive to MI2 or year 1 met the definition of improvement earlier than all other patient groups tested in that trial. Recently, Octagam reported a positive outcome of their IVIg trial in dermatomyositis. This is the program study. Based on these results, Octagam IVIg has now been approved in Germany for the treatment of dermatomyositis, which sets precedence for the total improvement score as an outcome measure. How exactly IVIg works is not fully understood. Clearance of auto IgGs is for sure one of the mechanisms of action. Let's take a look at the preclinical experiment. In these preclinical experiments, the best transfer of IgGs purified from the plasma of anti-SRP positive or anti-HMGCR positive necrotizing myopathy patients results in the loss of grip strengths and muscle strength in these mice. As you can see in the figure on the left, injection of mice with purified IgGs from anti-SRP-positive necrotizing myopathy patients results in the loss of grip strength as compared to mice injected with IgGs from healthy controls. When mice were injected with ITG-depleted plasma, no loss of grip strength was observed, indicating that this is purely driven by IgGs. Similarly, mice injected with IgG from an anti-HMGCR patients resulted in the loss of muscle strength. Two histopathological features of necrotizing myopathy are necrosis and complement the position on the muscle fibers. And exactly that is what has been observed in recipient mice where -- that were injected with these autoantibodies. These data show that auto-IgGs are responsible for induction of the disease. While necrotizing myopathy anchors the market opportunity as the best characterized part of physiology around autoantibodies, we take a basket trial approach to develop efgartigimod also in inter-synthetase syndrome and dermatomyositis. Thereby, we'll be reaching out to even more patients as high unmet need based on a plausible autoantibody-based biology regimen. Having a precision medicine like efgartigimod targeting solely the IgGs may allow us to redefine all 3 subsets as being truly IgG-mediated diseases. So let's take a look at our trial design. Given, one, the high unmet medical need across these 3 subtypes; 2, the unifying IgG-based disease biology; and 3, the existence of an overarching primary endpoint being the total improvement score, we designed the following trial. Approximately 180 patients stratified for the 3 different subtypes and for the severity of their muscle weakness will be enrolled. Patients will be treated weekly either with 1,000 milligram efgartigimod subcu on top of standard of care, or with placebo on top of standard of care. The challenge is that we don't know whether all 3 subtypes will respond equally well. But here is where we can make the difference. This is an adaptive enrichment trial design. This means that we have the opportunity to perform an interim analysis after the proof of concept part 2 part of this trial. Guided by an independent DSMB advice, we will have the ability to continue with 1, 2 or all 3 of these myositis subsets and adjust the trial size accordingly. The primary endpoint will be based on the total improvement score. And the key secondary endpoints will include the durability of benefit, the quality of life in the independent components of the total improvement score. The IND filing is spent for the end of 2021, pending on the interactions with the division of clinical outcome assessments and the context innovative trial design division of the FDA. In conclusion, over 30,000 patients in the U.S. with necrotizing myopathy, intra-synthetase syndrome or dermatomyositis suffered from proximal muscle weakness. The first panel of IgGs, autoantibodies emerge as a key driver of muscle inflammation. There's clinical evidence that links IgG levels to the disease activities. The cases of the antigen, efgartigimod will clear all of these autoantibodies as these are predominantly IgGs. Thereby, efgaticimod will contribute to the elucidation of the myositis priority. Our adaptive investment trial enables us to enroll a broader patient population with a high unmet medical need. This basket trial design for myositis may support for future multi-indication trials based on unifying biology. For more information on myositis, I'd like to remind you to take a look at the presentation by Dr. Aggarwal. That presentation can be found on the website. Thank you for your attention. I'd now like to introduce my colleague, Peter Verheesen. He is a principal scientist at argenx, who is also the scientific lead for our skin blistering programs, pemphigus and bullous pemphigoid.

Thank you, Bas. This part of the presentation, I will give a quick overview of another new indication for efgartigimod, which is bullous pemphigoid, provide an overview of the disease and the pathophysiology to show how different therapeutic approaches impact the autoantibody levels and disease activity in bullous pemphigoid and present the design of the registration study for efgartigimod. I also encourage you to learn more about bullous pemphigoid from the presentation by Dr. Hall, which you can find on this website. Bullous pemphigoid is the most common autoimmune restoring disease and is driven by autoantibodies affecting the skin. Disease typically affects elderly people, and early key symptoms are itch and rash and patients develop fluid-filled blisters during disease progression. Let's have a quick look to the prevalence, burden, current treatments and unmet needs. The prevalence of bullous pemphigoid is 12 per 100,000 adults, and the incidence increases with age. Bullous pemphigoid has a high burden on affected patients, and the disease has a strong impact on the quality of life and has a high mortality. The mortality of bullous pemphigoid in the U.S. is 2.4 or higher than the mortality in the general population of the same age. There are currently no approved therapies available for bullous pemphigoid. First-line treatment consists of topical or systemic corticosteroids, which result in substantial morbidity and increased mortality, conventional immunosuppressants as corticosteroid sparing agents, rituximab and IVIg. The unmet needs for patients are the time to remission, the high relapse rate and side effects from corticosteroids. Bullous pemphigoid represents a significant market opportunity for efgartigimod. Bullous pemphigoid is a well-understood autoimmune disease, in which the binding of autoantibodies initiates a cascade of inflammatory events resulting in blister formation. Cellular targets of the autoantibodies are 2 hemidesmosomal proteins, BP 180 and BP 230. These molecules are involved in the stable attachment of keratinocytes to the underlying matrix. The autoantibody actions include mechanical disruption of keratinocyte addition and cytokine release. Immune complex formation initiates complement activation, leading to the recruitment of mast cells, neutrophils, eosinophils and other immune cells and to the release of proteases and inflammatory mediators. All these effects, which start with the binding of the autoantibodies induce the blistering observed in bullous pemphigoid. There's preclinical evidence of the pathogenicity of the anti-BP180 antibodies. In neonatal mice, pathogenic BP180 antibodies induced typical BP skin lesions clinically and histologically. When these mice are pretreated with high-dose IgG and injected with an identical dose of pathogenic IgG, we see that the competing high-dose IgG leads to lower anti-BP180 antibody levels and reduced disease scores. The disease phenotype is completely abolished at higher high-dose Ig doses. Interestingly, with the same experimental settings, FcRn-deficient mice are resistant to the pathogenic BP180 antibodies due to the reduction in the circulating level of these antibodies, and this shows the importance of FcRn in this. The clinical benefit with therapies targeting IgG in bullous pemphigoid was demonstrated in studies with IVIg, plasmapheresis and immunoadsorption. In the Phase III study with IVIg in 56 BP patients who are unresponsive to corticosteroids, clear therapeutic benefit was observed with a stronger response in severe disease and the observed improvement in the disease activity was fast. In a case series with plasmapheresis, all patients achieved complete remission. And concomitant prednisone doses were reduced by 70%. With protein A immunoadsorption, which selectively removes IgG antibodies in patients with severe or refractory bullous pemphigoid or with particular high disease activity as first-line treatment, it was shown that there was a strong initial drop in the autoantibody levels and the effect was also continued after treatment. The improvements observed in -- previous improvements were observed in previously treated and with the naive patients and all showed a significant reduction in autoantibody levels throughout the observation period. The majority of the patients achieved complete remission, and the proportion of them would taper off corticosteroids completely. Most patients needed only one cycle of immunoadsorption. In this slide, we see some data from the same studies. From the Phase III study with only a single cycle of IVIg, here shown on the X axis, we can observe the improvement on the disease activity and the first onset of effect. From the plasma exchange case series, we can see that all bullous pemphigoid patients achieved remission, and we can observe the 70% prednisone dose reduction. From the immunoadsorption data, again, selectively removing IgG antibodies, we can see that, together with the reduction of autoantibody levels, patients improved from active disease, here shown in black, to clinical remission or partial remission, shown in green and red, after 1 month and ultimate clinical remission shown in green thereafter. Together, these data show that rapid depletion of serum autoantibodies may be an effective treatment option in patients with bullous pemphigoid. We have learned a lot about efgartigimod in pemphigus, which is also relevant for bullous pemphigoid. In pemphigus, we have seen a clear correlation between IgG level reduction including autoantibodies and improvement in disease scores. We have observed a fast onset of activity, which was confirmed by a high rate of disease control at an early time point and a high rate of patients achieving complete remission with corticosteroid doses, which were much lower than normal. We have observed that with sustained maintenance treatment and keeping IgG levels low, that patients continue to improve on their disease activity. And efgartigimod demonstrated a very favorable safety and tolerability profile. Both pemphigus and bullous pemphigoid are well-characterized autoimmune diseases in which the autoantibody levels are part of the diagnosis and are used to measure treatment progress. For both diseases, international groups of experts have defined scoring systems and consensus endpoints, which we can use for our clinical studies. Specifically, for bullous pemphigoid which affects more fragile, elderly people, it is the favorable tolerability of efgartigimod in pemphigus and other indications that convince key opinion leaders to support a trial in bullous pemphigoid. With the proof-of-concept established in pemphigus, the clear biology rationale and the availability of international consensus guidelines, we believe that they can go right into a registrational trial for bullous pemphigoid for a population that will be newly diagnosed and relapsing patients within 1-year diagnosis. We aim to develop efgartigimod as first-line treatment. Patients will be randomized 1:1 between the efgartigimod and placebo treatment arms and will be treated for 36 weeks. Standard of care concomitant medication will consist of prednisone at the starting dose of 0.5 milligram per kilogram per day, and the dose will be adjusted with the disease activity and tapered off as quickly as possible. Primary endpoint is the proportion of participants in complete or partial remission of being off oral corticosteroids. Secondary endpoints relate to corticosteroid sparing, onset of activity, prevention of relapse and quality of life. And the study will be followed by an open-label extension study. To summarize this presentation, bullous pemphigoid is a well-defined disease. It is the most common autoimmune blistering disease and represents a significant market opportunity. Bullous pemphigoid is characterized by autoantibodies against the key antigens BP180 and BP230. Both antibodies are crucial players in the pathogenesis of bullous pemphigoid. We have learned a lot about efgartigimod from our study in pemphigus and the efficacy and safety data from pemphigus serve as proof of concept for bullous pemphigoid. Medical study of efgartigimod in bullous pemphigoid is designed to be registrational. I hope this presentation has given you a greater insight into bullous pemphigoid as a new indication for efgartigimod. I would now like to introduce my colleague, Albert Kovera, Senior Director of Global Marketing at argenx and marketing lead for all new neurology indications. Albert?

