Autolus Therapeutics plc (AUTL) Earnings Call Transcript & Summary

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 product 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 directly 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 Isenberg, 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 CARLYLE Phase I study. Most of the patients actually have been treated in David's clinic, and so I think it will 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, and then in the second part of the meeting, we'll dive into the opportunity in multiple sclerosis. And 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. And 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. So 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 hemato-oncology 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 evaluation and mitigation system. And 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 we also have to have the ability to make the product reliably. So our ability to actually manufacture commercially the product is a key capability that we've built over the last few years. And you see in the middle picture, The Nucleus facility north of London, that supports, obviously, the commercial launch of AUCATZYL in relapsed/refractory acute lymphoblastic leukemia, but also actually conserve 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 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 by the -- towards the end of the year, also the opportunity to move into the EU and from there, 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. And 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 to 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. And 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. And 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. So 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 a 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 a very profound reset of the B cell compartment in these patients. We obviously get complete remission in the majority of the patients. Patients that do get a remission tend to get very, very deep remissions. And you've 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 one in 1 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 the proportion of these patients in true long-term remissions with our earlier studies now going beyond 5 years of observation. So it gives us a 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 who obviously have localized disease, quite different from the bone marrow disease that we're treating with acute leukemia. But also there, we see very high levels of activity between the 88% and 95% level of complete remissions, metabolic complete remissions within the large B cell cohort, most of these patients in actual long-term remission. So also there, evidence for very, very deep, very sustained activity. And 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, when you think about the hemato-oncology 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. And 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 and ability to cure a good proportion of the patients. And so 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 were 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 an investigator-sponsored studies, and you'll 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 auto-reactive cells also try to remove, not only the B cells that carry the memory, but also the auto-reactive -- the cells that are producing the auto-reactive antibodies. And that's 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. And obviously, the desire is here to actually get to a place where we actually have sustained effects in these patients with a onetime therapy. So 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 approach in autoimmune disease, you'll hear quite a bit about that as we go forward. And 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 BAFF 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, they're primary failures. And then there is, over time, a relapse for those patients who responded that eventually relapsed from those therapies. So there's sort of a challenge on both ends that I think needs -- 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 that there is a limited amount of cells through the B cell development that you can actually target that is 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 data -- early data come out of the University of Erlangen with Georg Schett and Andreas Mackensen's team. Well, it's that they could not only actually get an effect in these patients that they could get a rapid effect, and what that suggested for the first time is that a CD19 targeting approach may actually also hit on the antibody autoreactive antibody-producing cells. And as it turned out, it actually -- that those cells look like there 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 and ability to make a very deep cut into 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 about the -- 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. And then there is structural damage as a consequence of that attack. And obviously, as these patients progress, you actually are accumulating structural damage. And so when you think about an approach that actually addresses B cells and plasma class. What that will do is will address the inflammatory component, but obviously, it doesn't actually address the structural change. And 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. And we also know that there's going to be an area -- 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. So 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's the window within which we think we can actually have a meaningful impact. So when we then look at it, what's the desired outcome from the therapy. Well, the desired outcome is to find a way to remove the autoimmunity memory and the auto-reactive antibodies. You want to stabilize impacted organs whichever organ that may be. And 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. So that's kind of, I think, important to understand that there is a framework that we're working with as we think about indications, as we think about impact we can have, and I think that's going to be one of the key areas that I think is important to keep in mind. So the two indications you'll hear quite a bit about this. The first one, is obviously refractory lupus nephritis or late-stage lupus nephritis. It is a high unmet 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. So when we look at the total number of patients treated for lupus in the U.S., 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 unmet need. There's obviously no therapy that gives you an ability to cure these patients today. We're somewhere depending on the data sets you're looking at, you're somewhere in the range of about 1 million people impacted in the U.S. Of those, you have about 300,000 patients or about 30% that have progressive disease. And 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. So 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, Professor David Isenberg. David joins us from University College in London. And we really appreciate you made the way and 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. 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 Vast Colitis and Antiphospholipid Syndrome, been sharing a number of very prestigious organizations in the field. And what's 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. So actually have an ability to score these diseases characterized and understand improvement or change in the disease are critical, and this is obviously also linked to his work as the Chair of the BILAG Group that they actually established one of the key scoring systems for these patients. Obviously, highly decorated with a set of prizes, including the Hess price 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 whenever you -- when would you have time to treat a patient because it seems an astonishing body of work that, obviously, David has been able to sort of produce and really impact in a very, very big way in the field. And very importantly, Dave is also acting as a musician at various events, and for some of you, if you see some of the titles or works that publications that David has, you might actually see references to certain songs from The Beetles 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, I 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 for that very kind introduction, and thanks to [indiscernible] for the invitation to come to New York. Therapies, Lupus. Where are we now? Where are we going? And I'd like to start with a little story. I get new trainees coming to see us, to be trained by us every few months. And if you want to go, new guy comes in and we would caught turning up lupus. And he said to me, treatment of lupus, I think that's all sorted out now isn't it? And that's really what I want to address because I try to answer him with this story, and it's a story about a peasant family, who had a house that struggled the border between Poland and Russia. So this whole -- they live in, split the border. And one day, some officials from Russia and Poland came by, and they said, this situation cannot carry on. You guys have got to decide, you want to be in Poland or do you want to be in Russia, you've got to choose. So the family got together and they sat in a little hub in their room. And they decided after some thought we want to be in Poland. So if you just signed all the papers, and it was agreed, the border will be adjusted very slightly. And all the way out, one of the officials said to the head of the family, just out of me just why Poland? And he said, well, we couldn't stand the thought of another one of those long cold Russian winters. That was the answer. And the moral of the story is very simple. It's perception. And the perception about the disease lupus is what I want to get across you this morning. Anybody who thinks that lupus is largely sorted out is very seriously mistaken. So here's a picture of published in 1851 by Dr. Anton Elfinger from Vienna. And you can see the very serious nature of the lupus rash in both the young women, on the left-hand side and the discoing nature of the rash on the young male on the right-hand side, that's 1851, when lupus was thought to be just a skin disease. In 1874, along comes [indiscernible] he have the sarcoma because actually there's internally organ involved in as well. So for 150 years, we've known that systemic lupus is generally a systemic disease. Our cohort size is now about 920, but we did a very detailed in-depth review where we got to 800. And the sex ratio was female to male was about 10:11:1. Disease duration at that time was about 14 years. London is a highly ethnic mix city. So not surprisingly, the majority of the patients were caucasians, but we have the black community, Afro-Caribbean just of 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%. Also it was quite close to China town in London, so we have over 40 Chinese patients, and we have others a variety of mixed ethnicities. One patient i remember came from the South American jungle and one ethnic group which -- she was it, 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 in pretty much around the world. We are -- rheumatology units and not surprisingly, the vast majority of the patients have arthritis. If we renal unit it would be 100% renal disease, but in terms of biopsy probe and renal cases, we have about 30%. That's the biopsy program model. There are clearly a number of others who have refused a biopsy or haven't had one for one reason or another. So the actual number of patients with renal disease and lupus is probably close to 40% overall. Rash present over half the patients is often photo-sensitive, significant alopecia, about 1/4 of the patients, recurrent crops of oral ulceration in also about 1/4 to 1/3 of the patients. Major central nervous system involvement meaning principally psychosis and seizures in 20% of the patients and serositis meaning pericarditis and sclerosis in just over 1/3 of the patients. How these patients done over this long period of time. The cohort was established by my predecessor, back in 1978. We've seen about 19% of these patients have now died. I want to point out that the mean age death of those patients is 54 years. And the age of death of women in the U.K. is 80 years. So for a small but significant number of patients' death continues to come way too soon. The range of that is kind of encouraging in the sense that, yes, we still have some very young deaths, but we're now patients living with lupus to 90s, but they tend to be the exception rather than the rule. The main causes of death are, I think, quite interesting. 50 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, what chances of having a heart attack are increased by 50x, and we still don't know why. Malignancy is particularly interesting. The rates of malignancy overall are a little different between general population and lupus. But in Lupus patients let me try this factor out for it. Lupus patients are substantially less likely to have cancer of the breast, the endometrium and the ovary. And when you think about it for a second, that's mighty strange because, of course, these are diseases of women, and yet women make up 90% of the patients with lupus and that fact is still not been adequately explained. In terms of overall survival of the 1950s, we were looking at full year survivals of about 50%. Today, we look at 15-year survivals of around 85% and that's pretty true worldwide. And you see this thing because you go that's not so bad, it's pretty good, much better and that's true, except for one small but an important thing. Imagine you were 20 years old and you've got diagnosed with lupus, what these figures are also telling you is that there's a 1 in 6 or 1 in 7 chance you'll be dead by the time you're 35. And seen in that way, you can see we still have quite a ways to go. And of course, aside from morbidity, there's also mortality, there's also morbidity. I mentioned cardiovascular events, I mentioned infection, osteoporosis and invariably linked dose 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 stand now for the less serious concerns. Patients with minor rashes of [indiscernible] can be treated very successfully with hydroxychloroquine, with nonsteroidal antiinflammatories. Even with arthritis and pericarditis and sclerosis, antimalarials motor steroids can be perfectly adequate for many of those patients, we might want to add something fairly mild in terms of immunosuppression such as [indiscernible]. Hematologic disease or severe hematologic problems, we'd often go to Rituximab or high-dose steroids, sometimes like [indiscernible]. Sinus disease is highly controversial. One of the problems is there have been so few trials that have been done. My experience with sinus lupus is that you have to provide a combination of immunosuppression, with an appropriate drug and [indiscernible] drug if the patients have seizures and antipsychotic drug, if the psychotic and time. CNS lupus patients do not get better quickly. It can be weeks, more likely months before they get better. But the real problem with lupus patients is, of course, the renal problems. And right at the top, you see the Class 1 lesions, which are virtually normal down to the bottom Class 5, which is [indiscernible], but it's the type 4 from the bottom there, defused proliferative bone narrow nephritis. That is the one 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 [indiscernible], [indiscernible] or in the case of pregnancy, azathioprine. Tight control of the blood pressure is essential. [indiscernible] turns out to be very important. If that approach doesn't work a number of other drugs are widely available varying 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 states. It's not while available in Germany, for example, whereas banister is and [indiscernible] is. But this has been more formalized very recently by some treatment guidelines have been updated by the ACR, where the idea is that use combinations of therapy, triple therapy. And that seems to to be more successful i'll come to the figures just a moment. But just to say this has now been more formalized, and this is the way to go, I think, for conventional treatment of this disease. But how are these patients with lupus nephritis have done over the years? We looked at 4 decades of patients and published this data, between 1975 and 2015. We had 219 biopsy proven lupus nephritis patients. The 5-year mortality rates increase -- or decrease quite quickly as I'll show, from 24% to approximately 5%. Progression to end-stage renal failure in out-patients at 17%, why are the patients with lupus nephritis going to kidney failure. Number one reason, the patients don't take their tablets. Number two reason that patients don't take their tablets. The number three reason, patients don't take their tablets, number four reason severity of disease. Adherence to treatment is very, very important if you wish to avoid a renal failure. And it's hard to say the outcome overall for lupus nephritis has not changed significantly in the past 30 years and hit some of that data. So if you look across the lines at the age of lupus diagnosis, the age lupus nephritis diagnosis. There was a fall in mortality, as you can see from the first period mortality. So mortality, 24% in the first period, it falls very rapidly. And I think there's because lupus nephritis [indiscernible] was introduced on a regular basis. I think better general care. But you can see that overall, if you look across the line, very little change, very little than in end-stage renal disease, age [indiscernible] hasn't changed. As [indiscernible] has changed very little. And so we conclude that nothing very much has helped. As we wrote in this article, despite the changes in treatment of lupus nephritis with [indiscernible] coming in 2000 and such as more 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. And it's not just our data, which says that. Here's a very nice data coming out of the Midwest Network Group in the United States, where patients with lupus nephritis were compared to mid-1970s to 2019. Estimated prevalence has increased from 168 to 212. And the lupus in the patients, nephritis patients had a standardized mortality ratio of over 6%, with no improvement in the mortality gap in the last 4 decades. 10-year survival was 70%. [indiscernible] disease was 17%. There is this 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 4-decades. They have poor outcomes with high rates of end-stage renal disease and mortality rate is 6x that of the general population. This is problem which has not got sorted out here. And I think our understanding of the immune response gave us some hope when this began to be recognized in 20 to 30 years ago, where we recognize that a key problem in the pathogenesis of lupus was the inefficient removal of [indiscernible] material. The whole process of apoptosis was sorted about 40, 50 years ago now by colleagues from Australia, and one from the U.K. And they recognize 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 [indiscernible] get into the circulation in a way which they would not normally do. These fragments have 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, the DNA to roll to [indiscernible], et cetera. We know that there's an enhancing pathway including the PDCs with each of them playing a very important role. And had [indiscernible], 10 years ago to give this sort of talk. I would have said, well, look, we've got all these great drugs coming through. It's all going to be very good in 10 years' time, you might be back and I'll be a very happy man. Well, I'm not a very happy man because unfortunately, we had something like 20 to 30 failed trials in lupus patients using all sorts of approaches, drug which block and alpha drugs which block the link between the antigen [indiscernible] and the T cell. Tocilizumab is not shown to be very successful in treating lupus or even lupus nephritis. We know that the B cells there are several targets. CD20, which I'll be talking about more in just a second, CD19 and even certainly 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 soft differences. So the CD19 molecule is present on pro-B Cell all the way through immature cells, naive B cell, [indiscernible], memory cells, plasmablasts and plasma cells. In contrast, CD20 begins to appear a little bit later at pre-B cell begins to disappear by the time we get to the plasma blasts. The majority of auto-antibodies come out of plasma cells, plasmablasts make a very small amount of antibody by comparison. But if we're going to use B-cell targeting approaches, when should we be doing that? Well, conventionally, we tended to use these approaches when everything else has failed. But my colleague who is based in London took a different approach and 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, and we'll look at her data in just a second. So the notion of using B-cell depletion as a form of treatment for autoimmunity developed through 2 [indiscernible] Cambridge, late 1990s, working principally with rheumatoid arthritis, said, we believe that B cells are important in the development of rheumatoid. This was regarded as a great [indiscernible] at the time. In those days, it was rheumatoid arthritis was a disease of T cells and a disease of cytokines. So the notion that B cells might be important was actually not widely regarded or even taken seriously. But 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. So in 1998, they published their theoretical paper and thank you, Rich. In early part of 1999, they began to treat patients with rheumatoid arthritis with Rituximab, which have become available in 1997, when it was approved by the FDA for the treatment of non-Hodgkin 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. So 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. So we've experienced with around 225 lupus patients given Rituximab. And the combination of Rituximab and cyclophosphamide and steroids as laid out here, was used initially by Edwards in Cambridge because these were the 3 drugs then available to help get rid of B cells. So they were just used a combination, and it seemed to be highly successful. In