Good morning, everybody. Thanks for joining us for our R&D event here at the Yale Club. It's fantastic to actually enjoy the sun in New York on a beautiful morning, and we'll hopefully have an opportunity here to really share with you, I think, a great outlook for the company. I think some fantastic new opportunities that we've been working on. We got a great group of speakers, I think, that will have very helpful context that they can provide on the disease areas we're going to be talking about, but also, obviously, elucidate some of the data that we are planning to review today. With that, on our next slide, I would like to just briefly remind you that, obviously, we're a listed company, so please look at our risk factors in our SEC filings to sort of have a full appreciation of the risk profile of the company, the products, and obviously be aware that we're making a number of forward-looking statements. Our agenda today is really focused on a set of topics that are really directed towards the opportunities that we have with our lead product in autoimmune disease. We have some great speakers invited for today. We got Dr. David Eisenberg, who will join us right after my introduction to talk us through the medical need in lupus, as well as in SLE, as well as in lupus nephritis, review the treatment landscape, and then also actually go through the early data that we have from the CARLYSLE phase I study. Most of the patients actually have been treated in David's clinic, and so I think it'll be very helpful to actually get an understanding, get the color of what it means to actually treat these patients with CAR T therapy. We will then hear from Matthias Will, our Chief Development Officer, on the next steps, and Matthias will introduce the path here to a pivotal study in lupus nephritis. We'll have a Q&A session to go through that segment on the lupus and lupus nephritis side, as well as the data. In the second part of the meeting, we'll dive into the opportunity in multiple sclerosis. We have the great luck here to have Mark Freedman from Ottawa, who will actually walk us through the landscape of the medical need, as well as the opportunities for treatment for patients with multiple sclerosis. Then we'll hear from Matthias on our planned study in this population, which is a phase I study to generate initial data in that setting. We'll take a look at the early pipeline and then have a wrap-up with a second Q&A session focusing on the entirety of the presentations. With that, what I'd like to first do is actually remind you of where we are with the company at this point in time. We believe we're actually very well positioned with the company in, obviously, a very, I think, unstable and very much a changing environment that we're currently going through. We have, obviously, our first product approved, and we do have an opportunity with that product to not only have the product active in the hematology setting, but also gives us opportunity in other disease settings. We're building on, obviously, a very high level of activity that we've seen with Obe-cel It's a unique mode of action that we have with the product. As you remember, it's a product that has a fast off-rate, which gives us a very physiological engagement of the T cell, of the target cells, and with that, an ability to have a very high level of activity combined with a good safety profile. This is the first CAR T product that actually was approved without the obligation to set up a REMS, a risk and evaluation mitigation system. I think it also reflects the overall safety data that we have with the product that you obviously are familiar with as it was published in the New England Journal at the end of last year. Important in this space is that you do not only have a product with an attractive set of properties, but you also have to have the ability to make the product reliably. Our ability to actually manufacture commercially the product is a key capability that we've built over the last few years. You see in the middle picture the nucleus facility north of London that supports, obviously, the commercial launch of Obe-cel in relapsed refractory acute lymphoblastic leukemia, but also actually can serve future expansion of the product as well into additional indications. When we look at the commercial footprint, these types of therapies, obviously, are delivered at specialized centers, typically your top transplant centers in the country. In the U.S., we expect to reach about 60 centers accredited by the end of this year, which will give us, from an acute lymphoblastic leukemia perspective, close to 90% coverage from a patient access point of view, and obviously gives us also a very strong foundation for any of the future clinical work we're going to be doing, because there's going to be familiarity at those centers with the product and the profile of the product. We also are expecting to add, as we go through the course of this year, the U.K. as a next geography, as well as hoping to get, towards the end of the year, also the opportunity to move into the EU, and from there on, obviously, look to build forward. Important in this environment, and when there is a lot of ups and downs in the markets, we have a strong cash position with £ 588 million in the bank at the end of last year, which gives us an ability to really drive the company forward, but also really unlock a lot of the value that we have within the company. Now, I did already mention the fact that the launch, obviously, is underway in the U.S. We have currently 38 treatment centers that are active and are recruiting patients, enrolling patients for treatment. That is, obviously, a very fast start from a launch perspective, and you can see a very good distribution across the U.S. Also, what's important is that the patients have an ability to also get coverage for those therapies, so they get actual proper access to this type of treatment. We do have a significant proportion of the U.S. population already covered with the current arrangements that are in place across the country. When we look at the distribution between commercial and government or other payers, we have approximately 60% of the patients on for acute leukemia, which are covered commercially. About 40% are covered through government and other programs. I already did mention the fact that we expect our move into the European side, first in the U.K. and then into the EU. You see that we've made a change here with regards to the anticipated decision in the U.K., which we currently anticipate in the second quarter. We had originally guided for the second half of the year. For the EU, we expect a decision in the second half of this year. As we think about rolling our presence out in the EU, we are certainly going to make this on a country-by-country basis. One of the key aspects there is that you obviously do not only need the approval from a regulatory perspective, but you also need to, obviously, go through the pricing and reimbursement negotiations, which are done on a country-by-country basis. With that, and this is kind of leading us now into where we're headed in this presentation this morning, I would like to actually look at the opportunities to expand Obe cel into additional indications. When we look at what we know about the product, we obviously do have quite a rich data set from our work that we've done in a set of clinical trials in B cell malignancies. What we learned with those trials is that we can get very profound reset of the B cell compartment in these patients. We obviously get complete remissions in the majority of the patients. Patients that do get a remission tend to get very, very deep remissions. You have seen some of the data presented at the end of last year that looked at levels of below 10 to the minus 6, so less than 1 in a million cells in the bone marrow being still positive for the disease or being basically at detection limit. What we also have shown is that, indeed, the level of reset is so profound that we do get a proportion of these patients in true long-term remissions, with our earlier studies now going beyond five years of observation. It gives us very unusual information about the ability to truly reset the B cell compartment in, obviously, a very, very difficult-to-treat patient population. We've also seen the analogous outcomes in patients with non-Hodgkin's lymphoma. Those are patients that obviously have localized disease, quite different from the bone marrow disease that we're treating with acute leukemia. Also there, we see very high levels of activity between the 88%-95% level of complete remissions, metabolic complete remissions, within the large B cell cohort, most of these patients in actual long-term remission. Also there, evidence for very, very deep, very sustained activity. Obviously, it gives us an opportunity here to build on a very strong foundation, both from a safety perspective as well as from an efficacy perspective in terms of our understanding of our product here. Now, when we think about what is sort of the most attractive positioning for a product with this type of properties, the first is, if we think about the hematology side of the equation, it is the settings where you go into frontline consolidation, where you have an initial way of actually reducing tumor burden, and then actually have the CAR T therapy as the way to clean up the residual cells in these patients. One of the challenges that we have when we think about those types of aggressive leukemias and lymphomas is that we have, with the standard of care, an ability to cure a good proportion of the patients. We're getting into a very interesting situation where, if we just keep adding to the standard of care, we start overtreating patients who actually already had a chance to be cured, and we actually intensify further the therapy for them. That's not a good way to go. We see that happen in our space, and we see diminishing returns. What I think we need to focus on, as we've seen it in the leukemia space, is we have to focus on those patients that have evidence of residual disease and actually treat them to consolidate them, and with that, maximize the outcome, but also minimize the toxicity that we expose the patients to. There's quite a lot of activity that's going on in that direction, and a lot of interest from investigators across the U.S. as well as Europe to actually explore also in investigator-sponsored studies. You will see a lot of those activities be rolled out over the next 12 to 24 months. The second area, which will obviously be the focus of this set of presentations, is on B cell-mediated autoimmunity, where we would like to find a way to actually reset the B cell compartment, remove the autoreactive cells, also try to remove not only the B cells that carry the memory, but also the autoreactive, the cells that are producing the autoreactive antibodies. That is obviously one of the key areas that, if you can do both, you should have a relatively quick impact on these patients, and you should have a sustained impact as well. Obviously, the desire is here to actually get to a place where we can actually have sustained effects in these patients with a one-time therapy. That's kind of where we think the sweet spot is for this type of a therapeutic approach and an ability to remove the B cell compartment in a very profound way. Now, when we think about B cell targeting approaches in autoimmune disease, you'll hear quite a bit about that as we go forward. We've obviously had a remarkable set of products that were coming through that were looking to impact the B cell compartment. You have CD20 targeting antibodies. You have BAF and interferon receptor antibodies that have been developed and are actually available commercially. What's quite typical for these types of products is that they have a certain amount of patients that actually do respond, which also means there is a certain group of patients who do not respond or are primary failures. There is, over time, a relapse for those patients who responded that eventually relapse from those therapies. There is sort of a challenge on both ends that I think sort of needs addressing. When we look at the B cell compartment, one of the things that's quite clear when you look at the various antigens we can work with is that if we take an antigen like CD20, there is a limited amount of cells through the B cell development that you can actually target that are CD20 positive. What's quite interesting is that the CD20 doesn't actually expand or reach into the plasma cell compartment. What was quite remarkable when we saw the early data come out of the University of Erlangen with Georg Schett and Andreas Mackensen's team was that they could not only actually get an effect in these patients, they could get a rapid effect. What that suggested for the first time is that a CD19 targeting approach may actually also hit on the autoreactive antibody-producing cells. As it turned out, it actually that those cells look like they are the plasma blasts, which are CD19 positive, early stages of plasma cell development. Also, what we do know from CD19 and our own experience is that, obviously, you have a wider range of differentiation states, and combined with a very potent mechanism of action, an ability to make a very deep cut in the compartment, which obviously is much more challenging if you look at this from a monoclonal antibody perspective, which obviously has a limited level of activity. Now, when we think more broadly about autoimmunity and B cell-mediated autoimmunity, we have sort of two kind of mechanisms that I think do matter here. One is an inflammatory mechanism, which is obviously typically the initial part that actually where the reaction starts, and you have an initial attack of the immune system onto tissue. There is structural damage as a consequence of that attack. Obviously, as these patients progress, you actually are accumulating structural damage. When you think about an approach that actually addresses B cells and plasma blasts, what that will do is will address the inflammatory component, but obviously, it doesn't actually address the structural change. That's important to keep in mind as we think about the patients that we want to treat, what we think we can expect from these types of therapies. We also know that there's going to be a range of patients that are suitable for this type of therapy, but there's also a range of patients that may be beyond the stage where, indeed, B cell-mediated intervention can actually have an effect. When we think about CD19 CAR T therapy, we believe that we think the positioning is on the severe or refractory patients, but there are certain elements of patient selection that do matter. We believe we need to have an active inflammatory disease, limited chronicity of the disease, evidence for organ involvement, but limited extent of organ damage. That is the window within which we think we can actually have a meaningful impact. When we then look at what is the desired outcome from the therapy, the desired outcome is to find a way to remove the autoimmunity memory and the autoreactive antibodies. You want to stabilize impacted organs, whichever organ that may be. If you think about the upside, you may, in certain patients, see an upside where you see improved organ function based on the level of reversibility of damage that has already occurred. That is kind of, I think, important to understand that there is a framework that we are working with as we think about indications, as we think about impact we can have. I think that's going to be one of the key areas that I think is important to keep in mind. The two indications you'll hear quite a bit about are the first one, which is obviously refractory lupus nephritis or late-stage lupus nephritis. It is a high-end medical need. These patients typically have gone through B cell targeting already based on antibody therapy as well as usually a calcineurin inhibitor. When we look at the proportion of patients that actually are in that bucket, it's a relatively small fraction of the total proportion of patients that are impacted. When we look at the total number of patients treated for lupus in the US, that's about 350,000 patients. We think that at a level of around 10% of that number, that we are looking at the patient population that we believe would actually be suitable and are the right population to consider, at least initially, for a CAR T therapy. When we look at the second indication that we'll talk about, which is progressive multiple sclerosis, obviously, there as well, a very high-end need. There's obviously no therapy that gives you an ability to cure these patients today. Whereas somewhere, depending on the data sets you're looking at, you're somewhere in the range of about a million people impacted in the US. Of those, you have about 300,000 patients, or about 30%, that have progressive disease. We believe that it's within that range of patients that an approach like a CD19 CAR T approach could possibly be attractive if, indeed, we can see the relevant level of activity in our initial clinical work. That's just as a brief orientation in terms of the opportunities and the areas that we're focusing on. With that, I'd like to introduce actually our first external speaker. That's Professor David Eisenberg. David joins us from University College London. We really appreciate you made the way, and you joined us here in New York. David's obviously been in the field for a substantial period of time. He's one of the leading academic rheumatologists in our space and obviously has been running a very long-standing practice for patients with systemic lupus at University College. Currently, there are about more than 900 patients that are being managed through the practice at the University College London. David's done a lot of work not only on the treatment side, but also looking at the underlying disease mechanisms and has done a remarkable body of work on a range of autoimmune diseases, especially in systemic lupus as well as vasculitis and antiphospholipid syndrome. Been chairing a number of very prestigious organizations in the field. What's been very important is he's been actually working on a lot of innovative approaches for a very substantial period of time, looking at various ways to impact the B cell compartment and induce change in lupus as well as in rheumatoid arthritis. Obviously, I mentioned already important roles with regards to the Society of Rheumatology in the