Hello, ladies and gentlemen, and welcome to this Autolus event to discuss the new opportunity for obe-cel and SLE. As a reminder, this conference call is being recorded. I would now like to turn the conference over to your host, Julia Wilson. Please go ahead.
Thank you, Gigi. Good morning or good afternoon, everyone, and thank you for joining us to take part in today's SLE call. I am Julia Wilson, Communications Consultant for Autolus. With me today are Dr. Christian Itin, our Chief Executive Officer, Dr. Edgar Braendle, our Chief Development Officer, and Dr. Maria Leandro, Consultant Rheumatologist and Associate Professor at UCL Hospitals in UCL, and a key thought leader in the SLE space. Before we begin, I would like to remind you that during today's call, we will make statements related to our business that are forward-looking under federal securities laws and the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These may include, but are not limited to, statements regarding the development or regulatory timelines for our product candidates.
These statements are subject to a variety of risks and uncertainties that could cause actual results to differ materially from expectations and reflect our views only as of today. We assume no obligation to update any such forward-looking statements. For a discussion of the material risks and uncertainties that could affect our actual results, please refer to the risks identified in today's press release and our SEC filings, both available on the investor section of our website. Please also note that we are scheduled to report our Q3 financial results on November 2. We won't be making any comments on our financials or projections in our prepared remarks today and ask that you save any of these questions for our results call next week. I'll now hand over to Christian to run through the agenda and introduce the call. Over to you, Christian.
Well, thanks, Julia. A real pleasure to have you all on the call today. We've been looking forward to updating you on our thoughts on the autoimmune space, and particularly the focus on SLE. I would like to move forward to slide number 4, where we have kind of the overview of today's conversation. I'll do a quick introduction, which will be followed by an overview from Professor Maria Leandro on the landscape and unmet needs that we have in SLE and also with a slightly broader view on autoimmunity as well. We're then going to look at the data that was generated by Georg Schett and Andreas Mackensen at the University of Erlangen, which will be summarized by Edgar.
And from there, we'll look, take forward, a forward-looking, position into the opportunity we see for obe-cel, why we think the product is well-positioned, in this, set of diseases, and the next steps, and then obviously go in a Q&A and final remarks. So with that, I'd like to move forward to just, the next slide, number five. So one of the things that's really interesting when you think about the field that we're in, is that a lot of the ideas that we, see now come to fruition actually have a long history. And that is certainly also true for the idea of removing the B-cell compartment, and with that, have an ability to have a profound impact on B-cell-mediated autoimmune diseases.
A lot of that actually became possible to investigate with the availability of rituximab in the late 1990s, and that led to early activities in the end of the 1990s, and then as we went into the early 2000s, also including a first exploration of the use of rituximab in SLE as well. Now, at the same time, also, there's a lot of work that was also done on CD19 as well as CD22 targets, and thirdly, also in the context of CD19, there also clearly was a view that there is an ability to sort of impact this particular compartment using a CD19 targeting approach. And remember, also writing, frankly, patent applications in the late part of the 1990s that included autoimmunity as one of the targets to go after.
So the idea that you actually have an ability to make a deep cut into the compartment, and that may actually reset the disease itself, is actually one that's been around for a long time. But it really has sort of changed in terms of our understanding to what extent that could actually be having an impact on these diseases, really by the work that was done by Georg Schett and Andreas Mackensen at the University of Erlangen, who conducted a rather courageous study using a CD19 CAR-T program that they actually had set up at the university to evaluate patients with severe forms or refractory forms of SLE.
Obviously, have seen quite remarkable outcomes that point to at least the opportunity for transformational outcomes. We'll hear more from kind of that study, also when Edgar will briefly go through that data. But it's quite a remarkable study, and it's also a group that's been working for a long time in this field, but also with CD19-based approaches. In fact, Andreas Mackensen was one of the key initial investigators on the blinatumomab or Blincyto program more than 20 years ago. So when we look at where we are and where we think there's a remarkable opportunity for us and with obe-cel, is that obviously with obe-cel, we have demonstrated we have a very unique profile for the product with a very high level of clinical activity.
Obviously, have demonstrated that we can actually make very deep cuts into the compartment by showing that we can get molecular remissions, patients in MRD- negative status, which is as close as you can actually measure, the removal of the B-cell compartment in acute lymphoblastic leukemia patients, both in pediatric as well as adults. So we have a lot of confidence around the potency and the ability of the product to really make that deep cut into the compartment. And at the same time, we also do know, obviously, that the product has a remarkable safety profile, which we believe is very important in the autoimmune setting.