terms of outcome, we used the BILAG systems, the Bridge lupus assessment system to define disease activity in patients. Full remission, meaning you get rid of all the BILAG-As and Bs, which are the most active parts we saw in 50 patients, we saw in 42%. Partial remission meaning we get rid of some of As and Bs, but not all of them in 47% and no improvement in 11%. So we're showing improvement at around 80% of the patients. And that data has been confirmed by the British House Lupus Group, which looks -- which utilizes the data for all the U.K. centers, well over 1,000 patients and numbers rather similar to that have been reported in the literature. But this is not a cure, that's number one, and it doesn't help everybody. That's number two, and you have to bear that in mind. And our big problem with Rituximab is at least 20% mouse protein. It started life as a mouse protein. It's been humanized, but not completely humanized. So 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 get into them because they're allergic to it or become allergic to it. But let me give you some examples of how this can work. So here's a patient who came to see me in 2003. This is a pretty awful rash, severe subacute cutaneous lupus. Now this is what this patient looked like after, I repeat, after a year on an average of 40 milligrams of steroids, 6 months accompanied by methotrexate, 6 months accompanied [indiscernible] therapy. That's what she looked like afterwards. And she turned on the great bind that I and my colleagues were using B cell depletion approach. She came to me and said, you know I'd like to try this because I'm pretty desperate and 3 to 4 months later after we gave her Rituximab together with cyclophosphamide and steroids, that's what she looked like. And she did very well for 3 years and then she flared. And she came back. It didn't look quite as bad as this, but it wasn't far off. And she said to me, that treatment that you gave me, she said, Rituximab, I liked. The cyclophosphamide, I did not like. I'd be very grateful if you can just give you Rituximab this time around, which we did. And she did just as well with Rituximab on its own. So by and large, these days, we're going to use B cell depletion, we often use Rituximab with a bit of steroids just really to prevent any reactions and often pass on the cyclophosphamide. Now in lupus, the one thing I've learned over the years is just when you think you see the worst, well, you haven't, there is worse to come. And here's a patient who was from Slovenia. She was married to a GI servicemen at Lake Heath based out of Cambridge just outside of Cambridge. And this is what she looked like after 2 months on steroids after 2 months on steroids, pretty awful, as you can see. On her scalp, you can see the loss of hair and the terrible rash. And again, 3 to 4 months after the treatment of B cell depletion, she looked at downside better, as you can see. And it's 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 given to me by Ronald [indiscernible] from Amsterdam, rebiopsy 8 months later after Rituximab, a huge improvement. So we know that they 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 1 week to 4 weeks. Now the disappointment came when there were two big trials of Rituximab. One In non-renal patients, one in renal patients, and those trials conducted about 15 years ago did not meet their endpoints. But as you know very well, it's very frustrating when patients say to you things like Rituximab compared to placebo, no difference. It's never that. It's always lots and lots of background medication plus Rituximab versus lots and lots of background medication plus placebo. And many of those patients in this trial were on very substantial amounts of steroids. They came in on 60 milligrams, 40 milligrams. And although those numbers were reduced, they remained on substantial amount of steroids for months afterwards. So I think that may have had something to do with why these trials didn't work. But even within these failed trials, the devil must be in 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 Rituximab-treated patients, you see a statistically significant difference. If you look at a 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, so they didn't meet statistical significance, but the numbers are not unimpressive to me. And the requirement to start cyclophosphamide, much higher in the placebo group compared to Rituximab group. So there was evidence that this was doing something even if they've not met its endpoint in clinical trials. So my colleague, [indiscernible], as I mentioned, well, if it's going to work at the end of the lupus journey, let's give it at the beginning. So she reported in the [indiscernible] of rheumatic diseases 2013, 50 patients biopsy-proven lupus nephritis, not [indiscernible] 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 2 shots of Rituximab followed by mycophenolate and hydroxychloroquine. And the results are very interesting, low toxicity, and again, 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. And in terms of relapses, they are only beginning to kick in at about 2 years. So this was really pretty successful. Unfortunately, she tried very hard to do a very full-blown trial, investigator-led trial, which is difficult to do. And unfortunately, it failed partly because of problems with 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. But I want to emphasize, of course, that it's not just CD20 that can be blocked successfully, but also if you block anti -- molecule B-cell activating factors. So this was the data from the BLIGAN 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 the -- those patients who improved on the [indiscernible] compared to placebo was not that impressive, about 8%. But if you distinguish the patients in these trials who had a low C3 and the high DNA binding, the delta switches to 20%, which becomes a lot more impressive. So 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. So this is the non-renal patients. They subsequently went on to do a trial in complete -- in renal patients, and you can see the complete renal responses over here, comparing the patients given the Belilumab and the patients given the placebo, and you can see quite an impressive difference, which is sustained over quite long periods of time. So belilumab is now reckoned to improve a lot of at least some patients with nephritis. I will be honest with you and say, I've not been overwhelmingly impressed with belilumab. 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 1/3. You get some benefit in about 1/3 and in about 1/3, it doesn't work. It is very safe, but it is slow in its onset. It can be 3 to 4 months before you begin to see improvement even in patients with joint and skin disease, apart from renal disease. This was the BLISS nephritis trial. And if you compare the patients where the patients with the results favor belilumab compared to those that favor placebo, you can see an obvious difference. So this clearly is doing something. But for my money, it's not the greatest drug really. It's been compared incidentally to focus on the calcineurin inhibitor, and 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 BLISS lupus nephritis trial. So 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 bi-specific approaches, CD20-directed bi-specifics. We have Obinatuzumab, which, as you all know, has met its endpoint in both the secondary -- Phase II and Phase III trial. We have combination attempts combining Rituximab with Benlysta. And of course, we have CAR T cell therapy, which we're going to talk about in just a second. So this was the trial that came out last September, the REGENCY trial, where the Phase III trial met both primary and secondary endpoints, with a complete renal response of 46% versus 33% in the placebo arm, but only Benlysta is approved currently. Nothing else has changed with the treatment of nephritis. That certainly is going to change. And here's some of the data where you compare the complete response over here. And if you look at obinatuzumab compared to placebo, you can see highly statistically significant differences, certainly indicating that obinatuzumab does seem to be, as a fully humanized anti-CD20, a very effective way to go. In terms of combinations of therapy, Rituximab and Benlysta, we have a rather frustrating set of results. The B Cells trial was an investigator-led trial that was done in my start in my center. All of these patients over 52 of them got rituximab, half of them got Benlysta, half of them did not get Benlysta. The primary result was the reduction in antibodies to DNA, and that was encouragingly good. That was statistically significant. But what was very encouraging was a reduction in the flare frequency. On the 26 patients who got Benlysta or Rituximab plus Benlysta, there were 3 flares. In the patients who just got Rituximab without Benlysta, there were 10 flares, and that's 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 a primarily 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. But all of those patients got Benlysta and half of them got Rituximab. So maybe there is something to do with giving Rituximab first, maybe that is more advantageous. But we're left with these rather conflicting data. So we still don't 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 equals for chimeric antigen receptor. Many of you, I'm sure, will know about the procedures, which are somewhat complicated as we see here on the slide, this graphic. Patients clearly have to come into the hospital for at least 1 week or 2, and that adds to the cost of the approach. We now begin to see results coming in from a number of centers. It's early days, I have to stress that, but from the original center, which is called [indiscernible] in [indiscernible], we now have 19 patients have been treated, various groups, including [indiscernible] and Cabaletta have to 4 patients, 6 patients. Novartis have 11 patients, BMS have 10 patients. So 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. So we have to be a little bit careful about how much we read into this, although some of the results, especially those from [indiscernible] itself, 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 counter doctors that has been reckoned to occur in a number of these patients. Efficacy looks pretty impressive using the [indiscernible] criteria, which means that the patients go into complete clinical remission on a reduced dose of steroids down to 5 milligrams of steroids or less and a PGA less than 3. So efficacy looked very good in [indiscernible] and has looked pretty good in some of these other groups, too. So early days, but the numbers is 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 faced as a clinician trying to recruit patients into the [indiscernible] trial has been to persuade the patients to get involved. We've been relatively successful, as I'll show you in a second. We got 5 patients into the study with lupus nephritis. The patients have to be sick, but not very, very sick. They have to have a recent renal biopsy and they've got to want to do it. And it's quite demanding for the patients. And 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 50 patients who have this approach and show you data then. And of course, they wonder what's going to happen in 10 years' time, not just 1 year or 2 years or 3 years. So there are problems. But nevertheless, with the increasing data being put into the literature, we begin to see -- it will be easy to get patients into these studies, I think. And the concept really as put forward by Georg Schett has been a kind of complete resetting of the immune process. And we know that in lupus patients, as I've shown you, there are clearly B cell plasma cells, which are making a whole array of autoantibodies, some of which like antibodies and DNA are clearly directly concerned in the pathology of the disease. And what you're trying to do is to get rid of those cells and to, in sense, reset the immune system and bring back cells which are normal and which are not going to produce those kinds of antibodies. So we start off with the system in the very bad lupus patients where you've got these autoimmune B cells following treatment of anti-CD19 with CAR T cells. We develop a completely different set of cells, naive T cells without the autoimmune B cells being present anymore, which is great. So 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 -- I think 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, which looks like almost anything else. It's the great mimic. It can really generally look like almost anything you get 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 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 to try to sort of 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 Children's Hospital. They come across us as teenagers, and they are might be 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 these patients was very, very selective and he'd be the first person to admit that. He went for patients who are younger, who had their disease for a relatively short period of time, about 3 years. They have aggressive lupus nephritis, which have not responded to lots of other conventional treatment. They were in a very bad way, and they've done spectacularly well. I'm sure you've seen that data. But what would I, as a doctor looking after lots and lots of lupus patients be looking for? Clearly, I would have seen any drug, is it more effective than currently available treatments? Is it safe? That's kind of important. And of course, how much does it cost because the systems are very challenging and very expensive. And in the U.K., we have this organization called NICE or not so NICE as I like to sometimes think of it. And NICE does its job. It was set up by Tony Blair, when he was our Prime Minister 25 years ago. And it was there for one very simple reason to reduce the cost of drugs. And in that sense, it's done a fantastic job. This, for example, costs about 1/3 as much in the U.K. as it does in the United States. And [indiscernible], which costs about $90,000 per patient in the U.S. costs about 1/10 of that in the U.K. because 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. And that's the way that NICE works, and it's done quite well. But it does mean frustratingly, I cannot use Anifrolumab in the U.K. I cannot use it because the company concern are not willing or haven't been willing so far to take it to NICE because they realize the nice will force them to drop the price, and 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 morbidity and mortality still persist. We clearly have a much better understanding of the immunopathology of lupus. And clearly, blocking B cells is these are targeting therapies is addressing more precisely the targets or the routes which lead to lupus. So that's a good thing. But we have clearly reached the limits with conventional treatments, steroids, zypine and [ mycotherena ]. It's never going to get any better. We just can't 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. And I genuinely believe the future is bright. We got the successful result of the trial with Obinatuzumab last September, and [ dapilizumab ] was also approved. We have CAR T cells that we've been discussing. So the future is bright. We just have to get there, and we are not there yet, unfortunately. But 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. So the key inclusion criteria were pretty much as you would expect. The [indiscernible] of lupus is based upon the most recent classification. There have been quite a few over the years. The current one is the combination of ULAR, the European colleagues and the ACR. The patients have to have a positive [indiscernible] antibody and/or DN antibodies or anti-SM. They have to have severe refractory lupus with organ involvement. We exclude patients who have neuropsychiatric disease. We've exclude patients with very severe lupus-like flares. As I said, we've gone in for patients who are sick but not very, very sick. And we've excluded patients, I think, really for simplicity, who have other diseases. I should mention that 1/3 of lupus patients, at least 1/3 are not content to have lupus. They also have a second, third or fourth autoimmune disease. So approximately 10% to 15% of anti-phosphate antibody syndrome, 10% of [indiscernible], 4% of myositis, 4% of diabetes, 10% have hypothyroidism. Lupus comes together as a sort of family of diseases, if you like. So far, we have 6 patients aged between 19 and 50 years, 5 females and 1 male. And I want to emphasize that because it is a difference between the patients reported by Georg Schett with the patients were generally much younger with an average distance from diagnosis to CAR T cell therapy of 3 years. Some of the patients we're going to show 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 had lupus nephritis, mainly with [indiscernible] or diffuse disease, that's Class III, Class IV with 4 of the 6 also having Class 5 disease. Serum creatinine was elevated in the majority of these patients and the GFR was reduced in 4 out of 6 and 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 musculoskeletal and/or dermal manifestations. All of these patients have been tried on B-cell blocking agents with incomplete success or no success whatsoever. And 3 of 6 have been treated with prior [indiscernible] 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. So the cytokine release syndrome was seen in 3 patients out of the 6 that we've treated so far. So the cytokine release syndrome was seen in 3 patients out of the 6 that we treated so far, responded very quickly to tocilizumab. I can tell what has not been seen in this patient, and it will be interesting to see what some of my colleagues think, but that seems to me to be a bit different with the malignancy with the lymphoma literature. There does seem to be 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 would 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, but these patients begin to improve their hemoglobin levels within a few days, but this is not something which lasts for months and months. So that's very good. And of the infections, none of them have been fatal. In terms of the drop in the SLEDAI-2K score, this is a global index score, which has the advantage of simplicity, although it lacks a little bit of depth, but we worry about that just for the moment. And in the main, as you can see, the numbers are dropping from the time it's screening to month 8 in this patient over here. H3, H4, there's a little glitch over here in this particular patient who got a little slicker for a short while, and she got better again. This patient is coming down slightly more slowly as is this patient, but you see they've only been followed for a month. So after about 6 to 8 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 3 months. And remember, these patients had failed almost every other kind of treatment. They'd had mycophenolate, they had rituximab, they had steroids, and within 3 months, 50% of these patients have gone to complete renal response. That is pretty impressive to me, and this 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's almost certainly 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. So 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. So these patients are improving their C3, so 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, but we continue to reduce the steroids and the majority of these patients we have data from 4 of 6 so far, you can see the steroids are dropping to 5 milligrams or less. And just to highlight the point that what is the safe dose of steroids, a lot of work has been done by Michelle Petr in Baltimore, and she reckons that 6 milligrams is about the watershed. So 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 major steroid side effects. So this data is looking very encouraging, too. In terms of how the CAR T cells persist, the data is shown over here, and it's 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, so pretty much gone by month 2. Likewise, in terms of B-cell aplasia, B cells are pretty much disappeared by month 1 and beginning to reestablish themselves in a more healthy format by months 3 and 4. So 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. But these are early days yet, and I'm sure my colleagues will probably want to add a little bit more information to that. But again, it's all going, moving in the right direction. So in terms of conclusions, and I would say that they are tentative conclusions, but I think they're encouraging. Remember, these patients, these 6 patients had exhausted prior therapy options. They had B-cell depleting agents. They have BAF inhibitors. They've had calcineurin inhibitors, they had mycophenolate, they had steroids, 5 of 6 patients had diffuse proliferative disease, which is the worst kind. Kidney function was sufficiently impaired in 4 of the 6. In terms of safety, we've seen no DLTs. We've only seen CRS grade 1 or fever observed in 3 out of 6 patients, no ICANS, transient neutropenia, transient hypertension, which is kind of interesting because I was looking this morning at Schett's data and in his supplementary table, I think #9 in his paper published in New England Journal of Medicine, hypertension doesn't get mentioned at all. I suspect that might relate to the fact that these patients have had their lupus nephritis for much longer and probably got an element of damage. That may be part of the explanation. So in terms of efficacy, all patients have benefited from this treatment, including 3 patients with a complete renal response within 3 months. Complement has normalized. DNA binding has fallen dramatically. Musculoskeletal and dermal manifestations have resolved in all patients by month 3, which is, again, very, very encouraging. And I'll end with a little story just to sort of emphasize this to you. Patient #2 is a patient who I've 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. And she said to me, what she really finds almost magical, that was the word that she used, was that she now wakes up and she had kicked in at about week 4. She said I wake up these days and I look at my hands, I think they don't hurt anymore. They do not hurt anymore, and that's the first time in 20 years. Thanks, Will.