U.K., but also on the lupus assessment group. One of the important things with a lot of these diseases, and you'll hear more about that from David, is that the manifestation of the disease can be quite complex. Actually having the ability to score these diseases, characterize them, understand improvement or change in the disease are critical. This is obviously also linked to his work as the chair of the BILAG group that actually established one of the key scoring systems for these patients. Obviously, highly decorated with a set of prizes, including the Evelyn Hess Prize and being named a Master of the American College of Rheumatology. I looked at the number of papers and books you published, and I just wondered, when would you have time to treat a patient? Because it seems an astonishing body of work that obviously David's been able to sort of produce and really impact in a very, very big way the field. Very importantly, Dave's also acting as a musician at various events. For some of you, if you see some of the titles or works, the publications that David has, you might actually see references to certain songs from the Beatles that might pop up here or there. I'll leave it there. I'm pretty sure you'll find out where that is. With that, David, would love to have you up here and tell us about lupus and the medical need and where we're going to go. Thank you very much. Thank you very much for that very kind introduction, and thanks to Matthias Wuhl for the invitation to come to New York. Therapies for lupus. Where are we now? Where are we going? I would like to start with a little story. I get new trainees coming to see us, to be trained by us every few months. A few months ago, a new guy comes in, and we were chatting about lupus, and he said to me, "Treatment of lupus. I think that's all sorted out now, isn't it?" That is really what I want to address because I try to answer him with this story. It is a story about a peasant family who had a house that straddled the border between Poland and Russia. This hovel they lived in split the border. One day, some officials from Russia and Poland came by, and they said, "You know, this situation cannot carry on. You guys have got to decide. Do you want to be in Poland, or do you want to be in Russia? You've got to choose." The family got together, and they sat in a little huddle in their room, and they decided after some thought, "You know, we want to be in Poland." The officials signed all the papers, and it was agreed the border would be adjusted very slightly. On the way out, one of the officials said to the head of the family, "Just out of interest, why Poland?" He said, "Well, we couldn't stand the thought of another one of those long, cold Russian winters." That was the answer. The moral of the story is very simple. It's perception. The perception about the disease lupus is what I want to get across to you this morning. Anybody who thinks that lupus is largely sorted out is very seriously mistaken. Here is a picture published in 1851 by Dr. Anton Elfinger from Vienna. You can see the very serious nature of the lupus rash in both the young woman on the left-hand side and the discoid nature of the rash in the young male on the right-hand side. That is 1851, when lupus was thought to be just a skin disease. In 1874, along comes Moritz Kaposi, he of the sarcoma, who said, "Well, actually, there is internal organ involvement as well." For 150 years, we have known that systemic lupus is genuinely a systemic disease. Our cohort size is now about 920, but we did a very detailed in-depth review when we got to 800. The sex ratio female to male is about 10, 11 to 1. Disease duration at that time was about 14 years. London is a highly mixed ethnicity city, so not surprisingly, the majority of the patients were Caucasians, but we have the Black community, Afro-Caribbeans, just over 20% of the patients. Asian, meaning in this case, South Asian, because we have a lot of families coming from India, Pakistan, and Bangladesh, make up about 13%. The hospital is quite close to Chinatown in London, so we have over 40 Chinese patients. We have others, a variety of mixed ethnicities. One patient I remember came from the South American jungle, and what ethnic group she was in, I have absolutely no idea. We call that other. In terms of the clinical features of these patients, and I think our numbers are reflected pretty much around the world, we are a rheumatology unit, so not surprisingly, the vast majority of the patients have arthritis. If we were a renal unit, it would be 100% renal disease. In terms of biopsy-proven renal cases, we have about 30%. That is the biopsy-proven ones. There are clearly a number of others who have refused a biopsy or have not had one for one reason or another. The actual number of patients with renal disease and lupus is probably closer to 40% overall. Rash present in half of the patients. It is often photosensitive. Significant alopecia, about a quarter of the patients. Recurrent crops of oral ulceration in also about a quarter to a third of the patients. Major central nervous system involvement, meaning principally psychosis and seizures in 20% of the patients. Serositis, meaning pericarditis and pleuritis in just over a third of the patients. How have these patients done over this long period of time? The cohort was established by my predecessor, Mike Snath, back in 1978. We have seen about 19% of these patients have now died. I want to point out that the mean age of death of those patients is 54 years, and the mean age of death of a woman in the U.K. is 80 years. For a small but significant number of patients, death continues to come way too soon. The range of death is kind of encouraging in the sense that, yes, we still have some very young deaths, but we now have patients living with lupus till their 90s. They tend to be the exception rather than the rule. The main causes of death are, I think, quite interesting. Fifty years ago, the main cause of death would have been renal disease. That is no longer true. Infection, which invariably is driven by the amount of immunosuppression the patients get, is a big problem. Cardiovascular disease is fascinating. If you're a woman and you're between about 35 and 45, your chances of having a heart attack are increased by 50 times, 50 times, and we still don't know why. Malignancy is particularly interesting. The rates of malignancy overall are a little different between the general population and lupus. But in lupus patients, let me try this fact out for you. Lupus patients are substantially less likely to have cancer of the breast, the endometrium, and the ovary. When you think about it for a second, that's mighty strange because, of course, these are the diseases of women, and yet women make up 90% of the patients with lupus. That fact has still not been adequately explained. In terms of overall survival in the 1950s, we were looking at four-year survivals of about 50%. Today, we look at 15-year survivals of around 85%. That is pretty true worldwide. You see those figures, you go, "Oh, that's not so bad. That's pretty good, much better." Of course, that's true, except for one small but important thing. Imagine you were 20 years old and you got diagnosed with lupus. What these figures are also telling you is that there's a one in six or one in seven chance you'll be dead by the time you're 35. Seen in that way, you can see we still have quite a ways to go. Of course, aside from morbidity, there's also mortality. There's also morbidity. I've mentioned cardiovascular events. I've mentioned infection, osteoporosis, invariably linked to doses of steroids. Infertility can be an issue. Hypertension is certainly an issue in relation to renal disease, and a whole variety of other steroid side effects in particular, including cataracts and diabetes. In terms of the treatment of lupus, it's fairly standard now for the less serious concerns. Patients with minor rashes, arthralgia, can be treated very successfully with hydroxychloroquine, with nonsteroidal anti-inflammatories. Even with arthritis and pericarditis and pleuritis, antimalarials, low-dose steroids can be perfectly adequate for many of those patients. We might want to add in something fairly mild in terms of immunosuppression, such as azathioprine. Hematologic disease, for severe hematologic problems, we'd often go to rituximab or higher-dose steroids, sometimes cyclophosphamide. CNS disease is highly controversial. One of the problems is there have been so few trials that have been done. My experience with CNS lupus is that you have to provide a combination of immunosuppression with an appropriate drug, an anti-epileptic drug if the patients have seizures, an antipsychotic drug if they're psychotic, and time. CNS lupus patients do not get better quickly. It can be weeks, more likely months, before they get better. The real problem with lupus patients is, of course, the renal problems. Right at the top, you see the class I lesions, which are virtually normal, down to the bottom class V, which is membranous, but it's the type IV, penultimate one from the bottom there, diffuse proliferative glomerulonephritis. That is the one that you really want to avoid if you have any choice in the matter. Those are the patients who tend to succumb to their lupus nephritis. In terms of therapy for lupus nephritis, it's fairly conventional to use steroids, like mycophenolate, cyclophosphamide, or in the case of pregnancy, azathioprine. Tight control of the blood pressure is essential. Hydroxychloroquine turns out to be very important. If that approach doesn't work, a number of other drugs are widely available, though varyingly so according to the nation that you happen to be living in. Rituximab is widely available in the U.K. It's not widely available in the U.S. It's not widely available in Germany, for example, whereas belimumab is and voclosporin is. This has been more formalized very recently by some treatment guidelines that have been updated by the ACR, where the idea is that you use combinations of therapy, triple therapy, and that seems to be more successful. We will come to the details of that in just a moment. Just to say, this has now been more formalized, and this is the way to go, I think, for conventional treatments of this disease. How have these patients' lupus nephritis done over the years? We have looked at four decades of patients and published this data between 1975 and 2015. We had 219 biopsy-proven lupus nephritis patients. The five-year mortality rates decreased quite quickly, as I will show you, from 24% to approximately 5%. Progression to end-stage renal failure in our patients, about 17%. Why do patients with lupus nephritis go into kidney failure? Number one reason, patients don't take their tablets. Number two reason, the patients don't take their tablets. The number three reason, patients don't take their tablets. Number four reason, severity of the disease. Adherence to treatment is very, very important if you wish to avoid renal failure. Sad to say, the outcome overall for lupus nephritis has not changed significantly in the past 30 years. Here's some of that data. If you look across the lines at the age of lupus diagnosis, the age of lupus nephritis diagnosis, there was a fall in mortality, as you can see, from the first period. Mortality, I don't want to completely mess this up, but let's see if we can fix that. Yeah. Mortality, 24% in that first period. It falls very rapidly. I think that's because that's when cyclophosphamide was introduced on a regular basis, and I think better general care. You can see that overall, if you look across the lines, very little change, very little change in end-stage renal disease. Age of diagnosis hasn't changed. Age of death has changed very little. We conclude that nothing very much has helped. As we wrote in this article, despite the changes in treatment of lupus nephritis with mycophenolate coming in in 2000 and cyclosporine about the same time, we've reached a plateau in terms of mortality and progression to end-stage renal disease, suggesting that new therapies, new management approaches are desperately needed. It's not just our data which says that. Here's some very nice data coming out of the Midwest Network Group in the United States, where patients with incident lupus nephritis were compared from the mid-1970s to 2018. Estimated prevalence has increased from 168 per 100,000 to 212. And the lupus nephritis patients had a standardized mortality ratio of over 6, with no improvement in the mortality gap in the last four decades. 10-year survival was 70%. Our figure of end-stage renal disease was 17%. Theirs is 13%. So it's pretty uniform around the world. Lupus nephritis remains a big, big problem in terms of management. And the conclusion from the American authors of this paper, the incidence and prevalence of lupus nephritis has increased in the last four decades. They have poor outcomes with high rates of end-stage renal disease and mortality rates six times that of the general population. This is a problem which has not got sorted out yet. Now, I think our understanding of the immune response gave us some hope when this began to be recognized some 20 to 30 years ago, where we recognized that a key problem in the pathogenesis of lupus was the inefficient removal of apoptotic material. The whole process of apoptosis was sorted out about 40, 50 years ago now by a colleague from Australia, one from the U.K. They recognized that in lupus patients, there seems to be a failure to efficiently remove apoptotic material, as a consequence of which structures such as DNA, such as histone, such as the antigen known as RO and LA get into the circulation in a way which they would not normally do. These fragments are picked up by the antigen-presenting cells, and the complex interaction between the APCs, the T cells, and the B cells results in the production of antibodies to DNA, to RO, to LA, to phospholipids, etc. We know that there's an enhancing pathway, including the PDCs, with interferon alpha playing a very important role. Had Mathias and Marty met me 10 years ago to give this sort of talk, I would have said, "Well, Mathias, look, we've got all these great drugs coming through. It's all going to be very good. In 10 years' time, you'll invite me back, and I'll be a very happy man. I am not a very happy man because, unfortunately, we've had something like 20-30 failed trials in lupus patients using all sorts of approaches, drugs which block interferon alpha, drugs which block the link between the antigen-presenting cell and the T cell, that's epitassept. Tocilizumab has not shown to be very successful in treating lupus or even lupus nephritis. We know that in the B cells, there are several targets. We have CD20, of which I'll be talking about more in just a second, CD19, and even CD22. Even with all of these theoretically encouraging approaches, disappointment has really been the name of the game until very recently. Now, I want to highlight the point that Christian was focusing on about where CD19 and CD20 begin to put in an appearance because there are some subtle differences. The CD19 molecule is present on pro-B cells all the way through immature cells, naive B cells, germ cells, memory cells, plasma blasts, and plasma cells. In contrast, CD20 begins to appear a little bit later at pre-B cells and begins to disappear by the time we get to the plasma blasts. The majority of autoantibodies and antibodies come out of plasma cells. Plasma blasts make a very small amount of antibody by comparison. If we're going to use B cell targeting approaches, when should we be doing that? Conventionally, we tended to use these approaches when everything else has failed. My colleague, Liz Lightstone in London, took a different approach and said, "Well, actually, if B cell depletion works in lupus towards the end of the lupus journey, why not use it at the beginning of the lupus journey?" We'll look at her data in just a second. The notion of using B cell depletion as a form of treatment for autoimmunity developed through two of my colleagues, Joe Edwards and Joe Cambridge, who in the late 1990s, working principally with rheumatoid arthritis, said, "You know, we believe that B cells are important in the development of rheumatoid." This was regarded as a great heresy at the time. In those days, rheumatoid arthritis was a disease of T cells and a disease of cytokines. The notion that B cells might be important was actually not widely regarded or even taken seriously. Their argument was to say, "Look, if you look in the synovium of patients with rheumatoid arthritis, you will find B cells, and they are not there for a holiday. They are there for a reason, and it's not a good reason." In 1998, they published their theoretical paper. Thank you, Roger. In the early part of 1999, they began to treat patients with rheumatoid arthritis with rituximab, which had become available in 1997 when it was approved by the FDA for the treatment of non-Hodgkin's lymphoma. I took the view that if rituximab was going to work in rheumatoid, where the evidence that B cells was less compelling, in lupus, where we knew that B cells were very important, it really ought to work in lupus. In 1999, I treated my first patient with rituximab, and we've now treated sort of 8 to 10 patients with rituximab over the last 20, 25 years. We've experienced with around 225 lupus patients given rituximab. The combination of rituximab and cyclophosphamide and steroids, as laid out here, was used initially by Edwards and Cambridge because these were the three drugs then available to help get rid of B cells. They were just used as a combination, and it seemed to be highly successful. In terms of outcome, we used the BILAG system, the British Isles Lupus Assessment Group index, to define disease activity in patients. Full remission, meaning you get rid of all the BILAG A's and B's, which are the most active parts, we saw in 50 patients. We saw in 42%. Partial remission, meaning we get rid of some of the A's and B's, but not all of them, in 47%, and no improvement in 11%. We were showing improvement in around 80% of the patients. That data has been confirmed by the British Isles Lupus Group, which utilizes the data from all the U.K. centers, where there are 1,000 patients. Numbers rather similar to that have been reported in the literature. This is not a cure. That's number one. It doesn't help everybody. That's number two. You have to bear that in mind. The big problem with