Now, what's unique, I think, in terms of the position that we're in, is that we're obviously getting ready to file the BLA on a first, for, for our first approval in adult patients with refractory and relapsed and refractory acute lymphoblastic leukemia by the end of this year. We've gone through the whole ramp-up of on the commercial manufacturing side. We have a facility that's ready to go. And with that, also are preparing for launch, which will also put us into many clinics in the U.S. and in Europe, and will provide an opportunity for physicians to gain experience with obe-cel over the next few years, ahead of a potential path to an approval in an autoimmune disease setting.
We believe that's gonna be very supportive, and it particularly will help also because not only do we have the infrastructure, a very well-established program by the time we're gonna launch, but also we'll have a very substantial amount of safety data that will actually help us drive an accelerated path with the program forward and supplement the safety with the safety information that we have from the acute lymphoblastic leukemia work that we've been doing. So this is kind of, in a few words, I think, where we have a remarkable opportunity.
Obviously, we have already talked about in the past about our commercial manufacturing setup and the fact that they will allow us to actually get also attractive cost of goods, and that with that, I think, are gonna be very strong position, not only from a development and a data, but also from an economic perspective in this particular indication. So this is kind of the key, I think, in terms of, in a nutshell, why we're excited about this opportunity. And we also provide just a brief outline on how we actually plan to develop going forward. So before I hand over to Dr. Leandro, just let me briefly introduce her to you. So first of all, Professor Maria Leandro works as a consultant rheumatologist at the UCL Hospitals here in London.
She's actually been in the field for quite a long period of time, starting her first activities back in the year 2000, in the using rituximab in SLE patients. So going back to what I briefly mentioned in the introduction, about the fact that this is an approach that's been evaluated and sort of explored for an extended period of time. And certainly, Maria was there from, in the very, very early days, and actually translating this type of an approach into the clinical setting and has gained an enormous amount of experience. There's a good, very nice review that she wrote, on the 20th anniversary of rituximab's use or first use, in SLE patients, which was published in 2021, that I can recommend for anyone to have a look at.
Maria actually had both obviously an MD and PhD degree, and has particularly focused on mechanism of disease and rheumatoid arthritis, and particularly following B-cell depletion. Has worked enormous amount on the pathogenesis of B-cell mediated autoimmune diseases. So with that, I'd like to hand over to Maria, and I'm looking forward to a great presentation. Thanks, Maria.
Can you hear, can you hear me?
Yes, we can hear you.
Thank you very much for the invitation to Autolus from Autolus to participate in this meeting. If I could have my first slide, slide 7. I'll say a few words on SLE, epidemiology, prognosis and survival, on current treatment strategies, on its pathogenesis, and also on B-cell depleting strategies. SLE is a systemic autoimmune disease. It can cause different symptoms in different individuals, from arthritis, kidney inflammation, skin rashes, heart and lung inflammation, central nervous system abnormalities, and blood disorders. The kidney involvement occurs in up to 40% of patients, can evolve to kidney failure, requiring dialysis or transplantation, and is associated with a higher risk of death. Important to say that patients are prone to flares of their, of their disease, and it often results in long-term ill health and often poor mental health.
Next slide. It's a relatively uncommon disease, the in the U.K., the estimates are approximately 1 case per 1,000 individuals. There's a more recent meta-analysis of studies in Europe and North America that show an overall mean prevalence of 24 per 100,000 population. It has a higher incidence and prevalence in Afro-Caribbeans, Asians, and Hispanics, so patients from that, with that descent. It has a higher incidence and prevalence in females than males, varies with the studies, often 9:1. Its peak incidence is between 20 and 30, so usually it presents from teenage years to 40 years of age. The survival of patients with SLE has improved substantially in the last 70 years, but has plateaued probably from the 1990s.
The standardized mortality rate in most studies at the moment is still 2-3 times higher than in the general population. It can be a severe disease and associated with increased mortality from a variety of causes, from the disease activity itself, when vital organs and systems are involved, from complications of treatments such as infections, from chronic comorbidities that to which patients are at higher risk of, such as cardiovascular disease. Next slide. There's different recommendations for management, and different drugs are used on the left side. So glucocorticoids are one of the bases of our treatment, particularly for flares. We use immunomodulators such as hydroxychloroquine, and then conventional standard immunosuppressive drugs such as methotrexate, azathioprine, mycophenolate.