Good morning. My name is Albert Kovera, and I am a member of the global marketing team at argenx with a specific focus on indications and development. Today, I am very pleased to have 2 leading physicians with us to discuss our new efgartigimod indications, myositis and bullous pemphigoid. We have Dr. Rohit Aggarwal, Professor of Medicine, Medical Director of the Arthritis and Autoimmunity Center and Co-director of the Myositis Center at the University of Pittsburgh Medical Center; and Dr. Russell Hall, the J. Lamar Callaway Professor of Dermatology at Duke University Medical Center. Welcome, Dr. Aggarwal and Dr. Hall. Thank you so much for being with us today to share your insights and expertise. So I'd like to begin with you, Dr. Aggarwal, if I could. And if you could provide us with a brief overview of your clinical practice and the number of myositis patients you treat as well as a description of your academic research interests.

Sure. First of all, thanks for having me on this panel discussion with Dr. Hall. So we have a myositis center at University of Pittsburgh. We call it as UPMC Myositis Center. And currently, we have about 200 to 225 active myositis patients that we follow. Overall in our registry, we have more than 1,000 myositis patients over the last couple of decades. And in terms of research interest, I specifically focus in myositis in clinical trials, for novel therapeutics as well as outcome measure -- meaningful outcome measure development.

Thank you very much. And Dr. Hall, if you could answer the same questions as well, please.

Sure. Thank you very much, and it's a pleasure to be here and to talk about bullous pemphigoid. I am the J. Lamar Callaway Professor of Dermatology, and as such, we have a very active autoimmune blistering skin disease section. And we also follow many patients with bullous pemphigoid following at any one time, 40 to 50 patients with approximately 10 to 20 patients new each year that we see. Our effort is a collaborative effort, and these patients are oftentimes enrolled in various clinical trials for the treatment as well as for the pathogenesis of the disease. My research interest that focus on both discovering new treatments through clinical trials as well as using those clinical trials to do mechanistic studies that can help us understand how these drugs work, whether they work on the B cells or the antibody or the inflammation or what exactly is the pathogenic mechanism for which these drugs work.

Thank you very much both. And Dr. Hall, I'd like to continue with bullous pemphigoid for a moment. As we move to the next topic, which is the role of the autoantibody in each disease. Could you please highlight the role -- or roles of autoantibodies in bullous pemphigoid? And how well understood do you feel that these roles and/or functions are within the dermatology community?

Well, the story of antibodies in autoimmune blistering skin disease is a very interesting one, in the sense it started in the late '60s and early '70s when we first developed antibodies against human immunoglobulins. And a medical student at the University of Buffalo decided to look and see if there are any antibodies in the skin of patients with bullous pemphigoid. And they looked and found that there was indeed a very specific deposition of IgG that's seen in the skin of patients with bullous pemphigoid that was localized exactly where the blister formed. After they found that this IgG was also found in their blood and did not -- and reacted with normal human skin, suggesting that it was an autoantibody that is, it was an abnormal antibody directed against a normal antigen. This was followed very closely thereafter by the definition of the antigens for bullous pemphigoid, which are predominantly the bullous pemphigoid antigen 180 or BP180 and the bullous pemphigoid antigen of 230 [ kilovolts ], BP230. With the establishment of these antigens that we were able to develop an antibody test that could look at the levels of the antibody, and we found that the antibodies did correlate especially in large populations with the development of the disease activity. So the evidence became very strong that these antibodies did play a critical role in the development of this disease. And it is well accepted that these antibodies are part of the specific manifestations of bullous pemphigoid.

So Dr. Aggarwal, I would argue that perhaps the function of the autoantibody in myositis might be, let's say, somewhat less understood as Dr. Hall was highlighting in the case of bullous pemphigoid. Maybe even this difference occurs between subsets such as immune-mediated necrotizing myopathy, anti-synthetase syndrome, dermatomyositis, et cetera. So could you also perhaps elaborate a bit on the pathological manifestations of these differences between the subsets?

Sure, sure. Well, first of all, I agree with you that the role of our antibody is not as established and as historical as Dr. Hall was saying in BP. However, in the last 2 decades, we have recognized the role of myositis-specific antibodies in myositis more and more. Whether you start from animal models of pathogenesis, whether the autoantibody leads to immune complex formation and then ultimately leading to complement activation, leading to the injury of the muscle, or you talk about interferon pathway activation through antibody. Regardless, these -- there are models put together where they suggest there may be a direct pathogenic link of these myositis-specific antibody. Moreover, these myositis-specific antibodies are highly specific. It means if you have these antibodies, then you have the disease. It doesn't matter -- you may vary with about your clinical presentation, but you have that particular category of the disease. Thirdly, we have done studies in which we have showed that the serum level of myositis antibodies correlate with the disease activity over time. And also, we know that there's a significant role of these myositis antibodies in terms of management that certain myositis antibodies, certain type of treatment are preferred as compared to some other myositis-specific antibody.

And there's multiple -- it sounds as if there are multiple myositis-specific antibodies across the various subsets. Would there be an instance where one myositis-specific antibody may be used for diagnosis for 2, 3 or 4 different subsets? Or how does that differentiate?

Well, I think that's a very good point. So we -- since then -- since 1975 Bohan and Peter criteria, we have updated a new classification criteria, which has been validated and adapted by American College of Rheumatology and European League Against Rheumatism, and it's called ACR EULAR classification criteria. And in that criteria, you see that there's an entry of at least the most common myositis-specific antibody called Jo-1 antibody. Most expert believes that criteria should be changed to any myositis-specific antibody. And I tried to explain them when the criteria was developed, we just didn't have enough data on all other antibodies because this is -- you've talked about 10, 12 years ago. But now we have a lot more data that suggest that any myositis-specific antibody should be included in the classification criteria, just because of its high specificity itself.

In the next 5 to 7 years, what do you think generally that we will be able to understand more effectively?

What it will prove is that DM itself is just an umbrella term. And each autoantibody is this unique disease itself. So we're going to move from clinical classification of dermatomyositis on immune-mediating and necrotizing myopathy or anti-synthetase syndrome to more serological classification. We're going to call them MDA5-positive disease or HMGCR-positive disease or SRP-positive disease because we will recognize that at each one of them, these myositis-specific antibody, play a very unique role in not only pathogenesis but also can help in management prognostication. As I told you, the levels of these antibody also fluctuate. If somebody flares, the level go up. Somebody goes in remission, the level goes down.

All right. I'd like to have a few questions for you, almost coming from the view of the patients and their perspective. And with the other indications that argenx is investigating, we've seen that there are some common patient-related themes across the various autoimmune diseases. And one of these common patient themes really is the, let's say, terrifically arduous journey for the patient to ultimately or finally obtain an actual diagnosis for their condition. Now Dr. Hall, in your opinion, can you talk a bit about what you consider to be the typical patient journey to a diagnosis? And perhaps how that quality of life for the individual is impacted along that journey before he or she comes to you in your office?

Sure. I think that one of the most interesting things about bullous pemphigoid in terms of its journey to a diagnosis is that oftentimes, the first trip to the doctor is not to see a dermatologist but rather to see the general -- your private practitioner, whether it's a general internist or a family physician or your primary care provider. And in that instance, this rash generally comes on very quickly, and it has the characteristics of a rash that's red and itchy and it's giving the patient a lot of problems. So their journey may start with their primary care provider who looks at the rash, so this looks like an inflammatory itchy rash and it needs some steroids, just like you would treat somebody with poison ivy or allergic contact dermatitis, you give them a short 2-week course of steroids. It gets better and it goes away and it never comes back. And so the patient gets treated with steroids, and it goes away. And of course, in the 5 to 7 days, it markedly improves and the doctor says that's great. We'll take you off the steroids. Send you on your way, you shouldn't have any problem with this again. But then 3 to 5 days after going off the steroids or even as the steroids are being reduced, it flares up again and shows even worsening characteristics. And it's at that point that these patients oftentimes go to the dermatologist and it's at that point, they get the diagnosis. Luckily, because our organ is so accessible and we can do biopsies very easily on these patients with very little morbidity to the patient and very little cost, these patients are biopsied generally at that visit and the diagnosis of bullous pemphigoid is made because the tests are very commonly available now, no matter where you live or no matter how the expertise of the dermatologist at reading slides, the biopsies can be obtained and the diagnosis can be made. This is complicated in pemphigoid because these patients are oftentimes over the age of 60 and 70, in fact, with a median age oftentimes in the 80s for the onset. So these patients oftentimes have other problems that make the use of steroids quite difficult. They have difficulty controlling their diabetes or their hypertension or they may have a lot of peripheral edema. They'll see changes in their mood and their behavior sometimes with the high-dose steroids. So at that point in time, it's an issue of both the diagnosis has been made, it's how are we going to manage it and treat it with the effective therapy that can minimize the adverse events, yet control the very significant symptoms of generalized blistering and incredible itching. And that's when they come into the academic dermatologist and that's where other therapies such as steroid-sparing therapies, immunosuppressive therapies or even new therapies in clinical trials often come. And that is why the patients are very eager to get these new medications because their symptoms just cannot be controlled without the severe adverse events associated with systemic steroid use.

So now Dr. Aggarwal, being mindful that we talked about the different subtypes, is there -- can you take a moment to describe the -- I don't know if typical is the right word, but the path to diagnosis for what patients may go through in your scenario?