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 6 patients at 50 million cells. And 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's a quantifiable, nice and clear endpoint. The current guidelines, which just have been updated in 2024 for lupus nephritis patients with an NIH Class III or IV define a triple therapy, which includes either a B-cell depleting agent or a calcineurin inhibitor as the standard of care together with mycophenolate plus steroids. So we have the basis of those patients, which we have seen in the first cohort of 6 patients in terms of previous treatment represented in the guidelines. And 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. And those patients have no treatment options, which opens up a path for a potential fast pivotal approval study. And last but not least, we will be learning from this to be started Phase II study of patients with Class III, Class IV lupus nephritis about further development in earlier lines. I think this is alluding to what David shared from his colleague, when do you use a B-cell depleting agent as last line or why not in the front of line. Eventually, this will lead to the fact that after our Phase II 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. And the primary endpoint of this study will be complete renal response. The key secondary endpoint is a DORIS at 6 months. David reminded us that this is a complete renal response in conjunction with the reduction of steroids to 5 milligram or less. And 6 months is also an attractive endpoint. And 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, and we anticipate an enrollment window of 24 months. Again, this is 30 patients, and we have within this and a 1-year follow-up. The Phase II study already has cleared with the FDA. We had a very collaborative discussion with the agency over the month of February, and we have a defined patient population with the clear unmet need. The eligibility will be defined by a panel consisting of a rheumatologist, nephrologist and pathologist. And they will beyond the prior lines of therapy exposure with the B-cell modifying agent and calcineurin inhibitor, also determined based on the histology, the appropriate class association, Grade 3 and 4 in each class lupus nephritis. And we will have an independent review committee, which will determine the complete renal response as a primary endpoint. And this is concluding the discussion on the lupus nephritis.