rituximab is that it is 20% mouse protein. It started life as a mouse protein. It's been humanized, but not completely humanized. I have the frustration in London of having a cohort of about 25 patients with lupus who did beautifully with rituximab, but I can't give it to them because they're allergic to it or they've become allergic to it. Let me give you some examples of how this can work. Here's a patient who came to see me in 2003. This is a pretty awful rash, severe subacute cutaneous lupus. This is what this patient looked like after, I repeat, after a year on an average of 40 milligrams of steroids, six months accompanied by methotrexate, six months accompanied by azathioprine. That's what she looked like afterwards. She'd heard on the grapevine that I and my colleagues were using B cell depletion approach. She came to me and she said, "You know, I'd like to try this because I'm pretty desperate." Three to four months later, after we gave her rituximab together with cyclophosphamide and steroids, that's what she looked like. She did very well for three years, and then she fled. She came back. It didn't look quite as bad as this, but it wasn't far off. She said to me, "You know, that treatment that you gave me," she said, "the rituximab, I liked. The cyclophosphamide, I did not like. I'd be very grateful if you could just give me rituximab this time around," which we did. She did just as well with rituximab on its own. By and large, these days, if we're going to use B cell depletion, we often use the rituximab with a bit of steroid just really to prevent any reactions and often pass on the cyclophosphamide. In lupus, the one thing that I've learned over the years is just when you think you've seen the worst, you haven't. There is worse to come. Here's a patient who was from Slovenia. She was married to a GI serviceman at Lake and Heath Bath, just outside of Cambridge. This is what she looked like after two months on steroids, after two months on steroids. Pretty awful, as you can see. On her scalp, you can see the loss of hair and the terrible rash. Again, three to four months after the treatment of B cell depletion, she looked a darn sight better, as you can see. It is not just the skin and the joints that are improved, but also the kidneys. On the left-hand side, you see a classic picture of a patient with diffuse proliferative glomerulonephritis. This picture was given to me by Ronald van Valehoven from Amsterdam. Re-biopsied eight months later after rituximab, a huge improvement. We know that it can help pretty much every kind of lupus. It can certainly help the hematology of lupus with low levels of hemoglobin and platelets improving within one week to four weeks. The disappointment came when there were two big trials of rituximab, one in non-renal patients, one in renal patients. Those trials conducted about 15 years ago did not meet their endpoints. As you know very well, it is very frustrating when patients say to you things like, "Well, rituximab compared to placebo, no difference." It is never that. It's always lots and lots of background medication plus rituximab versus lots and lots of background medication plus placebo. Many of those patients in this trial were on very substantial amounts of steroids. They came in on 60 milligrams, 40 milligrams. Although those numbers were reduced, they remained on substantial amounts of steroids for months afterwards. I think that may have had something to do with why these trials didn't work. Even within these failed trials, the devil, of course, being the detail, Joe Merrill from the United States has looked in great detail at some of these rituximab trials and points out that if you look at 50% reduction in proteinuria comparing the placebo-treated patients with the rituximab-treated patients, you see a statistically significant difference. If you look at complete response or partial response in terms of proteinuria, statistically significant difference in favor of rituximab. Interestingly, if you look at ethnic responses, it looks to be better in the Black patients. It did not meet statistical significance, but the numbers are not unimpressive to me. The requirement to start cyclophosphamide is much higher in the placebo group compared to the rituximab group. There was evidence that this was doing something, even if they had not met its endpoint in clinical trials. My colleague, Liz Lightstone, as I have mentioned, said, "Well, if it is going to work at the end of the lupus journey, let's give it at the beginning." She reported in the Annals of Rheumatic Diseases, 2013, 50 patients biopsy-proven lupus nephritis, not iffy or butting lupus. This was the real thing. These patients had no kind of treatment apart from rituximab, which she gave them as soon as she got the biopsies back. They got two shots of rituximab followed by mycophenolate and hydroxychloroquine. The results are very interesting, low toxicity. If you look at the results here, in terms of complete response and partial response after a year, 85% of these patients are in complete or partial response, 50% in complete response. In terms of relapses, they are only beginning to kick in at about two years. This was really pretty successful. Unfortunately, she tried very hard to do a very full-blown trial, an investigator-led trial, which is difficult to do. Unfortunately, it failed partly because of problems recruiting patients and partly because the company, which I will not name, pulled out their funding halfway through the trial, which was not a very nice thing for them to do, actually. I want to emphasize, of course, that it's not just CD20 that can be blocked successfully, but also if you block the BAFF molecule, B cell activating factors. This was the data from the belimumab trial in non-renal lupus that was published about 14 years ago, which really paved the way for official approval for drug trials in lupus. The initial trial had 1,100 patients, and the delta, the difference between those patients who improved on the belimumab compared to the placebo, was not that impressive, about 8%. If you distinguish the patients in these trials who had a low C3 and a high DNA binding, the delta switches to 20%, which becomes a lot more impressive. Whenever I've spoken to various companies over the years, I've always said, "Well, look at the difference between the patients who have serologically very active lupus, which you might see a response as good as that." This is in the non-renal patients. They subsequently went on to do a trial in renal patients. You can see the complete renal response that's over here, comparing the patients given the Belimumab and the patients given the placebo. You can see quite an impressive difference, which is sustained over quite long periods of time. Belimumab is now reckoned to improve the lot of at least some patients with nephritis. I will, however, be honest with you and say I've not been overwhelmingly impressed with Belimumab. In my experience, and I've now treated about 30 patients in London with it, it does definitely seem to be very helpful in about a third. You get some benefit in about a third, and in about a third, it doesn't work. It is very safe, but it is slow in its onset. It can be three to four months before you begin to see improvement, even in patients with joint and skin disease, apart from renal disease. This was the BLIS nephritis trial. If you—sorry, let's go back. If you compare the patients where the patients favored the results favor Belimumab compared to those that favored the placebo, you can see an obvious difference. It clearly is doing something, but as I say, for my money, it's not the greatest drug, really. It's been compared, incidentally, to Voclosporin, a calcineurin inhibitor. That's the Aurora trial on the left-hand side, where you can see the difference between the voclosporin-treated patients and the placebo-treated patients is obviously rather more impressive than in the BLIS lupus nephritis trial. For me, the voclosporin looks to be a rather better bet, although it is very expensive, certainly, in the United States. In terms of other drugs and other approaches, we now have more bispecific approaches, CD20-directed bispecifics. We have obinutuzumab, which, as you will know, has met its endpoint in both the secondary phase two and phase three trial. We have combination attempts combining rituximab with belimumab. Of course, we have CAR T cell therapy, which we're going to talk about in just a second. This was the trial that came out last September, the Regency trial, where the phase three trial met both primary and secondary endpoints with a complete renal response of 46% versus 33% of the placebo arm. Only belimumab is approved currently. I think that's just changed with the treatment of nephritis. That certainly is going to change. Here's some of the data where you compare the complete response over here. If you look at obinutuzumab compared to placebo, you can see highly statistically significant differences, certainly indicating that obinutuzumab does seem to be, as a fully humanized anti-CD20, a very effective way to go. In terms of combinations of therapy, rituximab and belimumab, we have a rather frustrating set of results. The Beat Lupus trial was an investigator-led trial that was started in my center. All of these patients, there were 52 of them, got rituximab. Half of them got belimumab. Half of them did not get belimumab. The primary result was the reduction in antibodies to DNA, and that was encouragingly good. That was statistically significant. What was very encouraging was a reduction in the flare frequency. Of the 26 patients who got belimumab or rituximab plus belimumab, there were three flares. In the patients who just got rituximab without belimumab, there were 10 flares. That is highly statistically significantly different. These patients were split between renal and non-renal, almost equal, actually. CALIBRATE was a study for safety done out in California, looked at 42 patients with renal disease. As I said, primarily a safety study, no difference between the arms. The real disappointment was the BLISS-BELIEVE study, which was a non-renal study which showed no difference. All of those patients got belimumab, and half of them got rituximab. Maybe there is something to do with giving rituximab first. Maybe that is more advantageous. We are left with these rather conflicting data. We still do not know for sure whether combining biologic drugs is going to be an optimal way to go. Let's turn now to the CAR process, CAR T, of course, for chimeric antigen receptor. Many of you, I am sure, will know about the procedures, which are somewhat complicated, as listed here on the slide, this graphic. Patients clearly have to come into hospital for at least a week or two, and that adds to the cost of the approach. We now begin to see results coming in from a number of centers. It is early days, I have to stress that. From the original center, which was Schett in Erlangen, we now have 19 patients who have been treated, various groups, including Caverna and Cavaletta. They've looked at four patients, six patients. Novartis have 11 patients. BMS have 10 patients. With numbers beginning to creep up, in the main, these patients have a combination of type 3 and type 5 lupus. Some have type 2, some have type 4. The data is beginning to accumulate. We have to be a little bit careful about how much we read into this. Although some of the results, especially the ones from Schett himself, were quite astonishing for reasons we'll discuss in just a moment. In terms of side effects, I know the ICANS is very much a concern of the cancer doctors, with that has been reckoned to occur in a number of these patients. Efficacy looks pretty impressive using the DORIS criteria, which means that the patients go into complete clinical remission on a reduced dose of steroids down to just 5 milligrams of steroids or less, and the PGA less than 3. Efficacy looked very good in Erlangen, and it has looked pretty good in some of these other groups too. Early days, but the numbers beginning to stack up to numbers which will enable us, I think, to say with more confidence that this is an approach. Because one of the challenges that I've faced as a clinician trying to recruit patients into the AUCATZYL trial has been to persuade the patients to get involved. We've been relatively successful, as I've shown in a second. We got five patients into the study with lupus nephritis. The patients have to be sick, but not very, very sick. They have to have had a recent renal biopsy and got to want to do it. It's quite demanding for the patients. Patients are pretty smart people, and they say, "Well, actually, this is all a little bit experimental. I'd like to come back and talk to 150 patients to further this approach and show me your data then." They want to know what's going to happen to me in 10 years' time, not just a year or two years or three years. There are problems. Nevertheless, with the increasing data being put into the literature, we're beginning to see it'll be easy to get patients into these studies, I think. The concept really, as put forward by Georg Schett, has been a kind of complete resetting of the immune process. We know that in lupus patients, as I've shown you, there are clearly B cells, plasma cells, which are making a whole array of autoantibodies, some of which, like antibodies to DNA, are clearly directly concerned in the immunopathology of the disease. What you're trying to do is to get rid of those cells and to, in a sense, reset the immune system and bring back cells which are normal and which are not going to produce those kinds of antibodies. We start off with the system in the very bad lupus patients where you've got these autoimmune B cells. Following the treatment, anti-CD19 with CAR T cells, we develop a completely different set of cells, naive B cells, without the autoimmune B cells being present anymore, which is great. Currently, it's being administered at several specialist centers. We need to move, if we can, to more outpatient procedures because that will make the process much cheaper. We need data from well-designed clinical trials to assess the treatment more effectively. We struggle a little bit in lupus in terms of how we define disease activity. As I think Christian was mentioning, lupus is the disease par excellence, which looks like almost anything else. It's the great mimic. It can really generally look like almost anything you care to mention. We do need larger numbers of patients to be studied and for longer-term periods. The ongoing and unmet needs, I think, will be obvious to you from this talk. We need early diagnosis and to commence treatment sooner. We try desperately to minimize long-term steroids. I've always felt that the best dose of steroids is the lowest possible dose for the shortest possible period of time. Patients, I think, do need to be referred to specialist centers. Lupus is a tricky disease to manage. We have room to try to sort out how to manage patients who are poorly compliant. This particularly applies to our adolescent patients. We have a number of patients that we inherit from the Great Ormond Street Hospital. They come across to us as teenagers, and they are mighty difficult to treat at times. We have to manage patients with very aggressive disease in ways which are better than we have currently available. Schett, in his treatment of his patients, was very, very selective, and he'd be the first person to admit that. He went for patients who were younger, who'd had their disease for a relatively short period of time, about three years. They have aggressive lupus nephritis, which had not responded to lots of other conventional treatments. They were in a very bad way, and they've done spectacularly well. I'm sure you would have seen that data. What would I, as a doctor looking after lots and lots of lupus patients, be looking for? Clearly, I want to see in any drug, is it more effective than currently available treatments? Is it safe? That's kind of important. Of course, how much does it cost? Because the systems are very challenging and very expensive. In the U.K., we have this organization called NICE, or Not So Nice, as I like to sometimes think of it. NICE does its job. It was set up by Tony Blair when he was our prime minister 25 years ago. It was there for one very simple reason: to reduce the cost of drugs. In that sense, it's done a fantastic job. Belimumab, for example, costs about a third as much in the U.K. as it does in the United States. Voclosporin, which costs about £ 90,000 per patient in the U.S., costs about a tenth of that in the U.K. NICE says, "Well, your drug is quite good, but it's too expensive. Make it cheaper, come back to us, and we'll perhaps give you permission to prescribe it." That is the way that NICE works, and it has done quite well. It does mean, frustratingly, I cannot use anifrolumab in the U.K. I cannot use it because the company concerned are not willing or have not been willing so far to take it to NICE because they realize that NICE will force them to drop the price. That remains a problem for me. So conclusions. Although the outcome for lupus patients is clearly better in 2025 than it was in the 1950s, major problems of mobility and mortality still persist. We clearly have a much better understanding of the immunopathology of lupus. Clearly, blocking B cells is going to be targeting therapies is addressing more precisely the targets or the roots which lead to lupus. That is a good thing. We have clearly reached the limits with conventional treatment: steroids, azathioprine, and mycophenolate. It is never going to get any better. We just cannot do that. To improve the long-term outcome, we clearly have to move earlier, possibly to combinations of biologics, possibly to CAR T cell therapy, possibly to both in different patients. I genuinely believe the future is bright. We got the successful result of the trial with obinutuzumab last September. Indapilizumab was also approved. We have CAR T cells that we have been discussing. The future is bright. We just have to get there. We are not there yet, unfortunately. Let me turn now to the initial results that I can tell you about from the study using the Obe cel approach in patients with severe lupus and lupus and organ manifestations. The key inclusion criteria were pretty much as you would expect. The diagnosis of lupus is based upon the most recent classification. There have been quite a few over the years. The