Yes. So I think the journey, to some extent, depends on what subtype are we talking about, but I will try to generalize everything. So what happens in myositis world, they have various different clinical features that don't always present all in one go. So there is a lack of understanding initially amongst the patient themselves. Sometimes, when they present with muscle weakness, they kind of shrug it off as maybe I'm just -- not have done enough exercise or maybe I'm getting older. Maybe my ligament is pulled or something else is wrong with me, there's nothing serious wrong with me, and they kind of brush it off until it gets more and more severe. And sometimes, we have patients who come to us at a stage where they are not even able to get up from their chair, where they need 2 people to pull them out of the car because they just can't get up, or they can't even lift a grocery bag or any -- or a gallon of milk or anything significant, they can't just hold it, or having difficulty in shower. To do shower, you have to raise your hands over your head, and they just can't do that anymore. So there's oftentimes a significant delay from patients themselves. Sometimes, they develop joint pain and rashes that they don't understand. Eventually, they get to a primary care doctor who obviously have very little experience about this disease. This is a rare disease. They have never probably seen in their whole practice, may have had 1 or 2 cases in their whole life span of 10, 20 years of their practice. So they don't know. So oftentimes, they say, okay, let's give a little bit of steroid, let's just do some lab work. And lab work could also be pretty much normal if they're not looking for muscle enzyme, for example. After a couple of visits of the primary care doctor, the primary care doctor recognize this could be rheumatological because not only of muscle weakness, rash, having joint pain, you have multiple different symptoms. Once they get to a rheumatologist, generally, there's about 3- to 6-month wait to get to a rheumatologist. Eventually, they reach a rheumatologist. Now rheumatologists or dermatologists or neurologists often able to recognize this could be inflammatory myopathies. However, there are many mimickers of inflammatory myopathy, so they want to be sure. For that, they often refer to centers like us who see myositis patient day in, day out. Again, now there's another 2, 3 months or 6 months wait, depends on where you go to a specialist, neurologist, dermatologist or rheumatologist. And once the patient comes to us, clinically, we recognize based on the history and exam that yes, we are dealing with myositis. However, we need to be sure as well. So we have to have a serious series of battery of tests, whether it's an EMG, a muscle MRI, muscle biopsy, skin biopsy and so on, to confirm what we think is correct and then the treatment journey starts. So the diagnostic journey is very convoluted and problematic. On an average, it could be anywhere between 6 to 12 months before they can get treatment initiated. So the diagnostic journey itself is a problematic journey itself. Now you asked about treatment, I think, as well. So even the treatment journey isn't that easy. We have to use high doses of steroids for long term to improve strength of these patients or improve rash and other clinical manifestation. Now the treatment itself becomes a big headache for us, because these high doses of steroids for a long-term period leads to significant comorbidities, whether it's osteoporosis to muscle atrophy, to obesity, cardiovascular disease, avascular necrosis, you name it, I can go on and on about the side effects of long-term steroid. But we have to use them. Otherwise, these patients are not going to be functional. And these patients have functional disability in their day-to-day life. So we exchange one problem for another problem, essentially. And then we often have to use non-steroid immunosuppressive drug. Again, we are trying to lower the dose and the length of steroid used by using these non-steroid immunosuppressive drug. Now these non-steroid immunosuppressive drugs are not specific for myositis. These are general immunosuppressive drugs. So obviously, they're not going to work excellent for all our patients. They do, in some cases. But we feel that 1/3 of our patients, at least the ones that get to us, are refractory to these treatment. And even another 1/3 who initially improved, and we taper their immune suppression, they flare up, they relapse. So we have a significant problem in terms of management of these patients. And many of these patients, they eventually go to clinical trials and other areas. But even though, at least in our center with our experience, we are able to improve a lot of our patients. Even then, if you truly interview our patients whom I would say we have done a fantastic job in improving their condition, they will tell you that is not true. They will tell you, I suffered everyday. I have fatigue issue. I have muscle endurance issue. I'm not able to do what I used to do. I can't keep up with the hours of job that I'm doing. Remember, the myositis patients are in an age group of 30 to 60. These people have to work in everyday 40 to 50 hours a week to be able to keep their income, which is not easy when you've been hit by a disease like myositis. So that's -- so there is a significant unmet need in terms of effective treatment, which does not lead to the significant side effect profile that we currently have.

So Dr. Hall, if you could spend a moment and highlight, what is your typical current treatment algorithm for bullous pemphigoid patients today? And the second part of the question is if you could highlight any key needs for a new medication to manage bullous pemphigoid.

Sure. Today, I think the most critical factor for a patient with bullous pemphigoid when they present to you acutely is you've got to do something to stop incessant and really debilitating itching and the development of blisters and acute inflammatory reactions in the skin. And that needs to be stopped as quickly as possible. That's very disruptive to every aspect of the patient's life, their social life, their physical life. And so at this point in time, that is done by systemic corticosteroids. And generally, we can achieve control on a fairly good dose of steroids, on a modest dose of steroids within 21 to 30 days. We can do that. It's just that we cannot maintain high-dose steroids for long periods of time without significant morbidity in a population that has a median age of 80. So the results of that are we have to search for a steroid-sparing agent. And we have a whole host of drugs that we choose from, ranging from drugs that work against the inflammation, such as doxycycline or dapsone or other kind of anti-inflammatory drugs, to drugs that are more traditional immunosuppressive drugs, very similar to what is used for myositis, with azathioprine or mycophenolate or methotrexate or other sorts of anti-inflammatory immunosuppressive drugs. And those are usually used, and we try to manage those -- control the disease while we're getting people off systemic corticosteroids. And these patients oftentimes take a year to 2 years to get totally off of systemic steroids, and it can be a very arduous task. And that's our real challenge. And I always tell patients, the first time I see them is that we have a sign-up, they can't see it, I have it painted in ink that only our long-term patients can see, that I will never go on prednisone again. So what we want is our goal of our patients. Now we don't always meet that goal, but that's what we strive for, and that's what our patients want. And we need to find new drugs that allow us to do that, because frankly our current drugs are -- it's very hit and miss, and some work for some patients, and some don't work for other patients.

So Dr. Aggarwal, from what you discussed previously and listening to Dr. Hall now, it seems as though perhaps the philosophy, treatment algorithm paradigm might be similar for myositis patients. Can you talk to us about that for a couple of minutes?

Sure. What Dr. Hall talked about could really be said for myositis as well. There are only few differences that I want to point out. But first, some similarities. Dermatomyositis including immune-mediated necrotizing myopathies, anti-synthetase syndrome, we don't have any FDA-approved treatment. So we face same significant trouble in getting non-steroid immunosuppressive drugs to our patients to help them manage their disease. The second point, I think what Dr. Hall was mentioning that we are able to give steroids in a month or so, patients improve. Here, I would say there is slight differences in dermatomyositis inclusion -- immune-mediated necrotizing myopathies and anti-synthetase syndrome. So when we treat our patients with steroid, it takes months, not a few days to weeks, to see improvement. We typically bring them back in 3 months, we even notice if there is any improvement that is happening or not. Each treatment, we have to try for at least 3 to 6 months to say, okay, this is not working, we need to move on to another treatment. So that means even if we have to find the right drug and if the right drug is available, it may take 6 to 12 months to 18 months to get to that drug just by the fact that you're going to try a different combination of steroid and non-steroid immunosuppressive drug. And all this time, you're going to have to use steroid to keep the patient under some control. And I will add a third aspect, that even if we are able to maintain for -- in some patients, we're able to maintain their treatment of their disease under significant control, when you ask the patient, the patient is still symptomatic. They still have fatigue, enduring muscle pain problems. We just have improved the disease to a certain extent that the doctor is satisfied, okay, the rash is minimal, muscle weakness is minimal, lungs are doing okay, you don't need oxygen. We are satisfied, but the patient is not because there's disability in their day-to-day life.

I'd like to ask this to the both of you. And as this is important for argenx as we continue our clinical development in the indications that we've been discussing today, what would you say to summarize are the key attributes of future therapies for either bullous pemphigoid or myositis? And I'll begin with you, Dr. Hall.

Well, I think that the discussion has led us -- hopefully, has led us to this point in the sense that it is clear that our most important aspect is that we achieve a very rapid and effective control of the initial symptoms of itching and blistering on the skin. And we have to get that under control in the short time as possible. So quick-acting control of itching and blistering in the skin disease is the #1 criteria. The second or part -- sort of part B of that first 2 things is do that with as little dose of systemic corticosteroids as possible, or hopefully at some point in time, no systemic corticosteroids to develop that initial early control of itching and control of blistering. The second criteria, it has to be, is that with this -- whatever this therapy is, is able to induce a complete remission and able to sustain that complete remission without the use or with minimal use of corticosteroids. So those 2 factors, quick and sustained remission with minimal to no systemic corticosteroids are 2 of the most important criteria. The third criteria that has to be included is minimal adverse events, the increased mortality that we see in our patients over the time of their disease. Even though patients are elderly, the death rate for bullous pemphigoid is 2 to 3x that for their age mass peers. So we would like to try to improve that so we can improve their life span.

Thank you. And Dr. Aggarwal, are some of those attributes or characteristics similar?

I think Dr. Hall has spoke very well about all the points that I would make. The only difference maybe in terms of the sequence. And Dr. Hall spoke about treatment that can cause complete remission. I would put my goal a little bit lower. I would be happy if I find a treatment that even improves the disease by moderate improvement by moderate response, but it has to be sustained long term. And we cannot continue to use the steroid the way we're using the steroid. I would be more lenient, maybe not a few weeks. I'm going to be happy with a few months of steroids even. But we cannot continue to give years and years of high dose of steroid for these patients.

All right. Well, on behalf of the argenx organization, I'd like to thank you both again. This has been incredibly helpful for our audience, for myself to hear about the serious debilitating autoimmune diseases, and how you manage your patients that are living with these conditions. We absolutely appreciate your time and commitment this morning. And I hope to have the pleasure of speaking with you both again in the future. So thank you both very much.

Thank you very much.

Thank you for having us. Thank you.

Thank you, Albert, Dr. Aggarwal and Dr. Hall. We're now going to move on to ARGX-117. I'd like to introduce my colleagues, Inge and Olivier.