So 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 and probably a good time -- yes, please, a good time for questions at this point. There's also opportunity if something pops in your mind a bit later on, we could also do that in the second round. But we'd like to sort of kick it off on the Q&A side.

Gil?

Gil Blum from Needham & Company. So maybe the main question as it relates to the pivotal Phase II design. How many patients do you expect are within that category?

You mean how many patients generally fall into the category? Well, in the current study we have enrolled, we have seen that 3 out of 6 patients fall in this category, and this is just with the most recent approval of Voclosporin in the U.K. So I think we will see in the United States and the countries we will enroll a sufficient number of patients with the enrollment period of 24 months.

And for the doctor, thank you for a very elaborate presentation and history lesson. But the main question from us is, who do you think is the ideal candidate for such a complicated treatment?

So the work as such indicates that patients who are a little younger, who have aggressive disease that doesn't respond to conventional treatment, they are kind of the ideal patient. But 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 the data in the 6 patients is more reflective of lupus cohorts as a whole with patients having had their disease for much longer periods of time. And what the patient I was mentioning to you at the end has shown very clearly, is a patient had disease 23 years, she's responded beautifully, really beautifully. And so it's not going to be restricted to that narrow group that Georg Schett went for. Now he's a very open-minded guy, and I've discussed this in some detail. And he said, look, we went for those patients because we wanted to see a good result, obviously. So we went for patients who we thought we would see a good result, and those are the ones that we felt in a sense deserve the treatment because everything else failed, but we also thought or hoped that those were the patients who we see some very good results, which they have done. But you have to broaden that out because there will be plenty of patients who don't come into that ideal category. So the numbers -- it will increase over time.

And last one from us. Any thoughts on that report on hypertension and how you would manage that?

Well, the patients that we've had a problem, we managed in very conventional ways with X Angiotensin X it's been very successful. But it's not been that difficult to control, but you do have to manage it. I don't have a simple explanation why she didn't report that at all. And if you -- I mentioned that in supplementary table, figure 9, it's worth looking at actually because it really shows the blood pressure absolutely flat lining, I know, it's 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, and that may make a problem of hypertension a little worse, but it can be managed in conventional ways.

Matthew Phipps, William Blair. Thanks for all that information, background and data. I guess you said the IND has been cleared by the FDA, but how much of the conversation was on this being able to support accelerated approval versus just the design of the trial and they agree that, that makes sense. And then 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?

So 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. And 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 the 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 6 patients, and we failed with 3 out of 6 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 agents 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 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? And then how many centers do you expect? And is this just a U.S. and Europe-based trial?

This study has a global footprint. We will have 1 or 2 countries which are outside of the United States and Europe. We are continuing our conversation with all agencies about the further designation, which includes omega based designation but these meetings haven't happened yet.

Kelly Shi from Jefferies. My first question is besides the CR rate bar setting at 40%, what are the other like efficacy metrics we could actually focus on to really differentiate CAR-T from other therapies given that Obi also showed, I think, a CR rate at 36% in SLE pivotal trial. Would you actually elaborate on that? That's the first question. And the second one on I, if I'm not mistaken, I feel like the pattern in terms of like the space -- 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 the different CD19 programs by looking at efficacy endpoint and maybe also even the B-cell dynamic?

I can take the first question first. What are the other endpoints we are considering and particularly efficacy endpoints, I think, was your question. So a key secondary endpoint is DORIS and 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, Belilumab, 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 and DORIS is a key secondary endpoint where we are trying to gate towards a low or no steroid use. So that's the key differentiator, I think, to all available biologics. And then 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...

Yes, you probably don't want to get into a great discussion about the different formats by which disease activity is defined because it gets very complicated and it gets very passionate actually. So 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. If 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 than the one who is the same or the one who is worse. So you can get 3 very different kind of clinical situations and you get the same number of points with SLEDAI, which is why I've never been a great fan of SLEDAI. I'm also one of the founding authors of the BILAG, so I have certain problems in this, as you might say. But I do think the BILAG would have given a better differentiation. And to be fair, SLEDAI does actually use the BILAG system. So 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 of those other studies as well as ones that Autolus have been using. So the very fact that 3 of these patients have gone into complete remission, irrespective, frankly, of what the SLEDAI is telling us is very, very important for the reasons that I was saying that renal disease is something you seriously want to avoid in lupus. And if you can get control of that very quickly, that to me outweighs any advantage as to whether SLEDAI was slightly better in one study than another study.