current one is a combination of EULAR, the European colleagues, and the ACR. The patients have to have a positive anti-nuclear antibody and/or DNA antibodies or anti-SM. They have to have severe refractory lupus with organ involvement. We exclude patients who have neuropsychiatric disease. We've excluded patients with very severe lupus-like flares. As I said, we've gone in for patients who are sick but not very, very sick. We've excluded patients, I think, really for simplicity, who have other diseases. I should mention that a third of lupus patients, at least a third, are not content to have lupus. They also have a second, third, or fourth autoimmune disease. Approximately 10-15% have antiphospholipid antibody syndrome, 10% have Sjögren's, 4% have myositis, 4% have diabetes, 10% have hypothyroidism. Lupus comes together as a sort of family of diseases, if you like. So far, we have six patients aged between 19 and 50 years, five females and one male. I want to emphasize that because it is a difference between the patients reported by Georg Schett, where the patients were generally much younger, with an average distance from diagnosis to CAR T cell therapy of three years. Some of the patients we're going to show you details on have had their disease for much, much longer. I know that because I've looked after them for a very long period of time. All of these patients have had lupus nephritis, mainly with focal proliferative or diffuse proliferative disease. That's class three and class four, with four of the six also having class five disease. Serum creatinine was elevated in the majority of these patients, and the GFR was reduced in four out of six. The baseline protein-creatinine ratio was elevated in all of the patients. As you'd expect, many lupus patients with nephritis don't just have nephritis. Many of these patients have had musculoskeletal and/or dermal manifestations. All of these patients have been tried on B cell blocking agents with incomplete success or no success whatsoever. Three of six have been treated with prior calcineurin inhibition. In terms of the side effects, I want to mention that these numbers that you see relate to the grade of severity, not the numbers of occasions. The cytokine release syndrome was seen in three patients out of the six that we've treated so far, responded very quickly to tocilizumab. ICANS, however, has not been seen in this patient. I'll be interested to see what some of my colleagues think. That seems to me to be a bit of a difference with the malignant, with the lymphoma literature. That does seem to be a bit of a difference. We see anemia in some of these patients. We see thrombocytopenia in some of these patients. We see infection, type 3, grade 3 is the more worrying kinds of infections in a small number of these patients. I will point out that the anemia and the thrombocytopenia often last are not that bad. The thrombocytopenia platelet count fell to 75, which is really no practical concern whatsoever. The anemia also fell. These patients begin to improve their hemoglobin levels within a few days. This is not something which lasts for months and months. That is very good. Of the infections, none of them have been fatal. In terms of the drop in the SLEDA2K score, this is a global index score which has the advantage of simplicity, although it lacks a little bit of depth. We will not worry about that just for the moment. In the main, as you can see, the numbers are dropping from the time it's screaming to month eight. In this patient over here, H3, H4, there was a little glitch over here in this particular patient who got a little sicker for a short while, and she got better again. This patient is coming down slightly more slowly, as is this patient. You see they've only been followed for a month. After about six to eight months, these patients are really looking much, much less active, which is exactly what you would hope and what you would expect given the experience that we've seen from Georg Schett. Three of the six patients have gone into complete renal response within three months. Remember, these patients had failed almost every other kind of treatment they'd had, mycophenolate. They'd had rituximab. They'd had steroids. Yet within three months, 50% of these patients have gone into complete renal response. That is pretty impressive to me. It is what Schett would have expected, except just to highlight the fact that many of these patients, several of these patients, have had the disease for 20 years. There is almost certainly not a lot of damage here, as well as activity of the disease itself. In terms of the DNA binding, the normal in this assay is about 10 units. You can see falls from 400 down to 10 or less than 10. Very, very impressive. A rise in the complement C3 is, again, a sign of immunological good health. These patients are improving their C3. That looks very good too. In terms of steroids tapering, by the time the patients are coming out of the therapy, we've reduced their steroids down to 10 milligrams. We continue to reduce their steroids. The majority of these patients, we have data from four of six so far, you can see that the steroids are dropping to 5 milligrams or less. Just to highlight the point that what is the safe dose of steroids, a lot of work has been done by Michele Petri in Baltimore. She reckons that 6 milligrams is about the watershed. If you get a patient down to 5, I wouldn't say you're laughing, but at least you're in a position where these patients are very unlikely to get any major steroid side effects. This data is looking very encouraging too. In terms of how the CAR T cells persist, the data is shown over here. It is pretty similar to the data that was published by Schett, as you can see, a kind of U-shaped, inverted U-shaped curve over here. Pretty much gone by month two. Likewise, in terms of B cell aplasia, B cells have pretty much disappeared by month one and beginning to reestablish themselves in a more healthy format by months three and four. This is all very encouraging data, I think. In terms of the nature of the B cells that are coming back, we want to see sort of these patients having this completely blue appearance. As you can see, that is the case here, with the disappearance of the double negative T-cells, which are not a good thing to have, and some of the memory cells. These are early days. I'm sure my colleagues will probably want to add a little bit more information to that. Again, it's all moving in the right direction. In terms of conclusions, and I would say that they are tentative conclusions, but I think they're encouraging. Remember, these patients, these six patients, had exhausted prior therapy options. They'd had B cell depleting agents. They'd had BAF inhibitors. They'd had calcineurin inhibitors. They'd had mycophenolate. They'd had steroids. Five of six patients have diffuse proliferative disease, which is the worst kind. Kidney function was sufficiently impaired in four of the six. In terms of safety, we've seen no DOTs. We've only seen CRS grade 1 or fever observed in three out of six patients. No ICANS. Transient neutropenia, transient hypertension, which is kind of interesting because I was looking this morning at Schett's data. In his supplementary table, I think number nine in his paper published in New England Journal of Medicine, hypertension does not get mentioned at all. I suspect that might relate to the fact that these patients have had their lupus nephritis for much longer. They have probably got an element of damage. That may be part of the explanation. In terms of efficacy, all patients have benefited from this treatment, including three patients with a complete renal response within three months. Complement has normalized. DNA binding has fallen dramatically. Musculoskeletal and dermal manifestations have resolved in all patients by month three, which is, again, very, very encouraging. I will end with a little story just to sort of emphasize this to you. Patient number two is a patient who I have treated for over 20 years. Now, for the best part of 20 years, she has had arthritis, woken up every day with stiff hands, stiff feet. She said to me what she really finds almost magical, and that was the word that she used, was that she now wakes up. She said it kicked in at about week four. She said, "I wake up each day and I look at my hands and I think they don't hurt anymore. They do not hurt anymore." That is the first time in 20 years. Thanks for listening. Matthias, I think you're next. Thank you very much, David, for sharing the data and being such a good partner in developing Obe cel in patients with systemic lupus and lupus nephritis. What I'm going to share with you today is the path forward. David has shared our first impression from the six patients at 50 million cells. We have put the development rationale together for Obe cel in patients with lupus nephritis, as we very much like the clear determined endpoints in lupus nephritis, which are measured by lab parameters. It is a quantifiable, nice, and clear endpoint. The current guidelines, which just have been updated in 2024 for lupus nephritis patients with an NIH class three or four, define a triple therapy, which includes either a B cell depleting agent or a calcineurin inhibitor as a standard of care together with mycophenolate plus steroids. We have the basis of those patients, which we have seen in this first quarter of six patients in terms of previous treatment represented in the guidelines. Lastly, for those who have failed both a B cell depleting or targeting agent as well as a calcineurin inhibitor, there is no standard of care defined for those patients, as David was saying. Those patients have no treatment options, which opens up a path for a potential fast pivotal approval study. Last but not least, we will be learning from this to be started phase two study of patients with class three, class four lupus nephritis about further development in early alliance. I think this is alluding to what David shared from his colleague, when do you use a B cell depleting agent as last in as last line or why not in the front of line? Eventually, this will lead to the fact that after our phase two single arm pivotal study, which will enroll 30 patients with lupus nephritis, we can look into how can we bring it into an earlier line versus standard of care, whatever these options will be at this point in time. I spoke a little bit about the design of this trial. Patients will have to have failed both a B cell targeting agent as well as a calcineurin inhibitor. They need to be defined as patients with lupus nephritis. They need to have one of the lupus-defining autoantibodies as a potential additional quantifiable secondary endpoint. The primary endpoint of this study will be complete renal response. The key secondary endpoint is a DORIS at six months. David reminded us that this is a complete renal response in conjunction with a reduction of steroids to 5 milligram or less. Six months is also an attractive endpoint. I'd like to remind you that most of the most recent randomized studies had an endpoint determination, which is 48 weeks or longer. The Regency study comparing obinutuzumab versus standard of care had a readout at 76 weeks. We are expecting that the first patient will be enrolled towards the year end of this year. We anticipate an enrollment window of 24 months. This is 30 patients. We have within this a one-year follow-up. The phase two study already has cleared with the FDA. We had a very collaborative discussion with the agency over the months of February. We have defined patient population with the clear unmet need. The eligibility will be defined by a panel consisting of a rheumatologist, nephrologist, and pathologist. They will be beyond the prior lines of therapy exposure with a B cell modifying agent and calcineurin inhibitor, also determined based on the histology, the appropriate class association, grade 3 and 4 NIH class lupus nephritis. We will have an independent review committee, which will determine the complete renal response as a primary endpoint. This is concluding the discussion on the lupus nephritis. What we would like to do, given that there was a lot of information, is actually have a short Q&A session. Also, David has shared with us a lot of insights. Probably a good time, yes, please. A good time for questions at this point. There is also opportunity if something pops in your minds a bit later on, we could also do that in the second round. We would like to sort of kick it off on the Q&A side. Gil? Good morning, everyone. Gil Blum from Needham & Company. Maybe the main question as it relates to the pivotal phase two design, how many patients do you expect are within that category? You mean how many patients generally fall into the category? In the current study we have enrolled, we have seen that three out of six patients fall in this category. This is just with the most recent approval of voclosporin in the U.K. I think we will see in the U.S. and the countries who will enroll a sufficient number of patients with the enrollment period of 24 months. For the doctor, thank you for a very elaborate presentation and history lesson. The main question from us is, who do you think is the ideal candidate for such a complicated treatment? The work from Schett indicates that patients who are a little younger, who have aggressive disease that does not respond to conventional treatment, that they are kind of the ideal patient. Of course, even within a large lupus group like ours, the number of patients in that particular group is modest, I would say. We do see now that the data in these six patients is more reflective of lupus cohorts as a whole, with patients having had their disease for much longer periods of time. What the patient I was mentioning to you at the end has shown very clearly. Here is a patient who has had the disease 23 years, and yet she has responded beautifully, really beautifully. It is not going to be restricted to that narrow group that Georg Schett went for. He is a very open-minded guy. He and I have discussed this in some detail. He said, well, we went for those patients because we wanted to see a good result, obviously. We went for patients who we thought we would see a good result. Those were the ones that we felt, in a sense, deserved the treatment because everything else had failed. We also thought or hoped that those were the patients that we'd see some very good results, which they have done. You have to broaden that out because there will be plenty of patients who do not come into that little category. The numbers, it will increase over time. Last one from us. Any thoughts on that report on hypertension and how you would manage that? The patients that we've had a problem with managing very conventional ways with antihypertensives, and it's been very successful. It's not been that difficult to control. You do have to manage it. I don't have a simple explanation why Schett didn't report that at all. If you mentioned that suffering figure nine, it's worthwhile looking at that, actually, because it really shows the blood pressure absolutely flatlining. That was quite a remarkable result, I thought. Again, it may reflect the fact that some of these patients haven't just got lupus activity. They've got a degree of damage. That may make the problem of hypertension a little bit worse. It can be managed in conventional ways. Hi, Matthew William Barr. Thanks for all that information, background, and data. I guess you said the IND has been cleared by the FDA. How much of the conversation was on this being able to support accelerated approval versus just the design of the trial? They agree that that makes sense. On one of the slides, you had a CRR equals 40%. Is that what you think the bar is that you need to exceed for accelerated approval? The discussion, actually, the majority of the discussion was particularly on the patient population. Our intent to design a study which is small enough but has pivotal intent. The agency in the back and forth gave us the option to either make it a randomized study and not requiring both a calcineurin inhibitor and a B cell targeting agent being failed. That would have brought you into the ballpark of a Regency type of design. However, given that we have the results from these first six patients and we failed with three out of six having a complete renal response, we are ballpark-wise in the range where we want to be in the patient population which we could commit to, which is failed both B cell depleting agent as well as calcineurin inhibitor. To your point, what's the 40%? Yes, we would have to see 12 out of 30 complete renal responses for the study to be successful. And then. It's against the threshold of 20%. Two quick follow-ups. Do you plan to file for breakthrough therapy designation to kind of help support this pathway? Do you expect how many centers? Is this just a US and Europe-based trial? This study has a global footprint. We will have one or two countries which are outside of the U.S. and Europe. We are continuing our conversation with all agencies about the further designation, which includes Armando Brexter designation. These meetings have not happened yet. Cali Shi from Jefferies. Thank you for a fantastic presentation. My first question is, besides the CR rate bar setting at 40%, what are the other efficacy metrics we could actually focus on to really differentiate CAR T from other therapies, given that OB also showed, I think, a CR rate at 36% in SLE pivotal trial? Would you actually elaborate on that? That's the first question. The second one, Selena, if I'm not mistaken, I feel like the pattern in terms of the speed of reduction is a little bit like slower than other CD19 CAR T programs, including Dr. Schett's data. Just curious, how do you actually differentiate different CD19 programs by looking at efficacy endpoint and maybe also even the B cell dynamic? Thank you. I can take the first question first. What are the other endpoints we are considering, and particularly efficacy endpoints, I think, was your question. A key secondary endpoint is DORIS. DORIS measures also the response, particularly in conjunction with steroid use. As David was alluding, toxicity of the current backbone therapies, including steroids, is a big concern because these therapies are given over years and years and years of patients if the patient is compliant and takes the pills. Please bear in mind that all available other therapies, belimumab, obinutuzumab, as