Thank you, Beth. Today, we will talk about ARGX-117, a monoclonal antibody that blocks complement factor C2. I want to start by giving a bit background on the complement pathways. Complement cascade consists of 3 pathways: the classical pathway, lectin pathway and alternative pathway and is essential in the defense against all kind of pathogens. All 3 pathways leads to the activation of the central molecule, C3, that in turn activate a final common pathway leading to the formation of the membrane attack complex, resulting in membrane damage and inflammation. So why do we target C2? First, it targets upstream of C5. And as you can see here, the inflammatory potential starts at the C3 level. Secondly, we leave the alternative pathway intact. And by doing this, you still have an antibacterial defense reducing the risk for infection. Third, we wanted to target both the classical and the lectin pathway. So 2 options are possible, C2 or C4. Of those 2, C2 was attractive because it has less abundant presence in circulation and has the mildest phenotype of all classical pathway deficiencies. C4 deficiency has a higher risk for developing lupus compared to C2 deficiency. ARGX-117 is a first-in-class antibody, optimally engineered for C2 blockade. If you look at its features, it binds in the pH and calcium tunnels [ matter ] to C2. And it has an IgG backbone, which is equipped with a LALA mutation to knock down effector functions and an enhanced mutation to enable health life extension. All those features result in a unique mode of action of ARGX-117. Sweeping antibody as depicted in the figure on the right. First, ARGX-117 binds to C2. It is taken up by pinocytosis entering in the endosome, where C2 is dropped off and degradated, whilst ARGX-117 is recycled back to bigger, new C2 molecules. So Olivier will explain the Phase I trial.

Thank you, Inge. Thank you for introducing ARGX-117. Today, I will share and present to you some of the key elements and studies that we have generated of our ongoing Phase I clinical study with ARGX-117. In this Phase I first-in-human clinical study, we are testing ARGX-117 to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of a broad dose range administered to healthy subjects. And in this particular study, we typically have included a typical single ascending dose part and a multiple ascending dose part in the study. ARGX-117 has been administered both intravenously as well as subcutaneously in these 2 study parts. And in our single ascending dose part of the study, we tested up to 80 mg per kg administered intravenously, and we tested up to 60 mg per kg administered subcutaneously. In our multiple ascending dose part of the study, we tested quite a broad different dose regimen, a dose regimen that were defined and selected to assess the safety and tolerability of repeated administrations but also dose regimen in particular to generate the data set to optimally inform a PK/PD model. And this PK/PD model will inform us on future dose regimen that will be tested in subsequent patient studies. Overall, we are pretty pleased with the progress we have made in this clinical study and has a substantial number of study participants have been included to date. In particular, 70 subjects have been included in the single ascending dose part of the study, and 32 subjects have been included in the multiple ascending dose part of the study. And overall, it has allowed us to generate a very comprehensive and robust clinical data set. And let's now have a closer look at some of the data that we generated. And the first step, we'll zoom in on the key safety results. But I would like to caution that our study is still ongoing. And as a sponsor, we are still blinded to the safety results. Being blinded implies that we can only share high-level results on a core level. As a reminder, this first-in-human clinical study is currently ongoing. We tested a broad dose range of different doses in the single ascending dose part and multiple ascending dose part of the study. And specifically for each cohort that has been tested, I would like to emphasize that we randomized subjects in a 3:1 ratio. This means that for every cohort, 6 participants received ARGX-117 and 2 participants received placebo. From a safety perspective, we attempted to summarize the key safety results through this table. In this table, you will see there's still the number of study participants and the percentage of study participants who develop treatment-emerging adverse events on a cohort level. The left part of the table summarizes the results for the single ascending dose part of the study, whereas for the MAD part of the study, those results are summarized on the right part of the table. We did see indeed treatment-emerging adverse events across all cohorts and that is typical for a first-in-human Phase I study. But the majority of these treatment-emerging adverse events were categorized to be Grade 1 or mild in nature. Very few Grade 2 or moderate treatment-emerging adverse events have been observed. And furthermore, no clear dose relationship with respect to treatment-emerging events were observed across the different cohorts that have been tested. As you can see, in the 2.5 mg per kg dose cohort, 1 subject developed a serious adverse event. This serious adverse event was characterized by an abscess that required a drainage. And that was categorized as such to be a serious adverse event, and this drainage basically resolved the AE. According to the principal investigator, the serious adverse event was considered to be not related to study drug, and that provided additional reassurance for us. Overall, based upon the totality of treatment-emerging adverse events and specifically zooming in on the infections, we have indeed concluded that no increased risk of infections was observed across the different cohorts that have been studied. But taking all the safety results into account and specifically the safety results that we presented here, we basically can conclude that single and multiple administrations of ARGX-117 or placebo yielded favorable safety and tolerability profile, supporting the investigation of study drug in patient studies. So let's now have a closer look at the PK/PD results from our first-in-human study. And now I will give you back to Inge.

Thanks, Olivier. In this slide, the pharmacokinetics and the pharmacodynamics of ARGX-117 of our single ascending dose cohorts are shown. If we look at the PK curves on the left, we see a classical PK pattern with a dose-proportional increase of Cmax. You can immediately notice that ARGX-117 stays long in circulation due to the enhanced mutation and has an estimated elimination half life of around 65 to 70 days, which was even longer than expected. And as a result, from single ascending dose cohort 3 on, subjects were followed up for a longer period. At the graph on the right, free C2 levels are depicted, which is one of our PD readouts. We observed a dose-dependent reduction of free C2 levels, and this reduction is sustained as free C2 levels are reduced by 95% for more than 100 days after 1 dose of 30 milligrams per kg or more. On the next slide, we see the pharmacodynamics and pharmacokinetics of the multiple ascending dose cohorts. First, looking at the PK profiles on the left. Accumulation of ARGX-117 is observed after multiple dosing, as expected, because we haven't reached steady state yet. These dosing regimens were chosen to optimally build a robust PK/PD model. When looking at free C2 levels on the right, again, sustained production in free C2 is observed after multiple dosing. When targeting complement, we need to consider the high levels of circulating complement factor that are present in circulation. That is the reason why the concept of a higher loading dose followed by a maintenance dose concept was tested. As you can see in the yellow curve, 60 milligram per kg loading dose lead to an immediate and fast drop of C2, which could be sustained over time with lower doses of 10 milligrams per kg. Higher dose PK and PD data were used to build a robust PK/PD model, enabling us to optimize dose selection and further development of ARGX-117. On this slide, 3 dose regimens are modeled, suggesting potential for infrequent dosing. To reach full complement blockage, which corresponds to more than 99% reduction in free C2 levels, several dosing regimens can be applied. Here, we show the concept of loading dose of 60 milligram per kg, followed by a maintenance dose of 10 milligrams per kg, shown in green, compared to every 4 weeks of 40 milligram per kilogram dose or every 8 weeks a 60 milligram per kg dose. All dose regimens are reaching the targeted PD effect. So to conclude, the model suggests a broad range of dosing possibilities. To briefly recap the Phase I data of ARGX-117, we have shown that ARGX-117 has a favorable safety and tolerability profile, that the sweeping antibody design enables infrequent dosing. We also have shown a consistent PK/PD profile across IV and subcu dosing. Overall, these data support a Phase II proof-of-concept trial in multifocal motor neuropathy. MMN or multifocal motor neuropathy is a serious neuromuscular debilitating autoimmune disorder. It is characterized by a slowly progressive muscle weakness due to motor neuron degeneration. It mainly affects hands and forearms, making patients become dependent. In the U.S., there are about 30,000 patients with MMN and this number is still increasing. Mainly men are affected and the median age is around 40 years. Diagnosis takes around 1.5 years, as it is initially often misdiagnosed as ALS. The first-line treatment is high doses of frequent IVIg, and MMN patients account for more than $0.5 billion of IVIg sales. So why did we select MMN? First, in IgM, IgM autoantibodies will bind to GM1, which is located on the nerve cells more specifically, on motor neurons at the node of Ranvier and it is also expressed on Schwann cells. Upon binding, these autoantibodies will activate the classical pathway of the complement as IgMs are potent activators of the classical complement pathway. As shown in the graph, the GM1 antibody titer is correlated to classical pathway complement deposition. Complement activation leads then to muscle damage and loss of grip strength. The current standard of care is IVIg, and IVIg reduces C3 deposition in vitro, resulting in less complement deposition. Through our collaboration with Erik Hack and Ludo van der Pol from UMC Utrecht, we have generated in vitro results showing that ARGX-117 efficiently can block complement deposition on nerve cells. This is shown on the slide. Let me start by explaining the model. Motor neurons or Schwann cells are plated on enclosures on glass slips. Next, serum from MMN patients containing IGM autoantibodies against GM1 were added to the cells. These will bind to their target, GM1. Next, serum which is a source of complement is added, resulting in complement activation. This can then be measured using the microscope and staining for C3. You can see strong C3 deposition when adding an isotype control on both Schwann cells and motor neurons, meaning that autoantibodies from MMN patients activate classical pathway of complement. When IVIg is added, reduction in C3 deposition is observed but not a full blockage. If you use C2 depleted serum, no complement is deposited. And when supplemented again with C2, C3 deposition is restored. Very nice to see is that when you add ARGX-117, it is capable of fully blocking C3 deposition on both motor neurons and Schwann cells, and this happens in a concentration-dependent manner, which is shown on the next slide. Here, you observe the dose-dependent reduction in C3 deposition of higher concentrations of ARGX-117. And moreover, it is dependent on C2 as C2 depleted serum that not activate C3 deposition and reconstitution of the depleted serum with C2 up to physiological levels towards dose-dependently restored C3 activation. So to conclude, ARGX-117 blocks C3 deposition in a dose-dependent manner. Next to that, we also collaborated with Hugh Willison from the University of Glasgow to evaluate ARGX-117 in an ex vivo model of acute motor neuropathy. Here, transgenic mice were used which exclusively express gangliocyte on their neuronal cells. From these mice, muscles were isolated and incubated with anti-GM1 antibodies, human serum as source for complement and ARGX-117 for an isotype control. Here, you can see that this ex vivo system, GM1, are able to activate the complement system as seen by C3 deposition at the nerve terminal. This complement activation leads to neuronal damage, as observed by the loss of the neurofilament staining. In contrast, when you use ARGX-117 instead of an isotype control, ARGX-117 blocks complement activation as no C3 deposition was observed, and hence, the nerve terminal stays intact, as seen with the positive staining for neurofilament. So to conclude, ARGX-117 protects the integrity of the axon by blocking complement. All of these data has led to the initiation of a Phase II trial in MMN patients, which will be explained by Olivier.