Just 2 quick points, Kelly. 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. So the reference is in the numbers, you cannot really compare those 2. Those are different instances. It will be a 0 for obinutuzumab from where we are, where we're going to be positioned, okay? So this is fundamentally different. The second aspect, I think, goes back to the SLEDAI score and 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. So what you really see and the big difference is really 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. And so 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 II, will all patients be biopsied for renal biopsy confirmation? And then have any of the patients from the Phase I trial fully tapered off their steroids since the data presented today? And then thirdly, Dr. Isenberg, are you -- would you say thus far, would you be willing to use Obe-cel in an outpatient setting, low CRS, no ICANS?

In terms of third question, we have 5 patients, who said, yes, we're happy, we'll do it, they've taken part. We have a number of others who are lining up. I think first question is probably more for Matthias.

Yes. So yes, all patients will be biopsied within a time window of up to 6 months prior to coming on to 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. And then your second question, the steroid taper. The lowest patient right now is on an alternating 2.55 milligrams. So it's somewhere in between 4.75 to 4.5, whatever is currently, but 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 milligram, but we are not guiding to a certain steroid taper. So it's 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 in the states that the renal physicians are very, very unkeen to reduce the steroids too quickly, but the Voclosporin study show that you can get down to 5 milligrams or less within about 3 months. And that's in even renal. So I think that's given a lot of people much more encouragement that you can get with those steroids right down. And as I was saying before, if you get below 5, your chances of getting steroid side effects begin to disappear seriously.

This is Karina from Truist. I had a question. You guys said CAR-T persistence of 3 months. How does this compare to other CAR-T clears in autoimmune? And how can this translate further into efficacy?

So the average was 3 months. I think the shortest was just 2 months and then one is out 6 months. I think right now, there is some difference, obviously, with the different doses and so far, we are exactly where we would like to be and where we feel we are comparing to others.

So 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, but be mindful, this is a logarithmic scale. So if this were linear, it's a sharp peak. But 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. So this is why you see the depiction and some of the things that you may have seen in other publications to actually not use logarithmic scales, which is, creates a bit of a confusion and is different from what you would do in the hemato-oncology side. But it's a very comparable. What's most important about those curves is the consistency of the curves. They're -- all these curves are very 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. And in terms of the peak, we're going to -- we're getting to if we express it the same way that it would have been expressed in Schett's trial is 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 hemato-oncology as well.

Yanan Zhu, Wells Fargo. Two questions. One, on dose level 2, what's your expectation for efficacy and safety? Is there room for additional efficacy do you feel? And 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 level of the upper level of normal. Do we see an even deeper reset? We had 1 patient, patient #2, 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, but this is speculation, and 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, but that's a kind of worrying time. So that occurs relatively soon. It's usually over in just a matter of a few days. But I think in that particular period, it will be a very good idea to keep a patient isolated out of the public's way.

Got it. And then a question on the role of SLEDAI in the pivotal trial. Looking from the first 6 patients, the SLEDAI, especially the renal component doesn't necessarily correlate with the complete response. You have patients who at month 1, patient 5 still have roughly the same SLEDAI score, but he had a complete renal response. How do we think about SLEDAI when you are working on the pivotal and presenting the pivotal data?

Yes. Why don't you go.

Can I say -- I look at B-cell depletion. And if you ask Schett what he thinks about CAR-T cells, he will say to you, it's expensive B-cell depletion. We published and BILAG has published, there's 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 hemoglobin, low platelets within 1 week to 3 or 4 weeks. It's quite dramatic actually. You see improvements in arthritis, in skin rashes in 1 to 2 months. And in my experience in B-cell depletion, it's often 2 or 3 months or 3 to 4 months before you begin to see really good renal responses. So it may be that those reports that you are concerned 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. So the data that we have currently or the company has currently is still relatively premature, but it's -- the vibe is clearly very good. It's all going in the right direction, and I think that's very encouraging. I think at month 6, something like that, I would be very disappointed given that if we won't see even more spectacular results.

Just building on this, the Phase II 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. So this is within the NHA scoring its in probably a little bit detail. But the importance is there is activity in terms of lupus inflammation in the kidney, but 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 urinary response, which is the primary endpoint of the second -- of the Phase II study is very well describing the kidney function and the protein excretion. The SLEDAI score, which is an activity score as for the kidney 4 dimension, which is casts, hematuria, pyuria and proteinuria. But for example, if you are a woman who is menstruating, you could have hematuria, which gives you 4 points on the SLEDAI score, even though it doesn't relate anything to the activity and the inflammation in the kidney. So that's why the SLEDAI score is a more imprecise description of what's truly going on in the kidney than, for example, the renal response, complete response scoring.

It's one of the key reasons also why we're going in lupus nephritis because there's actually a clear endpoint. One of the problems with the composite endpoint is the judgment involved, and that creates part of the challenges. And SLEDAI particularly has quite a bit of challenges.

We have one question from the webcast that Olivia will read.

Yes. So the question is from Rajan Sharma at Goldman Sachs, and he asks, assuming you achieve the target time lines for Phase II, when are you expecting first clinical data?

When are we expecting the first clinical data? So we have a follow-up time of 1 year after. If we enroll over 2 years, we would expect the first clinical data. There is no planned interim analysis, so probably in the third year.

We'll come back to questions at the end of the presentation.

Okay. Very good. Thank you very much.

And then it's my great pleasure to introduce our next invited speaker, Professor Mark Freedman from the University of Ottawa. Professor Freedman is an international renowned neurologist and multiple sclerosis expert. He is a 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 of the Canadian Bone Marrow Transplant Study in multiple sclerosis and the Canadian Mesenchymal Stem Cell Transplantation and Multiple Sclerosis Study, 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. And we are very glad that his past career ambition as a race car driver didn't come through, and 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. But in chatting with David just prior to the 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. So 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. So 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. So 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. And within various countries, the prevalence can be quite high. We have a very high prevalence in Canada. The reason is 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. And if you're Scandinavian, you sort of seek out temperate climates similar to your own, so you don't see very many Swedes in Jamaica and other places like that. So there's probably something to do with the genetic diaspora. There may be some involvement in vitamin D and lack of sun exposure. But probably the most interesting and evolving possibility and factor is the Epstein-Barr virus. And that's where it comes into meet the B-cell story. And how the B cells are involved in MS is very different than what you've heard about in lupus. So 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, 2 to 3x more women than men. But in the more progressive forms of the disease, at least from the descriptive nature, the male-female ratios tends to even out. We don't see much in the way of mortality, although the actuaries 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, and that's where I'll come back to. It's characterized at least early on by an inflammatory disease, and I'll get into that a little bit more carefully. What makes it, I'm going to say, a cleaner disease than lupus is it affects one organ, the central nervous system. That's it. We do not have extra CNS manifestations. You don't get lung disease and kidney disease and joint disease and skin disease. You don't get anything else. This is a disease that affects only central nervous system myelin. And myelin is present in the peripheral nerves as well, but it's different. So this is 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. And then if you look pathologically, you see the hallmark lesion, which is a perivenular inflammatory network of cells, often lymphocytes and monocytes and then 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, okay? These focal MS lesions, there's the perivenular infiltrate, so it's labeled as #1 here. What is curious though, and as time goes on, we tend to see these nests of cells that are situated in the meninges of the brain, that's #2, as you see here. And they sort of resemble what you might see in the lymph node as a lymphoid-like follicle. And when you look at those follicles more carefully, they're mostly B cells. So 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, and that's labeled, I think, number three, over there on the far right. So as we can focus down on a lesion that has developed early on, and now we're talking about it slowly evolving and slow means slow. This is months to years before you can actually measure the expansion of these lesions, but it can be done very sophisticatedly using imaging techniques, and then you've got this process that's undergoing the whole thing called diffuse gliosis, and 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, and that's a measure of that scarring process, which takes place once there's no more healing that can take -- that can ensue. And then 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. So there's a natural rate of atrophy of our brain, and that is always in the background of whatever we're going to measure as atrophy may be due to the disease. So just to reiterate and go through this, we have these white matter lesions. This is -- white matter is characterized by a lot of myelin. That's why it's called white matter, but there's white matter in the gray matter just to make life a little bit more confusing. But it's there everywhere, but that's where the myelin is. And you get an array of cells in these perivenular infiltrates that are mostly T cells, but there's also some B cells and plasma cells. And when you see these focal lesions, at least acutely, they light up with die on the MRI. That's where the gadolinium enhancing lesion is used. You have these slowly expanding lesions, which evolve from those early white matter lesions and the concentration of the cells is less and you get a little bit more of the microglial penetration into these slowly expanding lesions. And they are clinically associated with what we measure as disability, and I'll come back to how we do that in a moment. Then 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. And they are made up of mostly the B cells. And interestingly, probably a lot of the B cells are actually still EBV positive because that's where EBV lives in these -- in the B cells. And then the reactive microglia astrocytes is an indication of the scarring process, and 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, but 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. And in fact, there's a seminal paper due out imminently in the Lancet Neurology, which is redefining the diagnosis of MS. And 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. So above the clinical threshold, the patient may have symptoms, you're the doctor, you could see signs. The first time demyelination crosses that threshold, we call that the clinically isolated syndrome. But if you look to the left, under the threshold, there was some demyelination that took place that wasn't clinically evident, and that's picked up via MRI. So we know that the disease has started beforehand. So we know that the disease has started beforehand. I'm not sure what's happening here. We got a bird. Okay. Oops. Is that water?