tested in the Regency trial, are on the backbone of typically mycophenolate plus steroids. Our therapy, Obe cel, will be as a single standing CD19 CAR T cell. DORIS is a key secondary endpoint where we are trying to gauge towards a low or no steroid use. That is a key differentiator, I think, to all available biologics. I think your second question was in regard to the dynamic of the drop of the SLEDAI score compared to other studies. Do you want to speak to this? Yeah, you probably don't want to get into a great discussion about the different formats by which disease activity is defined in it because it gets very complicated. It gets very passionate, actually. SLEDAI offers an advantage in that it's simple. It's a global score system. It says, you've got a problem, you get points. Or you haven't got a problem, you get no points. The problem with that is that it doesn't allow, it doesn't distinguish the patient who is somewhat better from the one who is the same from the one who is worse. You could get three very different kinds of clinical situations and yet get the same number of points with SLEDAI, which is why I have never been a great fan of SLEDAI. I'm also one of the founding fathers of the BILAG. I have certain problems in this issue, as you might say. I do think the BILAG would have given a better differentiation. To be fair, Schett does actually use the BILAG system. I think it's early days yet to really see what's going to happen with the SLEDAI in all of the patients that are coming out of these different studies. We're going to have to look right across all those other studies as well as ones that all of us have been using. The very fact that three of these patients have gone into complete renal remission, irrespective, frankly, of what the SLEDAI is telling us, is very, very important for the reason that I was saying that renal disease is something you seriously would have avoided lupus. If you can get control of that very quickly, that, to me, outweighs any advantages to whether SLEDAI was slightly better in one study than another study. Just two quick points, Cali. First off, what you're referring to with obinutuzumab, obviously, is when the CD20 monoclonal antibody is still active. We're at the point where the patients have relapsed from CD20 monoclonal over one line further down. The references and the numbers, you cannot really compare those two. Those are different instances. It'll be a 0 for obinutuzumab from where we are, where we're going to be positioned. This is fundamentally different. The second aspect, I think, goes back to the SLEDAI score. The dynamic of the SLEDAI score is that when you look at even the starting point in the scores that you see in the Schett data, there's nobody with a 26, 27 point starting, which is pretty horrific. What you really see in the big difference is really that the nature of these patients is very different. They're older patients. They have long disease history. They have actual damage that has occurred and accumulated. That gives you differences in terms of the timing for the improvement. What was very remarkable is that we saw the improvement in every patient. For the phase two, will all patients be biopsy confirmed? Have any of the patients from the phase one trial fully tapered off their steroids since the data presented today? Thirdly, Dr. Eisenberg, would you say thus far, would you be willing to use obe-cel in an outpatient setting? Low CRS, no ICANS? In terms of the third question, we have five patients who said, yeah, we're happy. We'll do it. They've taken part. We have a number of others who are lining up. I think the first two questions are probably more from my thoughts. Yeah. Yes, all patients will be biopsied within a time window of up to six months prior to coming onto the study, must have had a kidney biopsy. This is, again, trying to have a very well-defined control patient population in a reasonably small study. Then your second question was. Steroid tapering. Steroid taper. The lowest patient right now is on an alternating 2.55 milligrams. It is somewhere in between 4.75, 4.5, whatever, is currently. The steroid taper, I guess, as you feel comfortable, will probably go down further. We are not guiding for any. The maximum in this phase I study, the maximum steroid use is 10 milligrams. We are not guiding to a certain steroid taper. It is up to the physician's decision. What I would say is the voclosporin studies have shown us that there is a new way to go because I think it's probably particularly true in the U.S. that the renal physicians are very, very unkeen to reduce the steroids too quickly. The voclosporin studies show that you can get down to 5 milligrams or less within about three months. That is in even renal lupus. I think that has given a lot of people much more encouragement that you can get those steroids right down. As I was saying before, if you get below five, your chances of getting steroid side effects begin to disappear, serious ones anyway. I think they're all here. Hi, this is Carina from OsteoCultureist. I had a question. You guys had CAR T persistence of three months. How does this compare to other CAR T players in autoimmune? How can this translate further to efficacy? The average was three months. I think the shortest was just two months. One is out six months. I think right now there is some difference, obviously, with the different doses. So far, we are exactly where we would like to be and where we feel we are comparing to others. Very comparable to the Schett data, which is probably today kind of the cleanest data. What you've seen is it's a U-shaped curve. Be mindful, this is a logarithmic scale. If this were linear, it's a sharp peak. What you really try to understand is actually what the lower end of the curve looks like. This is why we're doing this, actually, as a logarithmic scale. This is why you see the depiction. Some of the things that you may have seen in other publications do actually not use logarithmic scales, which creates a bit of a confusion. It's different from what you would do in hem-onc and the hem-onto oncology side. It's very comparable. What's most important about those curves is the consistency of the curves. All these curves are in a very narrow band and give us a very strong indication that indeed the product is behaving exactly the way we would have expected it to behave. In terms of the peak we're getting to, if we express it the same way that it would have been expressed in Schett's trial, we're somewhat higher in the peak than what was observed in Schett's initial data set. Again, consistent with what we're seeing across hem-onto oncology as well. Thanks. Yan and Drew Wells-Fargo. Two questions. One on dose level two. What's your expectation for efficacy and safety? Is there room for additional efficacy, do you feel? Safety-wise, any potential caveat for going higher? The question is a little bit with the higher dose of 100 million cells. Do we see a different dynamic in kinetic? Do we see a potential faster drop of the double-strand DNA antibodies below the upper level of normal? Do we see an even deeper reset? We had one patient, patient number two, if you remember, on the pie chart. The pie chart was not entirely blue. Is the reset and the repopulation of the B cells even more deeper? This is what we will use as guiding, other than, obviously, the safety events. So far, it's too early to tell. We need to see what we will learn about these patients at 100 million flat dose. Right now, there is no assumption that we would see a different safety profile. This is speculation. We need to see the data. I think from the physician's point of view, it's the time when the neutrophil count begins to drop very substantially. That's a kind of worrying time. That occurs relatively soon. It's usually over in just a matter of a few days. I think in that particular period, it would be a very good idea to keep your patient isolated and out of the public's way, as it were. Got it. A question on the role of SLEDAI in the pivotal trial. Looking from the first six patients, the SLEDAI, especially the renal component, does not necessarily correlate with the complete response. You have a patient who at month one and patient five still have roughly the same SLEDAI score, but he has a complete renal response. How do we think about SLEDAI when you are working on the pivotal and presenting the pivotal data? Yeah. Why don't you go first? Can I say? I look at B cell depletion. If you ask Schett what he thinks about CAR T cells, he will say to you, it's expensive B cell depletion. We published, Ed Vitale from Leeds has published, there are some very interesting differences in the way in which different organ systems respond to B cell depletion. You expect or you see improvements in low hemoglobins, low platelets within one week to three or four weeks. It's quite dramatic, actually. You see improvements in arthritis, in skin rashes in one to two months. In my experience with B cell depletion, it's often two or three months or three to four months before you begin to see really good renal responses. It may be that those SLEDAI reports that you're or concerns that you're worried about, over a little bit longer period of time, you're going to see that slope coming right down because there is a differential response in terms of timing according to the organs and tissues. The data that we have currently, or the company has currently, is still relatively premature. The vibe is clearly very good. It's all going in the right direction. I think that's very encouraging. I think at month six, something like that, I would be very disappointed given that, that we won't see even more spectacular results. Just building on this, the phase two study will look at a certain window of patients who have activity demonstrated in the kidney biopsy and a chronicity degree which is not too chronic. This is within the NHA scoring. It's probably a little bit detailed. The importance is there is activity in terms of lupus inflammation in the kidney. The chronic damage is not too much advanced that the potential benefit of reducing the inflammation can translate into the benefit of kidney. The complete renal response, which is the primary endpoint of the phase two study, is very well describing the kidney function and the protein excretion. The SLEDAI score, which is an activity score, has for the kidney four dimensions, which is cast, hematuria, pyuria, and proteinuria. For example, if you are a woman who is menstruating, you could have hematuria, which gives you four points on the SLEDAI score, even though it does not relate anything to the activity and the inflammation in the kidney. That is why the SLEDAI score is a more imprecise description of what is truly going on in the kidney than, for example, the complete renal response scoring. It's one of the key reasons also why we're going in lupus nephritis because there is actually a clear endpoint. One of the problems with the composite endpoint is there's judgment involved. That creates part of the challenges. SLEDAI particularly has quite a bit of judgment involved. We have one question from the webcast that Olivia will read. Yeah. The question's from Rajan Sharma at Goldman Sachs. He asks, assuming you achieve the target timelines for phase two, when are you expecting first clinical data? When are we expecting the first clinical data? We have a follow-up time of one year after. If we enroll over two years, we would expect the first clinical data. There is no planned interim analysis. Probably in the third year. We'll come back to questions at the end of the presentation. David, thank you. Thank you. OK, very good. Thank you very much. It is my great pleasure to introduce our next invited speaker, Professor Mark Freedman from the University of Ottawa. Professor Freedman is an internationally renowned neurologist and multiple sclerosis expert. He is the Senior Scientist at the Ottawa Hospital Research Institute and Professor of Medicine Neurology at the University of Ottawa. He has participated as a principal investigator in well more than 100 clinical trials for new treatments in multiple sclerosis with a specific focus on cell-based therapies. He led as the key investigator the Canadian bone marrow transplant study in multiple sclerosis and the Canadian mesenchymal stem cell transplantation in multiple sclerosis study in MASCAMS. He also led all versions of the Canadian treatment optimization recommendation guiding treatment recommendations for multiple sclerosis in Canada. He served on multiple editorial boards, including the Multiple Sclerosis Journal as well as Multiple Sclerosis and Related Disorders, published more than 400 papers and 550 research abstracts. He is the past president of the Canadian Network of Multiple Sclerosis Clinics and the recent past president of the American Committee for Treatment and Research in Multiple Sclerosis. We are very glad that his past career ambition as a race car driver did not come true. Hence, he is here today and giving an introduction in multiple sclerosis and B cell depletion. Welcome, Professor Freedman. Thanks for the kind introduction. I'm going to tell you a little bit about multiple sclerosis, a very different disease, as I'm learning from lupus. In chatting with David just prior to this session, I was telling him that we have a very close relationship and had a great relationship with rheumatology over the years, trying to gain from their expertise and apply it to a very different condition. I'm going to just walk you through some understanding. At the Ottawa Hospital, where we are, we have over 6,000 patients with multiple sclerosis that we look after. We're actually one of the smaller clinics in the country. We really focus our attention in Canada in these large academic centers to manage the over 100,000 or so patients with MS in Canada. I'm going to just very quickly go over some basics of the disease, tell you how we diagnose it and classify it today, some of the approaches we're taking, some understanding in the way the disease evolves, and then finally, a little bit about the unmet needs and possibly the role of CAR T therapy. Let's just start with this disease. It's really global. It's a global condition. It's got some interesting geography, which we are still trying to understand. Higher incidence the farther you get from the equator in either direction. Within various countries, the prevalence can be quite high. We have a very high prevalence in Canada, reasons not necessarily being all the white stuff that comes in the wintertime, but probably some genetic evolution. Many of the original cases that were described a few hundred years ago evolved from the Scandinavian population. If you're Scandinavian, you sort of seek out temperate climates similar to your own. You don't see very many Swedes in Jamaica and other places like that. There's probably something to do with the genetic diaspora. There may be some involvement in vitamin D and lack of sun exposure. Probably the most interesting and evolving possibility and factor is the Epstein-Barr virus. That's where it comes into meet the B cell story. How the B cells are involved in MS is very different than what you've heard about in lupus. This is a disease that, unfortunately, similar to, I guess, lupus, hits people in the prime of their life, mostly or more so women than men. That's the story for most autoimmune diseases, two to three times more women than men. In the more progressive forms of the disease, at least from the descriptive nature, the male-female ratio tends to even out. We do not see much in the way of mortality, although the actuarians are against us and usually lop off a few years in lifespan, mainly due to the patients who are getting into that progressive phase of disease for which we have no treatments. That is where I will come back to. It is characterized, at least early on, by an inflammatory disease. I will get into that a little bit more carefully. What makes it, I am going to say, a cleaner disease than lupus is it affects one organ, the central nervous system. That is it. We do not have extra CNS manifestations. You do not get lung disease and kidney disease and joint disease and skin disease. You do not get anything else. This is a disease that affects only central nervous system myelin. Myelin is present in the peripheral nerves as well, but it's different. This is a central nervous system myelin-specific condition. Early on, it's characterized by what we say is focal inflammation, pockets of inflammation that we can see. We can see it on the MRI. We can see it clinically because patients have relapses affecting the different parts of their nervous system. If you look pathologically, you see the hallmark lesion, which is a perivenular inflammatory network of cells, often lymphocytes and monocytes. These lesions can expand. It's associated with the loss of myelin, the so-called demyelination, and eventually the neuronal and axonal loss that ensues, which is irreversible. This is just a cartoon of some of the areas that I'm going to focus on, the so-called focal lesions of MS. These focal MS lesions, there is the perivenular infiltrate. It is labeled as number one here. What is curious, though, as time goes on, we tend to see these nests of cells that are situated in the meninges of the brain. That is number two, as you see here. They sort of resemble what you might see in a lymph node as a lymphoid-like follicle. When you look at those follicles more carefully, they are mostly B cells. As much as we have always thought that MS was orchestrated as a T cell disease, the B cells may play an important role, especially in the later stages where these follicles very close to the sulcus, that's a very close-up of the brain, very close to the gray matter of the brain, may be driving what may be the more progressive form of the disease, which is characterized at least now by MRI and pathologically by these slowly expanding lesions, so-called cells. That's labeled, I think, number three over there on the far right. We can focus down on a lesion that has developed early on, and now we're talking about it slowly evolving. Slow means slow. This is months to years before you can actually measure the expansion of these lesions. It can be done very sophisticatedly using imaging techniques. You have this process that's undergoing the whole thing called diffuse gliosis. That's an important thing when we talk about a little bit later. One of the biomarkers