Thank you, Inge, for nicely summarizing our in vitro and in vivo work. So based upon a very strong preclinical foundation and the clinical safety PK and PD results we have generated and that I presented earlier on, we are indeed well positioned to assess ARGX-117 in our first inpatient study in MMF. And I will now present and explain some of the study design elements of this Phase II dose ranging -- dose range finding study. But please bear in mind, our protocol is still in development, and we could potentially implement some changes in the very near future. As you can expect, the study design has been developed with the input from an esteemed panel of international experts and have taken -- and we have taken into account many of the lessons learned from other clinical studies that have been conducted in this patient population. The proposed Phase II study will include approximately 45 patients with definite or probable MMN. And here, we will use an adjudication committee by an independent panel of experts, an adjudication committee that is actually very similar to what the [indiscernible] CIDP study is implementing. The patient populations that will be included in our study will furthermore be characterized by the fact that they will be on stable IVIg regimen at screening, and they will have to fulfill the criteria for IVIg dependency. Following completion of the screening period, patients will enter an IVIg monitoring period. And during this IVIg monitoring period, we will basically assess clinical outcomes while patients receive their standard regimen. The reason for having this IVIg monitoring period is obviously to assess the clinical safety and efficacy of IVIg treatment. But in addition, we would like to demonstrate that IVIg has indeed some weaknesses where we believe that ARGX-117 can potentially make a difference for patients when they get [ study drug ]. Following completion of the IVIg monitoring period, patients will be randomized to 1 of 3 treatment arms. We have defined 2 ARGX-117 arm and 1 placebo arm. Following randomization and first IMP administration, patients who will go through a 16-week double-blind treatment period. During this treatment period, we will assess safety and tolerability, our primary study objective. But in addition, obviously, we will be looking at a series of efficacy outcome measures. We will be looking at time to IVIg retreatment. We will be measuring grip strength. We will be looking at mMRC sum score. We will be testing Nine-Hole Peg Test and MMN-RODS. In addition, we will collect a lot of data on patient-reported outcome measures, as well as pharmacokinetic and pharmacodynamic results, and we will be looking at disease-relevant biomarkers. Following completion of the double-blind treatment period, patients will indeed have the option to enter a long-term extension study and be exposed to prolonged treatment with ARGX-117. Again, as I've said in the beginning of my talk, we are in a pre-final stage of preparation of our Phase II patient study, but we are on track to start the study by the end of 2021.

Next to MMN, ARGX-117 is a pipeline-in-a-product opportunity. As you can see here, there are a lot of classical and lectin pathway-mediated diseases across our therapeutic franchises. Currently, we are preparing to select a second indication for ARGX-117. I've gone to the end of the ARGX-117 presentation, so thank you all.

Thank you to all presenters. We're now going to open up the call to Q&A, which, as a reminder, will be audio only. Operator, can you please provide instructions on how to ask a question?

[Operator Instructions] Our first question comes from James Gordon with JPMorgan.

James Gordon, JPMorgan. My questions were just about time line. So for BP and myositis, when would you most likely have clinical data? For BP, I can see it straight to pivotal. But from myositis, can you do something a bit like you have done in CIDP where the Phase II sort of feeds straight into a Phase III, if it works well? Or would you definitely need to do a set for Phase II and a set for pivotal trial? And actually, just on that, could you talk about those time lines for other trials as well? So for 117, what range of time lines might the Phase II be on? And how are you finding recruitment and trials going for IIP and BP and time lines there as well, please?

Thank you for being with us today, James I highly appreciate it. This is Tim speaking. I'm going to invite my colleague, Wim Parys, who's our Chief Medical Officer, to comment on your question regarding time lines and the ability to do something similar with the myositis trial, as what we have been doing with CIDP. Wim, can you take this question, please?

Yes, sure. I hope you can understand me well.

We can, Wim.

The question in myositis -- sorry? Okay. I trust you can hear me well.

Yes, we can, Wim.

Okay. Thank you. So the situation with myositis is, of course, a different one compared to CIDP, where we talk here about combining 3 different expressions of the disease. And therefore, that requires a different approach. What we could be looking at is an enhancement of the subtypes that could show -- and in that sense, it's a derisking scenario. And you might say it's similar in -- compared to CIDP because we also had an early derisking. Here, we do the derisking for the specific subtype. So we will be able to enrich any subtypes where we see a response. We could still change the sample size accordingly, referring back to predefined criteria. So in that sense, there is derisk within -- derisking within the design, but it is different from the CIDP situation and, as I just mentioned, because it's a different approach with 3 different subtypes included.

Thank you, Wim. And with regards to starting of the trials in bullous pemphigoid and myositis and MMN, can you comment on big-picture time line for starting these trials?

Yes. We are focusing on end of the year or early next year, so it will be a very busy time periods, but that's the time line we're aiming for. Some of the time lines depend on interactions that are ongoing. As mentioned in the presentations, especially for myositis, we're paving the path here, so to speak. We are trailblazing in a sense that, in terms of endpoints, we have interactions with the FDA also with respect to the innovative trial design. And depending on those interactions, the time line could be early, so still this year or early next year for a start.

Okay. Thank you, Wim. And then, James, on finishing studies, of course, we continue to stay away from any guidance here. We're still in full COVID pandemic in big parts of the world. So what we will do in the future, going forward, is what we said we would do. That is if MMN studies are fully recruited, we will talk about it in our quarterly earnings calls. And of course, you can monitor the start of the initiation of these trials through clinicaltrials.gov. Thanks for the question.

Our next question comes from Tazeen Ahmad with Bank of America.

So I think I was muted, sorry. Can you hear me?

Yes, Tazeen. We can hear you. Thank you.

Excellent. I'm just wondering given that the myositis indication might be quite large, and you talk about potential subgroups. Can you talk to us a little bit about how you're thinking about whether certain of those subgroups might be more amenable to treatment and whether or not your plan initially could be to study specific subgroups? And then as a follow-on question, I think one of the comments made during the presentation is that, for myositis, that treating with steroids often takes a long time to start to see efficacy. Based on what know the -- about the profile here, how long do you think it would take to start to see efficacy in patients?

Tazeen, thank you for being with us today. It is true that myositis, of course, is a set of indications. Here, I think, in the R&D slides, which were presented by Bas, we basically showed you how we went about identifying these subsets where we think that is most compelling evidence for IgGs mediating the disease, starting with IMNM then ASyS and dermatomyositis. And maybe, Bas, you can briefly repeat why we assume then on these 3 subsets. But we think within the universe of myositis, myositis is of 3 plausible subsets to interfere in a meaningful way with efgartigimod. Bas?

Indeed, in necrotizing myopathy, there, the rationale is fairly clear. The autoantibodies are driving the disease. There have been preclinical animal models that Peter showed that if you take and purify IgGs from the blood of patients and inject it into mice, then these mice, they develop exactly the same disease features as have been observed in these patients. So that's a fairly direct evidence that the auto IgGs are involved. Now for anti-synthetase syndrome and dermatomyositis, these direct evidences are not available yet. But what has been done for anti-synthetase syndrome and remember what Professor Aggarwal mentioned that the anti-Jo antibody is the most prevalent antibody in myositis, and it's an anti-synthetase antibody. So what there has been done is it is not a direct transfer of IgGs into mice, but what has been done is that mice has been immunized with the target of the anti-Jo antibody. This is the -- this is histidyl-tRNA transferase. And what these mice -- what happens in these mice is that these mice, they develop a very high titer of these antibodies against their target, so against the mouse anti-Jo antibodies. And these mice, they also develop the same disease features. So these mice, they develop muscle inflammation and lung inflammation, similar, that is observed in patients with anti-synthetase syndrome, the interstitial lung disease and the muscle weakness. Looking more at the clinical evidence and looking at the rituximab myositis trial 10 years ago, there you see that patients that have antibodies against Jo-1, so the anti-synthetase syndrome or against Mi-2, that's an antibody in dermatomyositis, these bases, they met the definition of improvement earlier than in other patients who were tested in that trial. And what is also demonstrated that the titers of these antibodies and that's very important that these titers of these anti-Jo antibodies and also for the Mi-2 antibodies, they correlate these -- all these core set measures of the total improvement score.

Yes. Thank you, Bas. And we have the benefit of having Dr. Aggarwal on the phone. So maybe Dr. Aggarwal, you want to build on what Bas has been saying. And maybe also comment on the fact that steroids seem to take some time to act and maybe draw a proxy from IVIg or another proxy you think is relevant for trying to estimate what time of response could be on an IgG-lowering agent. Dr. Aggarwal?

Yes. So first of all, Bas really nicely summarized the first question that the speaker asked about the evidence of autoantibody or evidence that lowering immunoglobulins may work. And I will add to just one more point that they're also evidenced in dermatomyositis in certain subsets, for example, anti-MDA5 positive antibodies. They have been thought to be sort of prognostic, and the levels of anti-MDA5 antibody sort of predicts how active or severe the disease is going to be. Similarly, an antibody called anti-TF1-gamma antibody, which is associated with cancer in dermatomyositis, what has been seen is once dermatomyocitis is active, these antibodies goes up. When it gets into remission, antibodies drop the level. And if the patient has a flare-up in future, you see again resurface -- increase in -- dramatic increase in these autoantibodies. So I was just completing the few additional points that Bas has already summarized nicely. And then the 2 question, how long does it take for patients to see a response. It's typically -- first of all, it depends on the onset of action of the drug. So let's say the drug works in 4 weeks or 8 weeks. I've always maintained it takes about 3 months for patients to see clinical response, a significant clinical response. Now based on IVIg Octagam data, we know the clinical response starts as early as 8 weeks. But to reach threshold, a significant clinical response, I believe, it still would take about 12 to 16 weeks. And that's why when we do myositis clinical trial nowadays, I recommend to have at least 16-week primary endpoint or up to 24-week primary endpoint. Longer is better because then you have more assurity that you will see the response in the given time. I hope that answers the question.

Yes. So would you have a guess on how much faster efgartigimod could work?

Now we're in the area of speculation, of course, Tazeen. So we do not know that. And of course, it's something which we will study in this clinical trial. We have designed a clinical trial in close concert with the experts, including Dr. Aggarwal. So we believe the duration of the trial is sufficiently long to pick up a convincing signal in any of the 3 subsets. In case efgartigimod would work, how fast it's going to work, we don't know yet. So I think we will need to wait for the data.

Our next question comes from Graig Suvannavejh with Goldman Sachs.