Apologies for those on the webcast, we need a brief pause here in the presentation. We'll return momentarily. [Technical Difficulty] For those on the webcast, please continue to hold and thank you for your patience. We have a water leak here in the presentation room that we're trying to resolve. And we will hopefully be back shortly. Thank you. Okay. I think we're going to try to get back on track here. Thank you for your patience. Apologies about that.

All right. Good. Welcome back, everybody. This was more excitement than we expected. It's not quite clear. So for those of you who are not in the room, one side of the room got flooded. And first, we thought there was just some of the people closer to the event were a bit getting itchy, but actually, it was a lot of water coming down. We are not quite sure whether we're going to have life jackets or floaties, but you might actually going to look out for those. But for the time being, we're going to get back together, and we're going to hand over back to Mark Freedman, who was on quite a roll. And I'm sure we're continuing as if nothing would have happened. Thank you.

Is this working?

Yes.

Okay. So we'll come back to diagnosing MS and the change in criteria. So I will show you on this graph that demyelination comes and goes. And the first time we're aware of it, we call that the clinically isolated syndrome. But to the left of that, there's demyelination that's under the clinical threshold that we pick up by MRI. The McDonald's criteria, which is the -- 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, as depicted here, compared to the original Poser criteria, which we're going back into the '80s, where you needed at least 2 attacks to call it MS. That led to great delays in making the diagnosis. And of course, now that we have treatments, the delay in the diagnosis also delay treatment, sometimes 5 to 10 years. So now we have this window where we diagnosed MS that has expanded over the years to include the CIS. And what you'll learn about later this year is the window has now completely expanded. And we are now able with fair accuracy to make a diagnosis solely based on MRI. And if you -- MRI meets that criteria, the patient can be diagnosed with MS without ever having had a symptom. And 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 a progressive phase. And 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're all identical. The only difference is whether the patient has had relapses to start their course or not. We don't think that's necessarily relevant, as I'll show you in a moment, because the activity can be just on MRI alone, so the patient doesn't have to have clinical relapses. There's 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. And if you look immunologically at what's going on, there are subtle but no great differences between these groups of patients. So we think of progressive disease as one entity. We do the testing. The testing is to really reinforce the diagnosis and differentiated 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 it's not MS. And so we want to be able to distinguish these conditions. So 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, but that's pretty well gone now. If you don't 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, and we use the spinal fluid it's really important because there is this hallmark, which we've 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 -- are really an Enigma. It's the hallmark of the disease. It's 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. But 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 and they're certainly not directed against myelin. So for years, people have been trying to figure out what that is, and 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 neuro sarcoidosis. Another condition, I think you guys look after there, David, I don't know if you do [indiscernible] but the rheumatologists sometimes help us with neuro sarcoidosis. So it's more of a marker of intrathecal inside the CNS activation. And as such, if you don't have any other reason for it, it's probably MS. So I'd like to look at this to try to put it in perspective of where we're thinking about treating these patients. So here's that clinical threshold again. There is the demyelination. We talked about the first attack. And what you should know is that underlying this, and this has been seen right from the earliest patient is this axonal loss that could be characterized by these so-called axonal button, as you see here on the far right, labeled with neurofilaments. And Bruce Trapp in a seminal paper ages ago, but some graduate students to, I don't know how he course them to sit in front of a microscope and literally count these axonal buttons in various types of patients. And what they looked at is this is not a chronic conditions. This is not something that occurs late in the disease. It actually occurs very early, as that histogram shows you, it's in an active plaque, which tends to occur at the earliest times of the disease. So that green line that I'm depicting here that starts well below the clinical threshold, we were not aware of that and 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're able to repair, they're able to get around things, tracks can take up new tasks. So we call that the plasticity of the nervous system. And it's not until you surpass all those compensatory mechanisms that the green line crosses the red line and suddenly you're aware of this progression. But as I'll show you in a moment, that's not true because it actually can be exposed with therapy. So therapy is directed at what we think is driving this, and that's that curve now of inflammation that comes and goes probably peak sometime in the midst of this relapsing remitting phase. That's the focal inflammatory components of the disease and starts to dissipate while we're into the secondary progressive phase. So if we're going to target that inflammation, it makes sense to target it at a time when it's prevalent. And that's where 95% of our therapies are going today in the relapsing form. They're targeting this inflammation. And 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. So when we think about therapy, we think about where this patient is in the window and 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. And there are ways to figure all this out, and I'll just touch on that in a moment. But 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. And then 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 so you don't see new MRI lesions, you don't see attacks. But all of a sudden, those patients are getting worse. And this is what has been referred to as PIRA, progression independent of relapse activity, it was now exposed by eliminating the relapses and then we saw this progression. And that was backed up by a lot of pathology, and I'm not going to go into that. But our historical perception of this disease is that you had this inflammation, you had a secondary stage that the inflammation die down and then you enter a progressive phase, and that has yielded to a new idea that we are looking at 2 parallel pathways here. Sorry about the -- this is the computer doing this. But we have a peripheral component, and we have a centralized compartmentalized type of inflammation and 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. So this is where we are coming into, moving from the left into the right. And to the right side there is where we start to see the physical worsening, the cognitive involvement and then 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 that -- this is the outcome measure that is going to be looked at. So 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, this is fully expanding lesions and something else that we call PRLs, 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 more a little bit more prominent. The axonal damage dominates the clinical picture and 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 and people spend various times at various levels, but there's important cutoffs at about 3. Most of you seeing somebody who is 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. And an 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, and it's an objective scale because it's measured by the neurologists as opposed to the subjective PROs that are used in a lot of other conditions. Okay. So how do you figure out what drug to use? We have to try to figure out whether the patient is going to have a poor prognostic? I know David, you asked me this earlier. So just throwing this back at you. These are the types of things that we would like a checklist go, yes, no, yes, no some things you can check off here that we can't change, like, well, I shouldn't say that. I was going to say gender, but at least biologically gender. Age, you can't do anything with and sometimes the family history is there for higher incidents. But there are other factors that can play a role here and all of those are considered. And if you think the patient has a more aggressive form of disease, you use a more aggressive treatment. There really is no idea of what mechanism is driving the disease at any given time. So when you think about what -- and I get this from companies all the time. Who is 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 and they say, "Oh, if you have this marker, this is a 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. And right now, it's a bit of trial and error. I would love to know which of these mechanisms is dominating in any given time. And it's 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 conditions, say, being driven by IL-6. And then you can come in with an IL-6 inhibitor. Except 6 months later, it may have switched to a different mechanism, and you're going to lose on an IL-6 inhibitor. So this is just a quick showing of the different drugs that we have that work at different stages. I like to group these into 3 categories when people ask me about treatment. We had for a long time, the so-called immunomodulators. Those are the safest drugs for MS. They don't 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. But if the disease escapes this, then 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. So 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. But you're not really doing anything to the underlying disease, and that leads to problems should you have to suddenly stop them. And one is natalizumab, that's an anti-adhesion molecule an antibody, which is very potent, but brought with problems because it's probably the #1 producer of PML today, a disease, which is much, much worse than MS. Then you have this whole class of drugs called the S1P receptor agonist. They also can cause a PML and a problem if you suddenly stop them. So they're used in a certain type of patient, but we know it's not a long-lived therapy. And then 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 Cladribine and Alemtuzumab 2 to the 3 or 4 now, we have anti-CD20 molecules and then ultimately to a bone marrow transplant, which can be done in patients who have very aggressive disease. How do we know you're winning this battle? This is an important one. We don't have something like a creatinine to measure whether or not your kidney is working. So it's kind of like evolving. Patients are always saying I'm taking this stuff and I'm having the problems, but how do I know I'm winning? Well, you haven't had an attack. Your neurological exam hasn't changed. Your MRI hasn't shown new lesions. But I already told you as the disease progresses, you get fewer MRI lesions and you get fewer attacks. So if you're using that as an outcome measure you're in trouble, because one day, your patients are going to come in drag in their leg going, you told me, this is working. I'm not having any attacks, so I'm not having any new MRI lesions, but my leg is getting weaker, and it's because it's not dealing with the PIRA, it's not dealing with progressive nature. So it would be nice to have a biomarker. And now we're getting a few of these that are at least fluid-based that help us to know that something is working. So there's all these MRI parameters that I won't get into. One of the conditions is that you do it often. And it's just not feasible in some places to do MRIs 3 or 4 times a year. It gets costly and in this country, what I've noticed is depending on who's your managed care group, they will allow it or they won't allow it. And so it's becoming a real problem in monitoring for treatment response. So 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 can't see anything. So now there are these automated programs that can look at MRI to MRI and tell you whether there -- that lesion has gotten bigger or smaller or whether there's like a degree of atrophy. But the error in a single patient is so high that it's 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 in the Danish I have just published this. And 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 is clinically happening to them but they develop 1, 2, 3 or 4 new lesions and you don't react to that, meaning move up to something more aggressive, what happens to them? And so at the top, if you have 1 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 4 years. But if you have 2 or more, if you don't 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. So silent MRI lesions in someone who's on a therapy are, in fact, important. And that's what the message was from this. So as I alluded to, there's no single metric that is useful, but we look at a few things. And then 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. PRLs are seen, the more commonly seen in the progressive, but they can be seen at any stage of the disease, but they tend to be more prominent and stay there as the disease progresses, and 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. But in Canada, they have been approved. And they are part of the patient's clinical record, and we use them routinely to manage the patients. There's -- 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. And I can tell you that the 2 that I'll talk about are really meeting those objectives. So 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. And if your biomarker does not go down, that's kind of a, I guess, an idea that the drug is not working as well as it should. And in the rheumatology world they've used these nonspecific markers have ESR and CRP to measure inflammation and they look for -- see that these things go down with their treatment. Well, this is now the equivalent of that. And we have 2. 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. So the higher the neurofilament is to baseline, the better the chances that those patients are going to have a more aggressive form of MS. And 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. And you can see that the more GFAP, the higher the GFAP score. This is the first graph, has confirmed disability worsening, so that's over the ensuing few years. It correlates with both gray and white matter atrophy, so you're getting an idea that this biomarker could change if you have an effective therapy that can address those things, but we have yet to find one that can do that. I just pulled this out because this is actual data from the 2 anti-CD20 trials using Ocrelizumab. On the left, was relapsing, remitting on the right was the primary progressive. And what I'm pointing out here is this arrow, right? So the arrow at the bottom at 48, that's where they started to measure the serum neurofilament light chain. So after a year of therapy on an anti-CD20, which I already told you, it races those relapses and reduces them to minimal and reduces new lesion formation by 90% to 95%. Despite that, the red curve, if you have a high NFL, you're getting worse. So you haven'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 and the same is true for the progressive patients. So 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. And we've yet to develop a therapy that really effectively slows it or stops it. And as the bottom things talked about, we're learning about the biological mechanisms, but we need something that will address that compartmentalized inflammation better. So where does the CAR T maybe play a role here. Well, unlike lupus, the antibody is unknown in MS. And the idea is not to reduce antibody formation, the antibodies are not as far as we know, pathological in this condition, whereas something like MOGAD, it is. So the B cell role in MS is thought to actually play a very important role in stimulating the T cells. So B cells can present antigens to T cells and if we think that is the major mechanism that's driving this, and as long as you have this unchecked group of B cells that are constantly presenting antigens to the T cell you're going to have perpetuation of the disease. They also encourage the development of the microglia and the microglia are good and bad, but the bad kind of microglia are the ones that I think are driving this slowly expanding lesions and the PRLs that we tend to see. So here's a role for the CAR T because although these monoclonals, the anti-CD20s, they work outside, a few of them listed here. They work outside and there's another one you have in the United States called [indiscernible], that's should be added to there, sort of glyco-engineered rituximab. They don't go into the brain, they're too big. So 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. So 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 tolebrutinib, someone is going to probably raise that question. That's a drug that just got study released in nonactive 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. And then that's for a subgroup of patients. That's the only BTKi that we know of that has been effective. There are 2 other ones at least that have been tested that were negative. But we really need something that can get into the brain and deal with this disease that's trapped behind the blood-brain barrier, and we still are in need of repair drugs, something that will repair myelin or at least encourage it. And those trials are ongoing as well, but we've yet to find anything. Sorry, I will stop there. And let's see, 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, and we are planning to do a heavy biomarker and imaging supported study that is evaluating up to 3 dose levels in patients with progressive multiple sclerosis. And this will then inform our dose expansion into Phase 2 and most likely selective study, which will be pivotal, either based on a Phase 2 or Phase 3 randomized design. [ Jonathan Wilmer ], who sits there behind David, is the neurologist on our team, and he leads this dose escalation study. Patients with progressive disease will be enrolled. There is a standard Flu cyclophosphamide lymphodepletion and then we are escalating dose levels starting with 100 million cells up to potentially 400 million cells if safety permits. And I mentioned already that this is a study that is heavily building on translational work, so 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 we 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. On a shorter term, we are looking at fluid and imaging biomarkers that may support the evidence for the biological effect, particularly reduction of CNS inflammation. And then we are hoping to see a reduction of oligoclonal bands, and Professor Freedman has told you that this is typically what stays with you despite of therapy and only change in oligoclonal bands has been seen so far in patients who received a bone marrow transplant. So we're hoping that we are able in conjunction with other biomarkers to identify a signature, which tells us that we want to something to take it into Phase II development. I'm going to summarize very briefly for you the section of our path into autoimmune diseases. So 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 II SL3 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, and it opens up the opportunity for future expansions. Future expansions, both in earlier lines of lupus nephritis, but also other adjacent diseases affecting the kidney, such as membranous glomerulonephritis and other immune globulin driven and B cell-driven autoimmune diseases of the kidney. And 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. And differentiated safety profile of Obe-cel, we believe, sets us apart from other CD19 CAR-T cells to do so. Insights will form 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, and it also serves as springboard how we can expand it to potentially other autoimmune neurological diseases. And 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 I wanted to highlight. There's obviously a number of studies that are ongoing or are prepared to get started in our collaboration with University College in 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 C19 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, and we're hopeful that we're going to get an update on that study towards the end of the year or early next year. And then 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. So let me briefly talk about the AUTO8 approach in plasma cell diseases. Obviously, you remember, we have treated a range of multiple myeloma patients, seen very nice levels of activity to the safety profile. And based on that decided to move into light chain amyloidosis again, a setting where there's a very significant medical need, and we believe that the product has an interesting positioning that we are obviously looking to sort of work out. So this is ongoing and is again sort of expanding the collaboration that we're having with University College. So 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. And we're also 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 I study, the CARLYSLE study, that was represented today by David. And we expect to add more patients. You've heard, obviously, Matthias talked about the fact, we're going to push the dose to the next level. We want to see whether there's any change in the behavior of the product. There may be no change, but that's what we want to figure out. But also, we're planning to include patients that are younger patients in this study because obviously, there is a very significant medical need for younger patients, and 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. And so we're looking to enroll some of those patients get an understanding what we can do for them. And then obviously, we're starting 2 studies, the pivotal study that we discussed today in SLE and the Phase I study in multiple sclerosis. We did talk about the fact that obviously we're well capitalized and we're in a good position to execute on these plans. So 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. And I'm happy to open up for Q&A.