that we're thinking of is important for MS. You can see the gliosis is being driven by one of the cells there called the astrocyte, which makes GFAP, glial fibrillary acidic protein, which you can measure. That's a measure of that scarring process, which takes place once there's no more healing that can ensue. In the background of all of this, of course, and unfortunately, is natural aging. I hate to tell you, but we're losing brain every single day. There's a natural rate of atrophy of our brain. That is always in the background of whatever we're going to measure as atrophy may be due to the disease. Just to reiterate and go through this, we have these white matter lesions. This white matter is characterized by a lot of myelins. That's why it's called white matter. There's white matter in the gray matter, just to make life a little bit more confusing. It's there everywhere. That's where the myelin is. You get an array of cells in these perivenular infiltrates that are mostly T cells. There's also some B cells and plasma cells. When you see these focal lesions, at least acutely, they light up with dye on the MRI. That's where the gadolinium-enhancing lesion ensues. You have these slowly expanding lesions, which evolve from those early white matter lesions. The concentration of the cells is less. You get a little bit more of the microglial penetration into these slowly expanding lesions. They are clinically associated with what we measure as disability. I'll come back to how we do that in a moment. You have these follicles, these meningeal-rich follicles that are there from the very start, from early on in the disease, but become more prominent in the more progressive forms of the disease. They're made up of mostly the B cells. Interestingly, probably a lot of the B cells are actually still EBV positive because that's where EBV lives, is in the B cells. The reactive microglia and astrocytes is an indication of the scarring process. We can pick that up using various tracers that can look at microglia. We're starting to do PET studies that can look at this. Also, you can measure it through the concentration of a biomarker like GFAP in the spinal fluid or serum. Today, we can diagnose the disease very differently. In fact, there's a seminal paper due out imminently in The Lancet Neurology which is redefining the diagnosis of MS. I'm just going to walk you through a little bit of these definitions. From the top there, you see what's called the radiological isolated syndrome, the first episode clinically isolated syndrome to clinically definite to transitional making its way into a progressive form of MS. The clinical threshold is where we know that something is happening. Above the clinical threshold, the patient may have symptoms. You're the doctor. You can see signs. The first time demyelination crosses that threshold, we call that the clinically isolated syndrome. If you look to the left, under the threshold, there was some demyelination that took place that wasn't clinically evident. That's picked up via MRI. We know that the disease has started beforehand. Not sure what's happening here. We got a bird? OK. Oops. Is that water? Apologies for those on the webcast. We need a brief pause here in the presentation. We'll return momentarily. Oh, my goodness. Something's happening to the sprinklers. There's two. Are you sure I'm not standing below one? There's a whole bunch here. Hopefully, they don't start. Wow. I'm sorry, Mark. That's OK. I've had lots of interruptions. This is unique. This is a new one. I've never seen it. I don't know. Yeah, we're just going to have to wait for a second. Oh, boy. The other one's the worst, which kind of moves forward. I hate to be on the—oh, my God. The whole length. It keeps going. That's worse than any of these. Yeah, the one back there is really bad. It's definitely worse. For those on the webcast, please continue to hold. Thank you for your patience. We have a water leak here in the presentation room that we are trying to resolve. We will hopefully be back shortly. Thank you. What's going to happen to the 21st floor? They have to find a switch to turn the sprinklers off. Otherwise, it's going to completely empty. OK. It will be a very memorable thought. Going to get you something to drink. It started raining. Going to get you something to drink. It started raining in the middle of my talk. What's that? That's the first. All right. I got my coffee over there. That's crazy. Thank you to everyone holding on the webcast. Apologies for the delay. We are working to resolve the issue here in the room and hope to be back shortly. It's like in the same room. I see patients with lupus. All right. OK, I think we're going to try to get back on track here. Thank you for your patience. Apologies about that. That's going to change now, then. For that, I am very happy. Good. All right. Can we get going? Yeah, go ahead. All right. Good. Welcome back, everybody. This was more excitement than we expected. It's not quite clear. For those of you who are not in the room, you know, one side of the room got flooded. First, we thought there was just some of the people closer to the event were a bit getting itchy. Actually, it was a lot of water coming down. We are not quite sure whether we're going to have life jackets or floaties. You might actually be going to look out for those. For the time being, we're going to get back together. We're going to hand over back to Mark Freedman, who was on quite a roll. I'm sure we're continuing as if nothing would have happened. Thank you. Is this working again? Yeah. OK. We'll come back to diagnosing MS and the change in criteria. I was showing you on this graph that demyelination comes and goes. The first time we're aware of it, we call that the clinically isolated syndrome. To the left of that, there's demyelination that's under the clinical threshold that we pick up by MRI. The McDonald criteria, which is now the scale used or the criteria that are used for making a diagnosis of MS, have evolved over the years. We've been able to use the MRI to show new lesions over time. That's depicted here compared to the original Poser criteria, which were going back into the 1980s, where you needed at least two attacks to call it MS. That led to great delays in making the diagnosis. Of course, now that we have treatments, the delay in the diagnosis also delayed treatment, sometimes 5-10 years. Now we have this window where we diagnosed MS that has expanded over the years to include the CIS. What you'll learn about later this year is the window has now completely expanded. We are now able, with fair accuracy, to make a diagnosis solely based on MRI. If MRI meets that criteria, the patient can be diagnosed with MS without ever having had a symptom. That gives us the opportunity to treat the disease even before it becomes clinically manifest. Some of the terminology has changed over the years. We talked about this relapsing, remitting phase that yields to a progressive phase. Now we realize that really progressive disease is the same. Whether you start progressing from the start, that means you see it as a progressive disease from the start, or you see it as a relapsing disease that evolves into a progressive disease, they are all identical. The only difference is whether the patient has had relapses to start their course or not. We do not think that is necessarily relevant, as I will show you in a moment, because the activity can be just on MRI alone, so the patient does not have to have clinical relapses. There is no real difference amongst the progressive patients. If you took the brain of somebody who had progressive disease and someone who had pure relapsing disease and gave it to a pathologist, they would not be able to tell the difference. If you looked at the MRIs of these individuals, there are really no differences. If you looked immunologically at what's going on, there are subtle but no great differences between these groups of patients. We think of progressive disease as one entity. We do the testing. The testing is to really reinforce the diagnosis and differentiate it from some of the mimics. We have another condition that's eating its way into the MS world called MOGAD, Myelin-Oligodendrocyte Glycoprotein-Associated Disorders, that can look like MS but is not MS. We want to be able to distinguish these conditions. Often, the testing is done to rule out other things. As I alluded to, MRI is one of the most important aspects of the disease. There was a time that we thought that if the MRI was negative, you could still have MS. That is pretty well gone now. If you do not have lesions characteristic of MS on an MRI, you probably have another entity. We use some neurophysiological measures to look at things like the optic nerve. We use the spinal fluid. It is really important because there is this hallmark which we have known about for years of the B-cell activation and the presence of so-called oligoclonal banding, which you can see in type 2 and type 3. There are clearly distinct bands in the spinal fluid that are not present in the serum. Those antibodies are a source or are really an enigma. It is the hallmark of the disease. It is a fingerprint for the patient. That fingerprint never changes. You could do a spinal tap at the beginning and 20 and 30 years later, and you'll see exactly the same pattern in these individuals. We don't know what the antibodies, the IgG—this is an IgG oligoclonal band—we don't know what those antibodies are directed against. They're certainly not directed against myelin. For years, people have been trying to figure out what that is. We still don't know. It may be just a nonspecific measure of intra-CNS activation of B-cells, which can occur in other diseases that can look like MS, including, by the way, CNS lupus. We've seen that in CNS lupus. We've seen it in neurosarcoidosis, another condition I think you guys look after there, David. I don't know if you do care. The rheumatologists sometimes help us with neurosarcoidosis. It is more of a marker of intrathecal inside the CNS activation. As such, if you do not have any other reason for it, it is probably MS. I like to look at this to try to put it in perspective of where we are thinking about treating these patients. Here is that clinical threshold again. There is the demyelination. We talked about the first attack. What you should know is that underlying this—and this has been seen right from the earliest patient—is this axonal loss that can be characterized by these so-called axonal boutons, as you see here on the far right, labeled with neurofilaments. Bruce Trapp, in a seminal paper ages ago, got some graduate students to—I do not know how he coerced them to sit in front of a microscope and literally count these axonal boutons in various types of patients. What they looked at is this is not a chronic condition. This is not something that occurs late in the disease. It actually occurs very early. As that histogram shows you, it is an active plaque, which tends to occur at the earliest times of the disease. That green line that I am depicting here that starts well below the clinical threshold, we were not aware of that. The patient is not aware of that because they are able to compensate in the brain for any kinds of problems that they have. They are able to repair. They are able to get around things. Tracts can take up new tasks. We call that the plasticity of the nervous system. It is not until you surpass all those compensatory mechanisms that the green line crosses the red line. Suddenly, you are aware of this progression. As I'll show you in a moment, that's not true because it actually can be exposed with therapy. Therapy is directed at what we think is driving this. That's that curve now of inflammation that comes and goes, probably peaks sometime in the midst of this relapsing, remitting phase. That's the focal inflammatory component of the disease and starts to dissipate while we're into the secondary progressive phase. If we're going to target that inflammation, it makes sense to target it at a time when it's prevalent. That's where 95% of our therapies are going today in the relapsing form. They're targeting this inflammation. We know that in the more progressive forms of the disease, when inflammation is dying out, the same therapies are just not effective. You can't stop that green arrow from getting any worse because already so much has accumulated in terms of axonal damage that you're not going to repair that. When we think about therapy, we think about where this patient is in the window. To try to figure out their prognosis for early progression, this is where we take either an aggressive approach or a not-so-aggressive approach. There are ways to figure all this out. I'll just touch on that in a moment. This is an important slide. This is the next one when I come back to this later. This was the typical course of disease, right? Relapses and remissions. Later, you see that progression with maybe a few relapses dotted in. That's how we perceive this disease. However, with potent therapy and some of the most potent therapies we have today actually are the anti-CD20s directed against the B-cells, we know we can suppress a lot of that focal inflammation. You do not see new MRI lesions. You do not see attacks. All of a sudden, those patients are getting worse. This is what has been referred to as PIRA, progression independent of relapse activity. It was now exposed by eliminating the relapses. We saw this progression. That was backed up by a lot of pathology. I am not going to go into that. Our historical perception of this disease is that you had this inflammation. You had a secondary stage that the inflammation died down. You entered a progressive phase. That has yielded to a new idea that we are looking at two parallel pathways here. Sorry about this, this is the computer doing this. We have a peripheral component, and we have a centralized, compartmentalized type of inflammation. That is what is not being targeted by most of today's therapies. We need to be able to get at this compartmentalized type of inflammation and stop this decline as time goes by. This is where we are coming into from moving from the left into the right. To the right side, there is where we start to see the physical worsening, the cognitive involvement. This is backed up by some of the MRI metrics of brain atrophy. Some people have called this the so-called smoldering type of inflammation that is yielding to PIRA. This is the outcome measure that is going to be looked at. In order to treat this disease and get rid of the progressive nature of it, we need to target this PIRA. The focal lesions, we can treat the SELs, the slowly expanding lesions, and something else that we call pearls, the paramagnetic rim lesions. These are the microglia that are depicting themselves on MRIs. We start to see those a lot more in the progressive phases. We also see those meningeal follicles become a little bit more prominent. The axonal damage dominates the clinical picture. We see these patients getting worse in the absence now of any kind of clinical attacks and the formation of new MRI lesions. There is a clinical scale that we use called the EDSS. This is purely a translation of the neurological examination into a composite, which is made up of all the components of the evaluation of the nervous system, the visual, the brainstem, the motor, the sensory, and all of that into a simple composite. It looks and displays as a linear, but it's anything but. It's actually an ordinal scale. People spend various times at various levels. There are important cutoffs at about 3. Most of you seeing somebody who's an EDSS 3 would say, "There's something wrong with this person." You don't have to be a neurologist to figure that out. At EDSS 6, you're already dependent on a walking aid. At EDSS 7 and higher, you're already in some form of a wheelchair or a scooter, that sort of thing, because you're non-ambulatory for most of the time. We hate the scale, but it's what we use. It's an objective scale because it's measured by the neurologist as opposed to the subjective PROs that are used in a lot of other conditions. OK, how do you figure out what drug to use? We have to try to figure out whether the patient's going to have a poor prognostic. I know, David, you asked me this earlier. I'm just throwing this back at you. These are the types of things that we would, like a checklist, go, "Yeah, no, yeah, no." There are some things you can check off here that we can't change, like, "I shouldn't say that. I was going to say gender." At least biologically, gender. Age you can't deal with. Sometimes the family history is there for higher incidence. There are other factors that can play a role here. All of those are considered. If you think the patient has a more aggressive form of disease, you'd use a more aggressive treatment. There really is no idea of what mechanism is driving the disease at any given time. When you think about what I get this from companies all the time. Who's the perfect patient for drug X? That's a precision medicine that belies us right now to try to figure out. The cancer guys are starting to be able to pick up a marker. They say, "Aha, if you have this marker, this is the drug. If you don't have this marker, you don't try this drug." This is good. I mean, if we can find something like that in autoimmune disease, it would be wonderful because we have so many different therapies. Right now, it's a bit of trial and error. I would love to know which of these mechanisms is dominating at any given time. It is a problem because if you think you have that mechanism, because maybe you can measure something in the serum that indicates that this is a pure type of inflammatory condition, say, being driven by IL-6, you can come in with an IL-6 inhibitor. Except six months later, it may have switched to a different mechanism. You are going to lose on an IL-6 inhibitor. This is just a quick showing of the different drugs that we have that work at different stages. I like to group these into three categories if people ask me about treatment. We had for a long time the so-called immunomodulators. Those are the safest drugs for MS. They do not cause immunosuppression. They can be used long-term. Many of them are safe throughout even pregnancy. They can control the disease in a lot of people a lot of the time. If the disease escapes this, you need to move up the ladder. We have this category called anti-trafficking