Can you hear me okay?

We can.

Hello? Can you hear me okay?

Graig, we can hear you. Yes, We can hear you, Graig. Thanks for joining us today.

Sure. Thanks for the R&D Day and all the details. I guess I've got 2 questions that are kind of related to each other. One, thanks for announcing 5 and 6, and I'm sure there are a lot of questions around 5 and 6, but I wanted to pick up on your comments around perhaps seeing efgartigimod approved in as many as 10 indications or getting to 10 indications. And so how are you thinking from a rationale or strategy in terms of indications 7 through 10? And how are you -- how do you prioritize whether it's based on the biology or the commercial opportunity? And kind of following up on that, I know in past presentations, going back a couple of years, you've highlighted indications, such as lupus and EB and ANCA vasculitis or RA. So I'm wondering if you can comment on whether you think those are indications that are still up for consideration. And then my last question is for Dr. Aggarwal. It goes back to perhaps something Tazeen might have asked about, but I'll ask in a different way, which is, as you think about the 3 subtypes that the company is going after in terms of myositis, how would you rank kind of based on the strength of the biology or the science of the 3 where you think efgartigimod is most likely to find efficacy if you have any initial impression?

Thank you, Graig. I will take question 1 and then indeed hand over to Dr. Aggarwal to talk about probabilities of success in the 3 subtypes of myositis which we have jointly selected. With regards to indication selection, Graig, we're not going to change strategy. We always start from a convincing -- a solid biology rationale. The type of rationale which we presented to you today in the slides. Ideally, these few PLEX, immunoabsorption data like we have shown you for bullous pemphigoid, but we also believe that's the type of evidence we collected for myositis, including some of the transfer models Bas described, is pretty compelling. So I think there's a very plausible biology rationale for both. Of course, the feasibility of running clinical trials is the second filter we consistently apply. And I hope that we could show you today an intelligent, logical trial design for both indications. And then third, the commercial rationale of course. I think we showed you data today on prevalence, data on what we think in addressable markets patient population could be for both indications. These are sizable, meaningful market opportunities. And as you can see today, we have been prioritizing indications, which help us to build out the commercial franchises being neuromuscular and being skin today. So we will continue to apply a similar logic to selecting the next indications, 7 through 10 or beyond 10. The list is very long. And I would also like to call out the strategic collaboration we have with Zai Lab, our partners. Zai Lab is not only the company which will be our commercial partner in China to take efgartigimod to patients there, but we publicly disclosed that Zai Lab will also be our partner to start adding proof-of-concept studies in additional indications. So you will see us ramp up to 10 hopefully fast. On your question regarding lupus or rheumatoid arthritis, I think it's very interesting today that with myositis, we start to see that the interface between muscle and probably rheumatology, because some of these patients are being seen by rheumatologists, so we're putting a toe in the water here in the rheumatology space without disclosing anything more. And we continue to believe that kidney could become a next franchise based on the biology of some of the indications, which would be amenable for efgart or for ARGX-117. So I would say stay tuned. We're just in a logical, consistent fashion, expanding our reach into high-conviction indications. And with that being said, I would like to turn again the call to Dr. Aggarwal to comment on his view on probabilities of success across the 3 subtypes which we have selected. Dr. Aggarwal?

Yes. Thank you. So I think it was an excellent question. What's the probability? It's still difficult to say. But I go -- if we go by the evidence, you have the direct evidence, most direct evidence in IMNM, okay? So from that standpoint, I would say I will pick IMNM as the top -- like the -- most likely the one that's going to show efficacy. The second one, I would pick anti-synthetase syndrome because I think the -- in terms of the total amount of evidence from mouse model and clinical studies done, we have the best evidence in the -- second-best evidence in anti-synthetase syndrome. In dermatomyositis, we do have evidence, but it's sort of more smaller studies and more circumstantial rather than a direct, solid evidence. So that's why I would put it at number 3.

Thank you, Dr. Aggarwal. Thank you very much.

Our next question comes from Joon Lee with Truist Securities.

The PK/PD of 117's sweeping mechanism of action is really promising, which is -- I mean it's sort of out there kind of question. But would it make sense for you to collaborate with AbbVie, say, to make a sweeping version of HUMIRA as well? I mean is there a limit to the target that you can sweep? And is this sweeping technology something that is protected by your IP? Or is this more in-house know-how? Or can others do that as well, if they so desire? And the second question is on the recent data from Ultomiris on gMG. Efficacy looked pretty impressive with evident efficacy at week 1 already and durable response out to week 52 with the Q8-week dosing. Does this, in any way, change your commercial strategy for efgartigimod? And what would you say is the biggest differentiator of efgart against Ultomiris and gMG?

Joon, thank you for being with us today, and a good morning. With regards to the sweeping technology, let me first comment on your question on to what extent it is proprietary. And then I will give the floor to my colleague, Hans de Haard, to conceptually -- the question on what type of targets are most amenable to a sweeping approach? And then I will give the floor to Keith Woods, of course, my colleague on the commercial front, to talk about differentiation from Ultomiris and how we look at our own data in light of this data release. So from an intellectual property point of view, in order to make a sweeping antibody, you need actually to have a couple of mechanisms built in into your molecule, right? So your antibody molecule should have a PH or a calcium dependent binding to its target, and that's something which we discovered to be a natural property of our C2-targeting antibody, so coming straight out of discovery. We did not have to engineer for that. On the other hand, you need, of course, an increased binding to FcRn in order to favor the recycling path over the degradation path and give your molecule a long half-life And here, of course, we have a unique patent position when it comes to the patents, which we in-licensed from Sally Ward's university, UT Southwestern. These are patents which we are prosecuting. We already have secured granted patents in the main territories, and we continue to prosecute them. So not everybody can make a sweeping antibody. I think it's a small select group of people who can make them and be one of them. Hans, maybe you want to add conceptually what type of targets we would consider for a sweeping approach, please.

Yes. I hope that you can hear me. And the type of targets which we consider are the targets which are abundantly circulating. So I think complement factors are an excellent example, as Inge also explained. But I think you were also referring to Ultomiris, where C5 is the target, and that is also abundantly circulating. So for TNF, for HUMIRA, I don't think it really makes sense because there are not such abundant amounts of TNF circulating in the bloodstream, so these are the most interesting targets. And other targets which can be considered are receptors which take away the antibody. So for instance, Chugai targeted the IL-6 receptor antibody -- with an antibody, which had a very short half-life. And more recently, they published about a version of [indiscernible], which was made sweeping, meaning that it can be internalized by binding to the IL-6 receptor but in the endosome due to the pH-dependent binding can be released. And then you combine this as mutations in the Fc like ENHANZE, you really can enhance, promote recycling back to the surface of the cell. And then again, the antibody is released and combined to other IL-6 receptor targets. So these are the typical targets which we consider for the sweeping concept.

Thank you, Hans. And let me remind the audience here that we do have a collaboration with Chugai. But actually, we have been accessing some intellectual property, which we think is of interest, going forward, into the future trying to build real differentiated molecules under our IIP umbrella. Keith, I would like to hand over to you to briefly comment on the question on the recent data released for Ultomiris in gMG, please.

Sure, Tim. Happy to do so. So I guess the first thing to say is I don't think the data was that big of a surprise. It's a C5. It's similar to Soliris. We figured that it would have similar results. It did. It was about a 57% clinical response rate on MG-ADL. That's very comparable to the REGAIN study that was at about 60%. It doesn't change the fact that it's a C5, and that's only going to affect your acetylcholine receptor positive patients. And it is also only dealing with the element of complement at the neuromuscular junction. And as we all know, the actual autoantibody plays -- complement is just 1 of the 3 roles that the autoantibody plays at the neuromuscular junction. With efgartigimod, we believe we play upstream of C5 because our mechanism of action is removing that autoantibody from the neuromuscular junction. Therefore, if it's not there, you're not recruiting complement. I'm not comparing trials, but I will say, I think we've set the bar quite high. If you look at a clinically meaningful response rate of about 78.5% of patients that are exposed to efgartigimod for 1 to 2 cycles have a clinically meaningful response. You know it's a very rapid onset of action. About 84% of those patients respond after 1 or 2 doses. And what's really meaningful is in a responder rate, almost 2/3 of patients reach minimal symptom expression. So I still believe we're going to play upstream. And you know that we also had the 0 negatives in our secondary endpoints as well, so potentially broader.

Our next question comes from Yatin Suneja with Guggenheim Partners.

Can you hear me well?

Yes. Welcome, Yatin.

Two questions for me. These are quick ones. So on the adaptive design for the myositis study, what are the criteria for you to abandon one of these subtypes, if you can walk us through that? And the other question I have is with regard to the IgG reduction required for different type of skin diseases -- or actually, the question is, is there a different requirement for IgG reduction for skin diseases versus something with a more of a systemic presentation? And then can you get enough skin tissue distribution or penetration with your subcu administration?

Yes. It's 2 great questions. Thank you, Yatin. So on my side, I'm going to give the floor to Wim, our Chief Medical Officer, with us today. We are not disclosing the fine details of the study designs. But indeed, there's an ability with an interim look at the data by the SMB to actually advise us to continue in 1, 2 or 3 subsets and also have the ability to potentially enrich in all of the subsets. Wim, do you want to talk conceptually about what it would take to continue in a subset, please?

Yes, sure. I can do that, but I don't know whether I can disclose much more than what you already said, Tim. I think it is important that there will be an adjudication committee, as was mentioned, to make sure that we have the -- in the 3 subtypes of population that fulfills the criteria for the disease. The futility analysis will enable us, and we will remain blinded, but the DSMB will look at...

Wim, we cannot hear you. [Technical Difficulty]

It appears we've lost connection to our speaker.

Yes. But that is okay. Yatin, think there's not too much we can see about the statistical rule we're going to use to declare an indication, a continuation indication, yes or no. But I think Wim captured the essence of it. There is a futility analysis where you would apply your typical statistical rule in order to continue or discontinue. And I think it's about -- it involves a significant number of patients in order to come to that point. On your question on IgG reduction, of course, that is a question we cannot answer completely. We know with efgartigimod, we have a PD effect of maximally reducing total IgG 70% to 75%. But maybe I can give the floor first to Peter to talk about his view on the ability of efgartigimod subcu to meaningfully reduce IgGs in the skin based on what we have seen for pemphigus. Right, Peter?