Daina Graybosch from Leerink Partners. I have a question on MS. I wonder if you considered directly delivering cells to the brain as we've seen in oncology from Stanford, for instance, that can be quite successful and you can do it without [ Cy Flu ], both maybe for proof of concept in Phase I. And then is that at all applicable commercially the trade off of direct delivery versus no lymphodepletion?

So we have some experience in delivering actually the product intrathecally. And you may remember that we had conducted also in collaboration with UCL, primary lymphoma study. And we were looking at both systemic delivery as well as intrathecal delivery. And as it turned out, the systemic delivery was very efficacious. There was no benefit and actually taken the extra burden of actually directly administering. One of the interesting things, obviously, where the CAR T cells is that they are actually very well capable of crossing the blood-brain barrier. And that is obviously one of the key things and key differentiators to other types of therapeutic approaches. So 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. But obviously, it's a lot more intrusive as a therapeutic routes and administration route, and 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. And there is some suggestion that these cells may work. But it's just not a feasible project, I think, in large groups of patients. We also don't know how many times you'd have to give it, and it's just not a great way of administering a treatment. I can tell you that they didn't try putting monoclonal straight into the spinal fluid, they've tried to putting an anti-CD20 in it and didn't work. So I think there's something about the cell itself that can actually do things that fluid types of treatments cannot. And that's where I think the CAR T may have an advantage.

Salim Syed from Mizuho. Just, I know you spoke about the progressive multiple sclerosis. But we've seen this with other companies, they've always started with progressive multiple sclerosis and then started talking about later on in their story line relapsed/refractory being the bigger -- being the bigger market here. Just curious what your thoughts are for this therapy in relapsed/refractory multiple sclerosis?

Are you directing that to me?

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 who's big side effect we worry about his ICANS, which is, in a sense, an inflammatory reaction that takes place in the central nervous system. The propensity or -- is that maybe that these patients will get worse or that the CAR T will excite some of this inflammation. So we -- I think it really needs some Phase I data in patients who have early inflammation to know that they're safe. Why would I want to do that? As I showed you, that PIRA, that starts in a very early phase. So 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 for reaching that stage? But you can't go there while the inflammation is going. So there's 2 thoughts, either you do it in conjunction with the therapies such as an anti-CD20 which will work and cut down the inflammation and use the CAR T as an adjunct. But you're muddying the waters there, you're 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. But 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. So it opens the entire spectrum for treatment.

Okay. And just one for Dr. Isenberg. Just curious to get your thoughts on NK versus T cell for your practice?

You talking about T cell engages?

Yes, NK versus CAR T for lupus.

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, but which way it's going to go. I don't think anybody can predict accurately.

Well, 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 taking about meaningful inputs in trials as a whole?

Specifically as you move to earlier lines and the larger SLE population, what do you think is a good...