medicines. They really stop the cells from getting into the brain. You've got all these autoimmune cells that are intent on attacking the CNS. You simply close the door, and they can't get in. You're not really doing anything to the underlying disease. That leads to problems should you have to suddenly stop them. One is natalizumab. That's an anti-adhesion molecule antibody, which is very potent but wrought with problems because it's probably the number one producer of PML today, a disease which is much, much worse than MS. You have this whole class of drugs called the S1P receptor agonist. They also can cause PML and are a problem if you suddenly stop them. They are used in a certain type of patient. We know it is not a long-lived therapy. On the far right, you have your more high-intensity therapies. These are the cell-depleting therapies that range from T and B-cell inhibitors like clozdribine and alemtuzumab to the three or four now we have of anti-CD20 molecules. Ultimately, to a bone marrow transplant, which can be done in patients who have very aggressive disease. How do we know you are winning this battle? This is an important one. We do not have something like a creatinine to measure whether or not your kidney is working. It is kind of evolving. Patients are always saying, "I am taking this stuff. And I am having the problems. But how do I know I am winning?" You have not had an attack. Your neurological exam hasn't changed. Your MRI hasn't shown new lesions. I already told you, as the disease progresses, you get fewer MRI lesions. You get fewer attacks. If you're using that as an outcome measure, you're in trouble because one day your patient's going to come in dragging their leg, going, "You told me this is working. I'm not having any attacks. I'm not having any new MRI lesions. But my leg's getting weaker. It's because it's not dealing with the PIRA. It's not dealing with the progressive nature." It would be nice to have a biomarker. Now we're getting a few of these that are at least fluid-based that help us to know that something is working. There are all these MRI parameters that I won't get into. One of the conditions is that you do it often. It is just not feasible in some places to do MRIs three or four times a year. It gets costly. In this country, what I have noticed is, depending on who is your managed care group, they will allow it or they will not allow it. It is becoming a real problem in monitoring for treatment response. We get to look at the different kinds of evaluations. Maybe the computer can help us here because looking at it by eye, you sometimes cannot see any things. Now there are these automated programs that can look at MRI to MRI and tell you whether that lesion has gotten bigger or smaller or whether there is a degree of atrophy. The error in a single patient is so high that it is still not, I think, mainstream for most patients. I just threw this up here because people are always asking what the meaning is of seeing MRI lesions in the absence of any kind of clinical things that have occurred. The Danish have just published this. More or less, they said, "If you start on a therapy of one of those moderate efficacy treatments and you're following the patient for at least a year and nothing's clinically happening to them, but they develop one, two, three, or four new lesions, and you don't react to that, meaning move up to something more aggressive, what happens to them?" At the top, if you have one lesion and you don't change, that doesn't matter. These are the number of patients who are going to be free of attacks over the ensuing four years. If you have two or more, if you do not escalate therapy, you can see what happens. The bottom line, the black lines represent the patients who are staying on that first-line therapy. Most of those will not be relapse-free. Silent MRI lesions in someone who is on a therapy are, in fact, important. That is what the message was from this. As I alluded to, there is no single metric that is useful. We look at a few things. We get into these slowly expanding lesions, which are not mainstream. This is something that can be done in clinical trials but cannot be done in the single patient simply because of the error in measurements. Pearls are seen, more commonly seen in the progressive. They can be seen at any stage of the disease. They tend to be more prominent and stay there as the disease progresses. We're now getting into some PET studies as well. The fluid biomarkers have, I think, changed things for us, at least for me, because we do it now routinely in most of our patients. I know the FDA hasn't approved these fluid biomarkers. In Canada, they have been approved. They are part of the patient's clinical record, and we use them routinely to manage the patients. The idea of biomarker would have influence on all of these. They would help you to assess the burden of disease, help you distinguish MS or this particular pathological process from something else, and have some high specificity and sensitivity. I can tell you that the two that I'll talk about are really meeting those objectives. They should be able to give you even a treatment response in the sense that if you measure the biomarker and the therapy is effective, that biomarker should change. In the case of some of these, they should go down. If your biomarker does not go down, that's kind of, I guess, an idea that the drug is not working as well as it should. In the rheumatology world, they've used these nonspecific markers of ESR and CRP to measure inflammation. They look for these things to go down with their treatment. This is now the equivalent of that. We have two. One that's mainstream now is the neurofilament light chain. We measure this in the serum. It correlates with disability. It predicts new attacks, as you can see here on the right. The higher the neurofilament is to baseline, the better the chances that those patients are going to have a more aggressive form of MS. In that case, you might choose a different therapy. The same thing is true for now, GFAP, a marker of that scarring process of the brain. You can see that the more GFAP, the higher the GFAP score. This first graph is confirmed disability worsening. That is over the ensuing few years. It correlates with both gray and white matter atrophy. You are getting an idea that this biomarker could change if you have an effective therapy that can address those things. We have yet to find one that can do that. I just pulled this out because this is actual data from the two anti-CD20 trials using ocrelizumab. On the left was relapsing-remitting. On the right was a primary progressive. What I'm pointing out here is this arrow, so the arrow at the bottom at 48, that's where they started to measure the serum neurofilament light chain. After a year of therapy on an anti-CD20, which I already told you erases those relapses and reduces them to minimal and reduces new lesion formation by 90%-95%, despite that, the red curve, if you have a high NFL, you're getting worse. It hasn't addressed the PIRA. That's that PIRA that I showed you in one of those first diagrams where you suppress the relapses and you get the PIRA. The same is true for the progressive patients. In terms of unmet needs, these are pretty well the major things. Progressive disease is subtle. It's going on even in the relapsing phase. You just can't see it. We have limited tools to measure it. Our scale, the EDSS, is rather insensitive to it. We've yet to develop a therapy that really effectively slows it or stops it. As the bottom things talk about, we're learning about the biological mechanisms. We need something that will address that compartmentalized inflammation better. Where does the CAR T maybe play a role here? Unlike lupus, the antibody is unknown in MS. If the idea is not to reduce antibody formation, the antibodies are not, as far as we know, pathological in this condition, whereas in something like Mogad it is. The B-cell role in MS is thought to actually play a very important role in stimulating the T-cells. B-cells can present antigens to T-cells. We think that is the major mechanism that's driving this. As long as you have this unchecked group of B-cells that are constantly presenting antigen to the T-cell, you're going to have perpetuation of the disease. They also encourage the development of the microglia. The microglia are good and bad. The bad kind of microglia are the ones that I think are driving these slowly expanding lesions and the pearls that we tend to see. Here is a role for the CAR T because although these monoclonals, the anti-CD20s, they work outside. There are a few of them listed here. They work outside. There is another one you have in the United States called rituximab that should be added to there. That is a sort of glyco-engineered rituximab. They do not go into the brain. They are too big. If you can get to the inside of the brain where those resident B-cells are, that's where the CAR Ts may play a role that none of the other antibodies have had a role to play. I'm just going to pretty well summarize here. This is a condition that's unique to the brain. It's nowhere else. It's a single organ. We've got lots of treatments that can address focal inflammation but nothing that really gets at the compartmentalized inflammation. You may have heard of tolobrutinib. Someone's going to probably raise that question. That's a drug that just got study released in non-active secondary progressive MS. It's going to get fast-tracked by the FDA. If we're lucky, we might see it at the end of maybe 2026, maybe, if it's fast-tracked enough. That's for a subgroup of patients. That's the only BTKi that we know of that has been effective. There are two other ones, at least, that have been tested that were negative. We really need something that can get into the brain and deal with this disease that's trapped behind the blood-brain barrier. We still are in need of repair drugs, something that will repair myelin or at least encourage it. Those trials are ongoing as well. We've yet to find anything. I will stop there. Matthias, I guess you're going to take it from here. Maybe I'll just hang for questions. Thank you very much, Professor Freedman, for the overview. I will give you a brief introduction into our planned clinical trial, which is a dose escalation study in multiple sclerosis, particularly progressive multiple sclerosis. We are planning to do a heavy biomarker and imaging-supported study that is evaluating up to three dose levels in patients with progressive multiple sclerosis. This will then inform our dose expansion into phase two and most likely selective study, which will be pivotal either based on a phase two or phase three randomized design. Jonathan Wilmer, who sits there behind David, is the neurologist on our team. He leads this dose escalation study. Patients with progressive disease will be enrolled. There is a standard flu cyclophosphamide lymphodepletion. We are escalating dose levels starting with 100 million cells up to potentially 400 million cells if safety permits. I mentioned already that this is a study that is heavily building on translational work. Everything you heard in the introduction from Professor Freedman, we will be looking at. We are looking at neurofilament light. We look at oligoclonal bands, GFAP, and certainly also multiple imaging time points. The plan is to assess the safety and determine the safe and potentially efficacious dose through the dose escalation and have early reads out on biomarkers followed also then by the clinical endpoint, which is the EDSS. What does good look like for this study? Clearly, we would like to demonstrate that we have the brain penetration potential for Obe cel, which is the core difference from the biologics targeting CD20. Shorter term, we are looking at fluid and imaging biomarkers that may support the evidence for the biological effect, particularly reduction of CNS inflammation. We are hoping to see reduction of oligoclonal bands. Professor Freedman has told you that this is typically what stays with you despite therapy. Only change in oligoclonal bands has been seen so far in patients who received a bone marrow transplant. We are hoping that we are able, in conjunction with other biomarkers, to identify a signature which tells us that we are onto something to take it into phase two development. I'm going to summarize very briefly for you the section of our path into autoimmune diseases. Based on the data which David shared with you from the SL1 study, we have a clear representation of the patient population we're going to evaluate in the phase two SL2 study. This is a study population with high unmet medical need or the highest unmet medical need who have all failed available standard of care prior therapies. It opens up the opportunity for future expansions, future expansions both in early lines of lupus nephritis but also other adjacent diseases affecting the kidney, such as membranoglomerulonephritis and other immune globulin-driven and B-cell-driven autoimmune diseases of the kidney. Last but not least, also non-nephritis systemic lupus. On the MS side, we believe that we are assessing the poster child of CNS diseases where we can assess the potential of Obe cel beyond the blood-brain barrier. The differentiated safety profile of Obe cel, we believe, set s us apart from other CD19 CAR T cells to do so. Insights will inform the path forward, how we can potentially get to an approval in multiple sclerosis, and particularly the progression independent of relapse activity, which Professor Freedman has told you is the highest unmet medical need. It also serves as a springboard how we can expand into potentially other autoimmune neurological diseases. Now I will hand it over to Christian for a snapshot on the early pipeline. Thank you. All right. After all the excitement that we had leading into MS, we're going to do a quick wrap-up in looking at our early-stage pipeline. As you know, there's a number of programs we've been active in. I think there's one thing that we wanted to highlight. There's obviously a number of studies that are ongoing or prepared to get started in our collaboration with University College London. One of the studies I want to briefly highlight is a study that we're starting in light chain amyloidosis for AUTO8. This is the CD19 BCMA dual-targeting CAR T program called AUTO8. All the other programs obviously do continue as we have actually, frankly, walked you through in the past. The neuroblastoma trial continues to enroll patients. We're hopeful that we're going to get an update on that study towards the end of the year, early next year. We have obviously on the T-cell lymphoma side moved back into the translational side and are doing a set of improvements on that program. Let me briefly talk about the AUTO8 approach in plasma cell diseases. Obviously, you remember we have treated a range of multiple myeloma patients seeing very nice levels of activity, good safety profile. Based on that, decided to move into light chain amyloidosis, again, a setting where there's a very significant medical need. We believe that the product has an interesting positioning that we are obviously looking to sort of work out. This is ongoing and is, again, sort of expanding the collaboration that we're having with University College. When we look at the upcoming milestones, I did mention that we expect to see the response or decision from the MHRA for a U.K. approval during the course of this quarter. Second half of the year, we're hopeful to hear back from the European Agency for a broader European approval. We're also obviously progressing with our pediatric study and expect to have data on that study towards the end of the year. We did obviously have a first peak review on the data on our SL1 data set from the phase one study, the CARLYSLE study, obviously presented today by David. We expect to add more patients. You've heard obviously Matthias talk about the fact we're going to push the dose to the next level. Want to see whether there's any change in the behavior of the product. There may be no change. That's what we want to figure out. We are also planning to include patients that are younger patients in this study because obviously there is a very significant medical need for younger patients. David mentioned that earlier when he mentioned about the patients coming over from the Great Ormond Street Hospital, which is a pediatric hospital in London, and those patients coming over into his practice and obviously tend to be very difficult to manage. We're looking to enroll some of those patients, get an understanding of what we can do for them. Obviously, we're starting two studies, the pivotal study that we discussed today in SLE and the phase one study in multiple sclerosis. We did talk about the fact that we obviously were well capitalized and were in a good position to execute on these plans. With that, I'd like to ask David to join us and actually have a final round and also Rob, a final round of Q&A. I'm happy to open up for Q&A. Hi, Dana Graybosh from Lyric Partners. I have a question on MS. I wonder if you've considered directly delivering cells to the brain, as we've seen in oncology from Stanford, for instance, that that can be quite successful and you can do it without Xiflu, both maybe for proof of concept in phase one. Is that at all applicable commercially, the trade-off of direct delivery versus no lymphodepletion? Thank you. We have some experience in delivering actually the product intrathecally. You may remember that we had conducted, also in collaboration with UCL, a primary CNS lymphoma study. We were looking at both systemic delivery as well as intrathecal delivery. As it turned out, the systemic delivery was very efficacious. There was no benefit in actually taking the extra burden of actually directly administering. One of the interesting things, obviously, with the CAR T cells is that they're actually very well capable of crossing the blood-brain barrier. That is obviously one of the key things and key differentiators to other types of therapeutic approaches. At this point, we're not actually contemplating that. I think if there would be evidence that we wouldn't see the level of activity that we would expect, then that's an option we can consider. Obviously, it's a lot more intrusive as a therapeutic route, an administration route. Obviously, if there is a chance to avoid it, I think you would want to avoid it. It has been tried with mesenchymal stem