Yes. Thank you very much, Tim. So indeed -- so we have completed our Phase II study in pemphigus. And what we have learned here from the IP formulation is that, together with the IP level production of autoantibody levels were quickly reduced and this translate into improvements in the disease activity scores. But what we have also learned is that we -- when we kept dosing for longer time periods, the patients continue to improve and that also the autoantibody levels were improving further. So that's very interesting. Now what we do is skin indications in pemphigus and in bullous pemphigoid with the registrational trials, as we have indeed changed to the subcutaneous formulation. All of you know subcutaneous formulation has a very similar pharmacodynamic profile as the IP formulation. We have very beautiful mimic there. So for bullous pemphigoid specifically, what do we know there about autoantibody level reductions and improvements on disease activities, [indiscernible] look to the Phase III randomized controlled trial of these 56 patients are responsive to corticosteroids, and they [indiscernible] type of IVIg. Nevertheless, we have observed these improvements, these fast improvements with an autoantibody level of production of about 50%.

5-0, 50%, yes.

50%. And what we also know is -- for instance, with corticosteroids, also the autoantibody levels are reduced to about the same degree for patients in remission. But of course, it takes as much longer time to get to that point. It takes months to get this 50% reduction.

So Yatin, we think that at 50% is well within reach for a molecule like efgartigimod. Bas, do you want to comment on anything we know about myositis in this regard?

Yes. I think that Professor Aggarwal already gave the answer. There is a correlation between the autoantibody titer and also the disease severity, also regard to certain symptoms. Regarding to your questions, whether it would have an effect in the skin as well, I think there we have the example of the ProDERM trial with Octagam IVIg, where they met the endpoint, and the total improvement score was also ahead and a very positive effect on the CDASI score in the Cutaneous Dermatomyositis Disease Area and Severity Index.

Thank you, Bas. And just for sake of clarity, Yatin, we should be able to match or beat the IgG level reduction observed with IVIg given this very specific mode of action of efgartigimod. Thank you for the questions.

Our next question comes from Jason Butler with JMP Securities.

I had 2. First on myositis, how are you thinking about the future evaluation of different doses or dose frequencies for different subtypes or severity of disease? And would you consider some kind of individualized dosing plan like you have in MG? And then for bullous pemphigoid, just -- again, how do you think about developing the drug or evaluating the drug as a monotherapy versus tapering steroids, i.e., adding the drug on top of a tapered or lowered steroid dose?

Thank you, Jason, and a very good morning. Thank you for being with us today. On your second question, before I hand over to Wim to talk about dosing and thinking about dosing frequency in myositis, on bullous pemphigoid, let me just clarify. We are dosing on top of standard of care, which is steroids, and yet the protocol will cater for the possibility to taper steroids as of when a patient is achieving sufficient response. So we will do that, and that is very similar, by the way, to the global Phase III registration trial, which is ongoing for pemphigus. Wim, do you want to comment on our views on dosing frequency and the ability to go into individualized dosing in an indication like myositis?

Yes, sure. And I hope that I'm not kicked out this time while responding to the question. So of course, this trial will give us a lot of insights on how efgartigimod reacts and the patients react to efgartigimod in the different subtypes. One could imagine that, given the pathology, that a more sustained therapy could be needed. But of course, as I mentioned, this trial will give us a lot of these insights to see how we continue in the registrational part of the study.

Thank you, Wim. I can imagine -- yes. Thank you, Wim. And I can imagine that similar to CIDP, once we have a convincing signal in the blinded study in an open-label extension, you would actually allow for the ability, to a certain extent, space out the dosing when patients go into remission wide. So that's a topic for the OLE. Jason, did we answer your questions?

Yes, that's great.

Thanks for being with us. Thank you.

Your next question comes from Joel Beatty with Baird.

This question is for the company or the docs. As you add more indications for efgartigimod, do you anticipate there may be a role to use diagnostics to pick out patients more likely to respond to treatment, either in clinical trials or the real world?

I'd like to give the floor to Dr. Aggarwal to comment on how, in general, the diagnosis and sub-typing of myositis is evolving more and more based on serology. But he's the expert we have in here today, so I would like to make maximum benefit of that. So Dr. Aggarwal?

Yes. So I think it's a good question. But what I would say is in 10 years -- last 10 years, we have seen significant advances in standardization and improvement in the diagnostics of these myositis-specific antibodies. To an extent that 10 years ago, when a commercial lab would report an autoantibody, I wouldn't really believe it. I would check it in my research lab. Whereas now in the last couple of years, we have abandoned doing repeat order antibody testing in our research lab because commercial assays are giving us very good results. So there will be -- there has to be an accompanying autoantibody testing, but what I would say is you don't need to develop a different accompanying diagnostics, the dose diagnostics that companies -- is already available in the commercial market, and those itself are getting better and better in terms of the sensitivity and specificity.

Thank you Dr. Aggarwal. And Dr. Hall, I think for BP, that is a very simple answer, right?

Yes. So I think for BP, the role of the antibody is central. And I think that there's -- the definition of responsiveness will probably be focused on just antibody levels and how high they are in disease severity. But I think that the relationship is so strong that there won't be a big differentiation in terms of biomarkers about who will be responsive because of the key role the antibody plays in the pathogenesis.

Thank you, Dr. Hall.

Our next question comes from Danielle Brill with Raymond James.

Dr. Aggarwal, I believe you mentioned that dermatomyositis is actually an umbrella term. And I'm just wondering if you could elaborate a bit on how disease pathogenesis or if the treatment response varies based on the autoantibody involved. And then as a follow-up, Tim, in your planned trial, will placebo controls be matched at the antibody level?

So good question. So dermatomyositis is a specific diagnosis of -- it's a clinical diagnosis. But when you come to a serological diagnosis or serological classification, then you see the dermatomyositis is actually made up of 5 different subsets serologically, and each different subset is represented by the myositis-specific antibodies. And these -- each myositis-specific antibodies have some unique clinical feature on the top of the common clinical feature of dermatomyositis. For example, anti-TF1-gamma antibody obviously have classic dermatomyositis but also have higher association with cancer. Anti-MDA5 antibody has a different pathogenesis and has an association with interstitial lung disease. Anti-MI-2 is your garden variety, very good prognosis dermatomyositis. So you see there's a commonality of clinical diagnosis of classification of dermato, but then there is uniquely different features. And these -- each unique different features stem from unique different pathogenesis that what we believe that each of these autoantibodies, not just represent unique clinical features as a biomarker, but they also represent an underlying pathogenesis, all of which lead to a common clinical phenotype or dermatomyositis in -- at the end of the pathway basically.

Thank you, Dr. Aggarwal. And on the second question, I think that's simple. We will be balancing the 2 arms, so active versus placebo, based on disease severity and not necessarily based on antibody titer. Now we are monitoring antibody titers to do some retrospective analysis, but we don't use it to basically balance the 2 arms, okay?

Our next question comes from Yaron Werber with Cowen.

Yes. So Tim, I got a couple of questions. The first one for BP. Just how big is the study? And are you dosing weekly until response? And at that point, once they pay for steroids, they can vary the dosing scheme? Or does that happen really after the 36 weeks? And then I have a question on myositis afterwards.

Yes. Yaron, this is a great question and a great opportunity for my colleague, Peter, to comment on trial size in BP and also how we envision the possibility of tapering the background corticosteroids. Peter?

Thank you very much for the question, indeed. So what we see from registration trials in BP is that the trial size is between 80 and 120 patients typically. So we also grow with a proposal of about 170 BP patients, randomized 1:1. Of course, we have the ambition to taper corticosteroids as quickly as possible and to allow for that. So that will be initiated 2 weeks after -- achievement of disease control, so consolidated disease control, 2 weeks later the taper will start.

Thank you, Peter. And then, Yaron, up to the second question, please?

Okay. So the second question on myositis. What's the background -- this is -- it sounds like this is a monotherapy study, right, with no background. Are patients naive or they relapse in myositis? And at what point do you expand into sort of the Phase III potential pivotal part of the study?

Yes. So first of all, the treatment is efgartigimod or placebo will be on top of standard of care, the first of all. And then we will, of course, do the randomization, 1-on-1 of the 3 different subtypes of myositis in that interim. We can do the futility analysis where we can either continue Phase I, II or III of the subtypes and do the sample size re-estimation accordingly.

Background mitigation would typically be, Bas, in myositis still like this?

Yes. This is a low dose of steroids, plus maximally one nonsteroid immunosuppressant. Thank you.

Yaron, is that answering your question?

Yes. And then is there a chance that you can go into -- each individual subtype can go into a full pivotal head-to-head against control with the size re-estimation, right? It's going to be seamlessly integrated in that sense.

That is correct. So if it works, we can gain a significant amount of time as compared to a classical scenario where you would do your Phase II, read out your Phase II at the end of Phase II meeting, then get your Phase III on the rails, that is taking a significant amount of time. So the aim of the design is to minimize time lost between the futility analysis and the readout of the Phase III registrational portion of the study.

Our next question comes from Douglas Tsao with H.C. Wainwright.

So just for the myositis trial. I'm just curious, again, I guess this is on top of standard of care, so are there any treatments that are excluded? Or is it basically just up to the clinician in terms of what they are allowed to have -- what therapies are allowed?

Thanks for the question, Doug. So looking here at my colleagues, Peter and Bas, probably a typical therapy, which would be excluded will be IVIg, right? Is that correct? Peter, you go first.

Yes. I think standard of care definitely excluded typically, of course, actually containing therapies of monoclonal antibodies. So IVIg, we know is, of course, having a natural [indiscernible] fragment. So it could be allowed as rescue medication in certain trials.

Rescue medication?

Yes.

And Bas, what about myositis?

Yes, I think the basis should be off therapy on IVIg or rituximab...

For a minimum period of time.

For a minimum period of time.

Yes. Okay. So very similar. I hope this is answering your first question, Doug. Do you have the second question?

Yes. It does. And then just also -- just in terms of the individualized dosing, I'm just curious from Dr. Aggarwal's perspective, how applicable or relevant do you think that is versus what they were able to achieve in myasthenia gravis for [ myositis ]?