Well, we touched on what we're discussing at the question of withdrawal of other drugs. And that's 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's, to me, as a clinician, we've seen the damage of steroids causes over the years. That's a very, very big plus. Likewise, if can stop Mycophenolate, if you can stop Cyclophosphamide, whatever was the patients are taking, that's very good because as we were discussing, one of the principal causes of death in Lupus is not disease activity, it's infection, and that relates almost entirely to the amount of immune suppression the patients have had. So if you could stop those drugs which cause that, that's clearly going to be a good thing.

And do you think the regulators are amenable to an endpoint like that?

Could be. I can't say definite. I just don't know.

Just adding on to this, I mean, right now, what you see many of the trials, which are randomized trials are the additional standard of care to evaluate the incremental benefit versus standard of care. So by nature, they include [ glucocorticoid steroids] or mycophenolate. I think hopefully, that this study, the Phase II 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 glucocorticoid steroids. So I think there is a path.

And I have 1 question for -- to both doctors. So curious, would you anticipate CD19 and CD20 as a different targeting strategy? Could it differentiate bringing treatment outcome in multiple sclerosis? Or in another word, what have been the discoveries on the cell marker status for the B cell population in MS? Maybe some like subset population like the B cells in the chronic active lesions. What's the difference on these 2 different targets? And also broadly, how does the cell marker different in MS versus other autoimmune disease like SLE?

If I understand the question, it's a subset of the B cell that you're thinking of. So they really haven't identified that. And 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, atacicept for one has actually made patients worse. And we were still trying to get our head around that because if you address the later B cell to the CD19 and CD20, you clearly have a benefit. So 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. And they do have a specific phenotype. And the drugs that have worked best in MS seem to be able to reduce B-cell memory cells. So we don't get that big reset that David was talking about in MS. We have to tread cautiously because at the same time, there's normal immune homeostasis that's going on in these patients. And this is our concern is that long-term B-cell suppression is not going to be viable. And at some point, you're going to need to stop it after you gain some benefits. But you're still not getting at what's going on behind the blood-brain barrier. There's another thought that those are EBV reactive B cells that have not been able to be targeted. And 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 EBV reactive B cells, but it didn't work. Either because they didn't penetrate or because it wasn't the dominant force at the time. But EBV is still front and center in trying to understand what's triggering ongoing disease in MS.

So just a little about the lupus context. So obviously, rituximab is pretty good at getting rid of the CD20 positive B cells. But it's believed that tissue based B cells are -- is likely to be CD20 negative for CD19 positive, which is why the CAR T cell approach in theory should be better.

Matthew Phipps, William Blair again. When you think about Progressive MS, do you have any sense or is anything you can look at for how much of a reduction in oligoclonal bands might actually be a marker for who will look to right benefit? Is there some cutoff? Do you want to see complete resolution? And then, I guess, similarly, if you're following like single-arm patients, how long do you have to see kind of stable EDSS until you feel confident that there really is a stable patient now versus somebody that is still kind of on a progressive decline?

Those are great questions, and 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 can see that change and that was just measuring the crude EDSS within a year, especially in the high neurofilament group. So 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. And then there's a subset of the patients who clearly are driving this disease. And if you're lucky, you have the power to see the difference between the treatment and the placebo. But 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 PRLs or already been able to show SELs and say, a lead-in of 6 months. Those are the patients who, at least in the studies that we've looked at are most likely going to progress in the first 6 months to a year. And now you have the power to see the difference between a therapy that may or may not work. So on the clinical side, I think we're there -- now I forgot your first question. Yes. Okay. So this is a problem. I think -- well, it's twofold. One is it really -- 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. As you can still measure it in some of our bone marrow transplant patients, oligoclonal bands were no longer evident in a year or 2. But their IgG levels also drops. And I've asked the question repeatedly from people to the biochemists, how much do you need on an Agarose gel or an immuno blot to actually resolve the bands. And nobody has done that experiment. So are they below the level of detection or are they absent? I think it's smooth because if you can eliminate or lower them below the level of detection, it's telling you you've got at those B cells that are behind the blood-brain barrier. And so it's just really a marker of have you been there or not. And the only other thing that has shown that just recently is actually cladribine. And we know that cladribine gets somewhat into the brain. It's a treatment that's used for MS. And they just presented data, I think, at the American Academy and the [indiscernible] 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 Baker from Redburn. It's 2 questions. The first is, do you think a lack of brain penetration explain the failure of high-dose ocrelizumab to show a benefit over a regular dose? And therefore, is CAR T superiority compared to ocrelizumab a plausible outcome? And the second question is on safety, Dr. Freedman said, in late last year, his biggest concern was brain toxicity in this setting due to existing information 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. Do you think the lack of brain penetration explains the failure of high-dose ocrelizumab to show a benefit over regular dose? And as CAR-T superiority that for a plausible proposal outcome?

Yes, yes. So let me answer that first. Ocrelizumab does not get into the brain. 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. So 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. And the second question was not related, but...

It was about safety. So last year, the safety about -- the concern about brain toxicity and existing information. Has that changed in the last year?

You mean the toxicity with CAR T?

He didn't say. I assume, yes, general toxicity of treatments in MS...

We don't give brain toxicity with any of the known treatments of MS. It's -- the concern is with regards to the CAR-T that -- and the [ iCAD ], 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 don't know.

Okay. And then there's one just from Jacob from KBC Securities. It's about lupus. So you 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 a potential label as well? Or could there be some flexibility regarding the need for biopsy as we've seen with recent approvals in other conditions such as NASH?

So it's a little bit premature to determine what the label will be, but it's not necessarily mandatory that the biopsy will be included in the label. It is more likely that a certain subclass of -- based on the NIH will be included in the label that lupus nephritis with patients of such class. But it's not necessarily determined that this will be based on a biopsy.

[indiscernible] question on MS, 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 [indiscernible] cell therapy in [indiscernible] and sorry, also for T cell depletion therapy, is there risk for PML...

I'll answer the second one first. So there have been cases of PML with anti-CD20 therapy alone in MS that wasn't carryover from some of the anti-trafficking drugs. But they tended to occur in really very old patients with numerous comorbidities. It's a very, very rare phenomenon. And I don't think that's been seen as yet with the CAR T at least -- and its early infancy in autoimmune disease like MS. The lymphoma patients, of course, that are at risk of PML with all the other stuff that they've been taking for a while. So that's just sort of muddies the waters for that. The bar for success can easily, I think, be defined. And the natural history for these patients is to worsen. So their lack of worsening is an important outcome. Are they going to improve? We see this in our early phases of a relapsing disease that happened in our bone marrow transplant patients, but similar to what Dave is doing with the lupus patients, they're younger, and they're less -- they're going into their disease like 5 years or something like that. So they have a better chance for improvement. But in these progressive patients, pretty unlikely they're going to improve. But if you have 2 groups and one is clearly worsening and the other one is not, and they received a therapy. That's a game, that's a winner. And you can define that on your scales. And now you can back it up with some imaging markers and some blood biomarkers that all go along with that.

Great. Could I just -- I don't know about PML in the lupus context. So I've seen that once in a long career, and that was a patient given [ azofibrinin and steroids ] didn't have any kind of rituximab or indeed any other kind of biologic drug. I've also seen a rheumatoid patient given methotrexate and steroids. So there have been several big reviews and they're literally looking to see whether they could tie rituximab in B cell depletion to PML, which failed to demonstrate it. Once, study goes back to 2015, 2017 published arthritis and rheumatism if you want to look them up or I can send you the references afterwards, but it seems that it's immunosuppression however that is achieved by conventional drugs as well as by B cell depletion, which could theoretically do it. But as Mark said, it's mighty rare, mighty rare.

Got it. Dr. Isenberg, 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, but I was wondering because that one debate is bispecific antibody or 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 2 modalities?

Well, it looks a very good question. But as I was saying to the question before, in the end, the proof of pudding will be in the eating, 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. But you're right. You do get antibodies to rituximab that can certainly happen. But what's going to happen with the T cell engagers? We're going to have to wait and see.

[indiscernible]. Dr. Freedman, you mentioned previously, I think it was -- you were talking about Atara's EBV targeting immunotherapy, that last year. And I think they were able to show that they crossed the blood-brain barrier. So just can you share what do you think went wrong there? And do they also target the T cell component?

I missed the first half. Sorry.

I think you mentioned Atara's EBV program, immunotherapy that we had last year? Or was it something else?

[indiscernible] cell program from 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 III. I don't know. I don't -- maybe John can tell you more about that. We don't know that -- I don't know if they got into the brain. They did? Okay.

So Jonathan ran the program that you just asked about. This is why the question whether he can answer it now, but it looks like he's comfortable saying that they did get there.

Although we haven't seen any publications right?

All right. So first of all, thank you very much for your patience, your interest. I wanted to thank our 2 phenomenal speakers, David, Mark, phenomenal backgrounds and I think really, really helpful to get a context in these diseases, which is challenging. They're complex. They're difficult to actually see and they change a lot every time. So that's incredibly helpful. I would also like to thank Amanda, Olivia and Susan for putting the event together. And for the staff, we actually stopped, they have a pretty impressive flooding of the room. So with that, I'd like to always say thank you all for coming. We'll keep you updated. We're going to have early May, our Q1 update. We'll talk about sales at that point. I know that was one of the questions. I appreciate you were not asking us today. But 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.