cells, for instance. There is some suggestion that these cells may work. It is just not a feasible project, I think, in large groups of patients. We also do not know how many times you would have to give it. It is just not a great way of administering a treatment. I can tell you that they have even tried putting monoclonal straight into the spinal fluid. They have tried putting an anti-CD20 in, and it did not work. I think there is something about the cell itself that can actually do things that fluid types of treatments cannot. That is where I think the CAR T may have an advantage. Hey, thanks for all the color. Salim Said from Azuha. Just Anit spoke about the progressive multiple sclerosis. We've seen this with other companies. They've always started with progressive multiple sclerosis and then started talking about later on in their storyline relapse refractory being the bigger market here. Just curious what your thoughts are for this therapy in relapse refractory multiple sclerosis. Are you directing that to me? Yes, Dr. Freedman. Yes, thanks. We have concerns, especially in the early phases of MS when they have already a lot of inflammatory activity in the brain. I don't know what happens when you would give a CAR T whose big side effect we worry about is ICANS, which is, in a sense, an inflammatory reaction that takes place in the central nervous system. The propensity is that maybe these patients will get worse or that the CAR T will excite some of this inflammation. I think you'd really need some phase one data in patients who have early inflammation to know that that's safe. Why would I want to do that? As I showed you, that PIRA, that starts at a very early phase. If you can prove in a very prominent progressive patient where PIRA dominates that you can address that process, why would you not want to address it early on and prevent the disability from reaching that stage? You cannot go there while the inflammation is going. There are two thoughts. Either you do it in conjunction with a therapy such as an anti-CD20, which will work and cut down the inflammation and use the CAR T as an adjunct. You are muddying the waters there. You are not going to be able to get the kind of data that you want. I think the idea is to go into progressive disease, prove your concept, prove the safety, and then little steps, get into the inflammatory phase, prove the safety again. If you've been able to clearly address this PIRA, you're going to want to get to it as early as possible in the disease. It opens the entire spectrum for treatment. OK, thank you. Just one for Dr. Isenberg. Just curious to get your thoughts on NK versus T-cell for your practice. Thank you. You're talking about T-cell engagers? Yeah, NK versus CAR I think the proof of the pudding will be in the eating. I don't think anybody can predict with any great accuracy what is likely to happen. We have to try it. We have to see. Which way it's going to go, I don't think anybody can predict accurately. Thank you. Hello. Gil Blum from Needham. Maybe a broader question as it relates to SLE and now on as you go to earlier lines and maybe the broader SLE populations. What do you think could be meaningful endpoints for studies in that stage? You're talking about meaningful endpoints in trials as a whole? Specifically, as you move to earlier lines and the larger SLE population, what do you think is a good endpoint? We touched on what we were discussing at the question of withdrawal of other drugs. That is very important, particularly when it comes to steroids. If you have a trial which simply reduces the level of steroids or stops the steroids, that is, to me, as a clinician who has seen the damage that steroids cause over the years, a very, very big plus. Likewise, if you can stop mycophenolate, if you can stop cyclophosphamide, whatever else the patients are taking, that is very good. As we were discussing, one of the principal causes of death in lupus is not disease activity. It is infection. That relates almost entirely to the amount of immunosuppression the patients have had. If you can stop those drugs which cause that, that is clearly going to be a good thing. Do you think the regulators are amenable to an endpoint like that? I didn't hear it either. Could be. I can't say definitely. I just don't know. Yeah. Your microphone's so beautiful. Just adding then to this, I mean, right now, what you see, many of the trials, which are randomized trials, are the addition of standard of care to evaluate the incremental benefit versus standard of care. By nature, they include glucocorticosteroids or mycophenolate. I think, hopefully, that this study, the phase two study, will demonstrate that the regulators indeed are also committed to evaluate single-agent therapies such as CAR T cells with hopefully only physiological levels of glucocorticosteroids. I think there is a path. Thank you. I have one question to both doctors. Curious, would you anticipate CD19 and CD20 as a different targeting strategy? Could it differentiate brain treatment outcome in multiple sclerosis? In another word, what have been the discoveries on the cell marker studies for the B-cell population in MS, maybe in some subset population, like the B-cells in the chronic active lesions? What's the difference on these two different targets? Also broadly, how does the cell marker differ in MS versus other autoimmune disease like SLE? Thank you. If I understand the question, it's a subset of the B-cell that you're thinking of. They really haven't identified that. One of the problems has been in the efforts to treat MS. We've tried a few other drugs that work earlier in the B-cell differentiation pathway. Atacasep, for one, has actually made patients worse. We were still trying to get our head around that. Because if you address the later B-cell, the CD19, CD20s, you clearly have a benefit. There's some thought that there are B-cells that are regulatory, and you don't want to knock those out. The one subset that seems to keep coming up when people are looking at phenotyping are the B-cell memory cells. They do have a specific phenotype. The drugs that have worked best in MS seem to be able to reduce B-cell memory cells. We do not get that big reset that David was talking about in MS. We have to tread cautiously because at the same time, there is normal immune homeostasis that is going on in these patients. This is our concern, that long-term B-cell suppression is not going to be viable. At some point, you are going to need to stop it after you have gained some benefit. You are still not getting at what is going on behind the blood-brain barrier. There is another thought that those are EBV reactive B-cells that have not been able to be targeted. That was the thought behind one of the experiments that failed, reported out a year ago, where they were trying to replenish the cytotoxic T-cells capable of taking out the E BV reactive B-cells. It did not work, either because they did not penetrate or because it was not the dominant force at the time. EBV is still front and center in trying to understand what's triggering ongoing disease in MS. Just a word about the lupus context. Obviously, rituximab is pretty good at getting rid of the CD20 positive B-cells. But it's believed that the tissue-based B-cells are as likely to be CD20 negative but CD19 positive, which is why the CAR T cell approach, in theory, should be better. Matt Phipps, William Blair again. When you think about progressive MS, do you have any sense or is there anything you can look at for how much of a reduction in oligoclonal bands might actually be a marker for who will derive benefit? Is there some cutoff? Do you want to see complete resolution? I guess similarly, if you're following single-arm patients, how long do you have to see kind of stable EDSS until you feel confident that that really is a stable patient now versus somebody that is still kind of on a progressive decline? Those are great questions. We've been able to address a couple of them now. I think that when you look at this PIRA, and you can even see in that one study I showed up there, the anti-CD20, you could see that change. That was just measuring the crude EDSS within a year, especially in the high neurofilament group. If you can enrich the population with patients who are likely to progress, and this has been a problem in most of the progressive studies to date, you throw everybody in because we really didn't know who was going to progress or not. There's a subset of the patients who clearly are driving this disease. If you're lucky, you have the power to see the difference between the treatment and the placebo. I think with these biomarkers, if you can enrich the population with those that are showing the high GFAP, NFL, maybe already demonstrating atrophy or increased number of pearls, or already been able to show SELs and, say, a lead-in of six months, the are the patients who, at least in the studies that we've looked at, are most likely going to progress in the first six months to a year. Now you have the power to see the difference between a therapy that may or may not work. On the clinical side, I think we're there. I forgot your first question. Yes. This is a problem, I think, of two, well, it's twofold. One is, are they really absent? Or have they fallen below the level of detection on a gel? Because you need a certain amount of IgG to resolve it on a gel. Because you can still measure it. In some of our bone marrow transplant patients, oligoclonal bands were no longer evident at a year or two. But their IgG levels also dropped. I've asked the question repeatedly from people, from the biochemists, how much do you need on an agarose gel or an immunoblot to actually resolve the bands? Nobody's done that experiment. Are they below the level of detection or are they absent? I think it's moot. If you can eliminate or lower them below the level of detection, it's telling you you got at those B-cells that are behind the blood-brain barrier. It's just really a marker of have you been there or not. The only other thing then that has shown that just recently is actually cladribine. We know that cladribine gets somewhat into the brain. It's a treatment that's used for MS. They just presented data, I think, at the American Academy and the ACTRMS meeting where oligoclonal bands in that few patients that they were looking at actually disappeared. We just have a couple of questions on the webcast. The first is from Simon P. Baker from Redburn (Europe) Limited. It is two questions. The first is, do you think a lack of brain penetration explains the failure of high-dose ocrelizumab to show a benefit over regular dose? Therefore, is CAR T superiority compared to ocrelizumab a plausible outcome? His second question is, on safety, Dr. Freedman said in Nature last year that his biggest concern was brain toxicity in this setting due to existing inflammation in MS brains. How has that view changed in the subsequent year? I'm sorry. I really couldn't get the first question. I tried. I'll say it again. Say it louder. Do you think the lack of brain penetration explains the failure of high-dose ocrelizumab to show a benefit over regular dose? That's what I thought you said. Is CAR T superiority therefore a plausible outcome? Yeah. Yeah. Let me answer that first. Ocrelizumab does not get into the brain. Period. It attaches to cells. And maybe some of those B-cells might cross. But it's very unlikely because they're going to be lysed in the periphery. That's the problem with all the anti-CD20s. The CAR T has the advantage of being able to penetrate and then carry that B-cell depleting nature into the brain and maybe attack the follicles. The second question was not related, but. It was about safety. Last year, the concern about brain toxicity and existing inflammation, has that changed in the last year? You mean the toxicity with CAR T? He didn't say. He did not say. I am not sure. I assume, yeah, general toxicity of treatments in MS. We do not need brain toxicity with any of the known treatments of MS. The concern is with regards to the CAR T and the ICANS, which so far was not seen in the few patients that you presented with this product but has been seen with other products. Will that be a game changer for the relapsing phase of MS? We do not know. OK. There is one just from Jacob from KBC Securities. It is about lupus. He had a question on the lupus nephritis program. Given that the study will require biopsy-proven cases, based on your conversations with the FDA, do you expect that this will need to be incorporated into the potential label as well? Could there be some flexibility regarding the need for biopsy, as we have seen with recent approvals in other conditions such as NASH? It is a little bit premature to determine what the label will be. It is not necessarily mandatory that the biopsy will be included in the label. It is more likely that a certain subclass based on the NIH will be included in the label, that lupus nephritis with patients of such class. It is not necessarily determined that this will be based on a biopsy. OK. Please. Hi. Yeah, Andrew Oakley, or Prabho, again. Question on MS. I was wondering what might be the bar for success at this juncture that you might think can be achieved by or the bar for success for cell therapy in MS on the EDSS end? Oh, sorry. Also, for B-cell depletion therapy, is there a risk for PML? Could that be a risk factor? Is it a different factor? I'll answer the second one first. There have been cases of PML with anti-CD20 therapy alone in MS that was not carried over from some of the anti-trafficking drugs. They tended to occur in really very old patients with numerous comorbidities. It is a very, very rare phenomenon. I do not think that has been seen as yet with the CAR T, at least in its early infancy in autoimmune disease like MS. The lymphoma patients, of course, are at risk of PML with all the other stuff that they have been taking for a while. That just sort of muddies the waters for that. The bar for success can easily, I think, be defined. The natural history for these patients is to worsen. Their lack of worsening is an important outcome. Are they going to improve? We see this in our early phases of relapsing disease. That happened in our bone marrow transplant patients. Similar to what David's doing with the lupus patients, they're younger. They've only been into their disease like five years or something like that. They have a better chance for improvement. In these progressive patients, pretty unlikely they're going to improve. If you have two groups and one's clearly worsening and the other one's not and they receive the therapy, that's a winner. You can define that on your scales. Now you can back it up with some imaging markers and some blood biomarkers that all go along with that. Great. Could I just add a note about PML in the lupus context? I have seen that once in a long career. That was a patient given azathioprine and steroids. Did not have any kind of rituximab or, indeed, any other kind of biologic drug. I have also seen a rheumatoid patient given methotrexate and steroids. There have been several big reviews in the literature looking to see whether they could tie rituximab and B-cell depletion to PML, which failed to demonstrate it. One study goes back to 2015, one in 2017. They published arthritis and rheumatism, if you want to look them up, or I can send you the references afterwards. It seems that it is immunosuppression, however that is achieved by conventional drugs as well as by B-cell depletion, which could theoretically do it. As Mark was saying, it is mighty rare. It is mighty rare. Got it. Dr. Eisenberg, I have a question for you for the next one. It sounds like you used rituximab in the past. I think this might be touched upon at an earlier question. I was wondering, because one debate is bispecific antibody, our T-cell engager, versus CAR T. I was wondering, given your past experience using antibodies, would you care to comment on how do you see these two modalities? Thank you. Look, it's a very good question. As I was saying to the question before, in the end, the proof of the pudding will be in the easy. We'll find out in the next few years. I don't think anybody really knows the answer to that question at the moment. Who knows what's going to happen? We just don't know. You're right. You do get antibodies to rituximab. That can certainly happen. What's going to happen with the T-cell engagers? We're going to have to wait and see. Carina, again, for us to cut through. Dr. Freedman, you mentioned previously, I think it was you were talking about Atara CPV targeting immunotherapy. That failed last year. I think they were able to show that they crossed the blood-brain barrier. Just can you share what do you think went wrong there? Did they also target the T-cell component? I missed the first half. Sorry. I think you mentioned Atara's EBV program immunotherapy that failed last year. Or was it something else? Wait. The T-cell program from Atara. Atara. Oh, Atara's there. It's Atara. Yes. Yes. I don't know the details of it. I wasn't involved in the actual trial, though I was waiting to get involved with the phase three. I don't know. Maybe John can tell you more about that. Maybe you shouldn't. I don't know. We don't know that. I don't know if they got into the brain. They did? Ok Jonathan ran the program that you just asked about. This is why the question whether he can answer or not. It looks like he's comfortable saying that they did get there. Although we haven't seen any publications, right? All right. First of all, thank you very much for your patience, your interest. I want to thank our two phenomenal speakers, David, Mark, phenomenal backgrounds. I think really, really helpful to get a context in these diseases, which is challenging. They're complex. They're difficult to actually see. They change a lot over time. It was incredibly helpful. I would also like to thank Amanda, Olivia, and Susan for putting the event together. For the staff, we actually stopped a pretty impressive flooding of the room. With that, I would say, thank you all for coming. We'll keep you updated. We're going to have the early May, our Q1 update. We'll talk about sales at that point. I know that was one of the questions that I appreciate you were not asking us today. We will give an answer at that point. Obviously, things are going well. And we're looking forward to updating you at that point in time. Thank you very much. Thank you.