Dr. Aggarwal?

Yes. I mean I may not have understood the question, but I think it -- obviously, you have to not allow IVIg and rituximab as concomitant drug. So what we really allow in most clinical trial is concomitant drug, which is basically a little bit of steroids, limited by one other immunosuppressive drug. But for this particular trial, obviously, you can't allow rituximab and IVIg as a concomitant drug trial. But we don't even allow that for other trials as such. I'm not sure I got the right question then, otherwise.

No, Dr. Aggarwal, I was just -- around the dosing and the dosing intervals.

Yes. So what we did in myasthenia gravis, which is what would we call a snowflake disease, that means that each individual patient is experiencing his or her disease in a unique individual way. We basically allowed in the trial, the Phase III trail, a tailor to dosing. So individualizing the dosing cadence to the individuals of the patients. As Wim already explained in an earlier Q&A, we think that for myositis, we would probably walk down the path like CIDP, where we will be looking for more chronic dosing, right? But thanks for the question. Thanks, Doug, I appreciate it.

Next question comes from Yanan Zhu with Wells Fargo.

So 1 question for the doctors and 2 questions for the company. The question for the doctor, Dr. Aggarwal and Dr. Hall is that in patients who achieved remission with efgartigimod in either the myositis trial or the BP trial, do you foresee maintenance treatment with efgartigimod, I mean not in the trial, but in a real-world setting? Would you foresee applicability of maintenance usage of efgartigimod? Or do you foresee patients come off therapy for extended time before they get retreated?

I'll answer for myositis. I think what I would expect would happen is what -- something that has happened in IVIg, where basically, if we give IVIg to put patients in remission, okay, so which could be a 6-month treatment, maybe a year of treatment, and then you taper it off assuming that the patient would not relapse or hoping the patient would not relapse and you taper the treatment off. And in most cases, the patients actually do very well on a very minimum amount of maintenance doses of a standard immunosuppressive drug like methotrexate or mycophenolate, and that's what we do in IVIg. But in some cases, we see when we taper the IVIg at the time when we're tapering or at the end of the taper, we'll see the disease starts to flare up, not that much, but disease starts to come back. And then we know, okay, this patient, we're going to have to do maintenance treatment with IVIg for longer time points. So we continue a lower frequency and dosing of the maintenance treatment for another 6 months or a year and then we try to taper again. And then we -- again, in many patients, we are successful. In some patients, we are not. So -- but that's for a minority of the patient. For most of the patient, I would expect that once the patient is in remission, a patient is able to maintain the remission on the basic immunosuppressive drugs. Maybe it will take 6 months or a year, it depends.

Dr. Hall?

Yes. So I think that the first answer to the question is there will be some patients that require long-term therapy based on the persistent production of autoantibodies by their body. And the -- how we'll identify those patients and whether we'll go into a tapering program, as Dr. Aggarwal suggested, will depend on the clinical response, do they develop small levels of disease, but also by monitoring the antibody levels, both in the skin and in the blood so that we will be able to watch patients. And I think the nice thing about the skin is we can see minimal disease activity so we can taper -- adjust the taper to the degree of disease activity. So that my anticipation is that there will be a long period of therapy perhaps up to a year and then a gradual tapering dictated by clinical response and autoantibody levels both in the blood and in the skin. And that over the course of the next 2 years, most patients will be able to taper completely off the therapy.

Thank you, Dr. Hall. Yanan, you had a second question, right?

Right. Two questions for the company. One is that -- thank you for providing some additional color on albumin. It looks very encouraging. I just -- I think I saw a little bit of increase in albumin in the efgartigimod-treated patients compared with placebo patients. Just wanted to hear your thoughts on whether there's anything there. And lastly, could you touch upon the ongoing -- your dialogue with the FDA on the BLA of efgartigimod in myasthenia gravis? Have you had a mid-cycle meeting with them? And what's -- how would you characterize your interaction with them so far?

Thank you for these questions, Yanan. Let me start by answering the second question. I will invite my colleague, Hans, to comment on the albumin level, which we presented and the thinking behind it. With the FDA interactions, I can confirm to you that we did have the mid-cycle meeting. And the way we would be able to summarize the interactions is that so far, so good. So this is, as you know, an ongoing Q&A. You get written questions. You supply written answers and that goes on and on. Meantime, or meanwhile, inspections are taking place for the clinical sites. We do know the plan for the inspection of the manufacturing site. So, so far so good. And Hans, maybe you want to take the question on the albumin level, please?

Yes. Thank you very much for this question. So indeed, in some trials, we did see a small stable transient increase in albumin within range of clinically normal, so not more than 10% increase. This confirms the fundamentally different subcellular [ fate ] with efgartigimod as compared to the full length FcRn-targeting antibodies which you see as the ultimate evidence of the difference between those 2 classes of [ FcRn ] antagonists. We are not aware of any literature associated with adverse events with this level of albumin increase. And we checked with our KOLs and they confirmed the same and said it could be even beneficial at these levels. So across clinical trials, even with longer chronic exposure, we remain within this band of normal. I hope that this answers your question.

It does. It does.

This concludes our audio questions. I would like to turn the conference over for any questions submitted via the webcast.

We have one. In the 2 new efgartigimod indications, do you expect that patients will need to fail steroids first? And then the second part of that is in BP, given the age of the patients, how long do you think the duration of treatment will be?

Thank you, Beth, for providing us with this question from the chat box. Again, I'm going to make use of the benefit here of having Peter and Bas in the room. But what about the inclusion, exclusion criteria to the extent we can be public about them, do we expect people to fail steroids before they can come on trial? Peter, you go first.

We aim to develop efgartigimod as first-line treatment in BP. So we will enroll newly diagnosed patients and they start at 0.5 milligram per kilogram per day of corticosteoroids. That's the answer for BP.

Thank you. And Bas, for myositis?

That's actually the same for myositis. So basically, newly diagnosed also can be on steroids during the trial except for low dose.

But then they do need to meet a minimum standards in regards to disease severity, right?

Yes, absolutely, yes, yes.

Okay. Beth, I think that answers the first question, right?

Yes. And another one on the review of the BLA. Do you think it's possible, given the REGAIN primary end point, that they would want to see data at 26 weeks? And how would you handle this, if so?

Well, the only thing I can say there, Beth, as an answer is, of course, we have been crafting the design of the ADAPT trial in close collaboration with all the stakeholders, not just the patients who express the desire for individualized dosing and the physicians subscribing to that, but, of course, also with the regulators. So we had buy-in in the ADAPT trial design from both the FDA and the PMDA. So we do know what they think about, the individualized dosing, the primary endpoints and the stringency of the primary end point because, remember, in order to be a respondent in that trial, you needed to have a clinically meaningful benefits in 4 consecutive visits, not just in 1. So I don't have any specific concern in my mind concerning the acceptance of the primary end points.

Okay. And I'm just going to put 2 more out there at once, and then we'll be done with the chat questions. The first is could you give an update on our partnered programs and include cusatuzumab in that? And then the second is could you talk about the opportunity of efgartigimod in BP compared to some of the potential competition like Dupixent?

Okay. I'll give the second question to Peter here to briefly comment on competitive landscape and actually lack of approved therapies. On the first question, I'm happy somebody is indeed still thinking about all the other opportunities, which are progressing in the hands of our partners. And I actually can be very brief about it. I think our partnerships with LEO Pharma, with AbbVie, they continue to progress. So these molecules continue to make progress in the clinic. As you may remember, we're only allowed to talk about these programs if and when they transition between the different phases of clinical development. But I can be affirmative, the LEO Pharma and the AbbVie collaboration are alive and progressing well. Same I think, for the AgomAb opportunity and the Staten opportunity, which continued to do well either in the preclinical or the clinical phase. For what concerns cusatuzumab, we are doing what we said we would be doing. We've been doing a very thorough analysis of the data. We will plot the path forward with cusa in a database fashion. I think what we said in the press release is that we believe there is value in the molecule. There is strength in the data, and we are exploring through a business development angle how we can actually take cusatuzumab forward. We will not bring cusatuzumab back in-house. We will not distract our ongoing efforts for our autoimmune programs, efgartigimod, ARGX-117 and ARGX-119. But we think we owe it to the AML patients to seek a path forward through some sort of partnership. Thanks for the question, Beth.

This concludes our question-and-answer session. I would like to turn the conference back over to Tim Van Hauwermeiren for any closing remarks.

Yes. I would just like to make a few concluding remarks for the audience. I really hope you enjoyed the R&D Day presentations, both with our in-house people and with our partners on the clinician side. And as we explained, collaboration is in the DNA of this company. We believe the future belongs to those who collaborate best. So I would like to thank Dr. Aggarwal and Dr. Hall for their active contribution but also all the other people and patients who contributed to disease evaluation, clinical trial design, et cetera. So I hope you like the compelling vision for argenx 2025. We think the global autoimmune market is exciting. It is growing. We believe we're at the forefront of what could be a revolution in the way we think about autoimmunity, the way we treat autoimmune diseases, now that precision tools like efgartigimod and ARGX-117 are becoming available, actually, to the extent that we have an opportunity to reclassify or redefine certain autoimmune diseases as being truly IgG-mediated or complement-mediated. This is the fifth and the sixth indication we're discussing today. We will be back to you talking about the other indications, 7 to 10 and hopefully beyond 10, and we will continue to build vibrant franchises in the neuromuscular space, the heme space, the skin and potentially, the kidney space. ARGX-117, we think, is an exciting molecule. The way it's coming out of Phase I is with very solid Phase I safety data warranting investigation in patients. We believe this is, again, a pipeline and a product opportunity with MMN being the first of hopefully many indications, which will fit the growing franchises. And rest assured, we continue to invest in our IIP program. We're building a company for the long haul. We have an abundance of opportunity in front of us through the immunology innovation program. And ARGX-119, I would say, stay tuned on that. That is the first one coming out of the autoimmune discovery efforts next to ARGX-117. And I would like to end by thanking all my colleagues working hard in the lab, in the clinical trials, on the commercial and pre-commercial front. It's only thanks to their dedication and commitment that we stand where we are today. So a big thank you. Very grateful for working with such a great team. Thank you, Beth, and thank you, colleagues.

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.