We use cyclophosphamide in courses of six pulses for three to six months and calcineurin inhibitors. On the right-hand side are the currently biologics used in lupus. Belimumab and anifrolumab are licensed. Belimumab targets the B-cell compartment. It's an anti-BLyS antibody, which is important for B-cell survival or homeostasis. Anifrolumab targets the interferon pathway. Rituximab is the B-cell depleting agent that was already mentioned, that targets CD20 on B-cell surface. Important to say that most patients do not achieve sustained remission, despite all the drugs that we have available at the moment, and need long life treatment. Next slide. Important again to mention the lupus nephritis occurring up to 40% of SLE patients and with significant morbidity and mortality.
So, for patients with lupus nephritis, for kidney involvement, the risk of end-stage renal disease or requiring dialysis or transplantation increases from around 11%-12% at 5 years to around a quarter, around between 22%-26% at 15 years. And once you develop end-stage renal disease, there is an increased mortality risk. And so the survival rates are 94% at 1 year and decrease to 40% at 10 years. That are actually lower than survival rates in end-stage renal failure for other causes. Next slide.
This is a figure from a recent review by Mary Crow, very well known in the lupus field, and just a broad view of the pathogenesis of lupus, with the risks and triggers, the drivers, the significant contribution of autoimmunity and inflammation, and the importance of organ vulnerability versus resilience. Next slide. When we think about pathogenic mechanisms in lupus, clearly, and these have been extremely useful to identify therapeutic targets. Clearly, B cells, plasma cells, and autoantibodies play a major role, and we can see they're mentioned. Belimumab, so the anti-BLyS drug, rituximab, and obinutuzumab, which targets CD20, and other drugs targeting either plasma cells or B
cells, including the CD19 CAR-T cells, that is already included. Next slide.
So regarding the autologous CAR-T cell therapy in SLE targeting CD19, it's been developed for the treatment of B-cell cancer, with a purpose mainly of eliminating malignant clones that are hard to reach, including tissue-resident tumor cells. As already mentioned, the recent report in SLE generated a lot of interest. Some trials are under preparation and or underway, and it's also being explored in other autoimmune rheumatic diseases, including myositis and systemic sclerosis. Next slide. For me, as a researcher and clinician, the main questions are, is a deeper B-cell depletion associated with better, more consistent responses? And there's a lot of previous data that suggest that this is likely to be the case.
The targeting of the CD19, as already mentioned, as it will include plasmablasts and the subpopulation of plasma cells, and how important is this for clinical responses? And the interesting observation and thought about it, thought around it, that it could it be associated with a resetting of the disease and so induction, inducing long-term remission? Next slide. And this is just to explain how when you target CD20, the smaller square with drugs like rituximab, you... And then when you expand and target CD19, you expand the subpopulations of B-cell lineage cells that you target, including the earlier precursors, but not the stem cells, which is important, and a subpopulation of the plasma cells. Next slide.
My final slide, just with some comments about the challenges of CAR-T cell therapy in an autoimmune disease. The current protocols include stopping immunosuppressants and limiting the steroid dose before removing the cells from the patient. And these will have some risks. Then are the autologous T-cells from the patients adequate to produce CAR T-cells, so in enough quantity and quality? And the data suggests that, yeah, that is the case. Then the balance between risk and benefit, given its potential side effects described in B-cell cancer. And in particular, the balance between risks and benefits of inducing a long duration of B-cell aplasia, if this is the case.
Finally, just some, you know, which everybody will be thinking about, the cost -effectiveness of such a therapy. I think that a lot of it depends on the disease resetting and whether that is observed. Thank you very much. If I can then pass to our next speaker.
Okay.
Edgar.
Yeah, thank you very much, Dr. Leandro. If you can move to my first slide. I think we all know, and everybody is aware, that CAR-T cells have become a standard of care in hematological disease, with the first approval of a CAR-T cell in 2017 from Kymriah in pediatric ALL. And as Dr. Leandro has pointed out, specifically in severe and refractory SLE, those patients require a long-term lifetime treatment with immunosuppressive agents. They are, to some extent, associated with significant toxicity, as well as, to some extent, limited activity. Now, as Dr. Leandro pointed out, the treatment of SLE, potentially with CAR-T cell, has the potential to have a deep reset of the immune system and may have a very, very new paradigm in the treatment of SLE.
And as Christian pointed out, I think we, with obe-cel, we have the possibility of an accelerated entrance into this space. On the one hand, we have shown with the FELIX study that obe-cel has the best-in-class risk-benefit. On the other hand, for the CD19 CAR T-cells, on the other hand, as Christian pointed out, we have built up a commercial manufacturing facility, and we're currently in the process of building up a commercial product delivery infrastructure. If you move, please, to the next slide. This is basically a summary of the data and the experience of the Erlangen Group with CD19 CAR T-cell in SLE. In this study, which have been reported in, in Nature Medicine, five patients were treated, with a CD19 CAR T-cell. And the CD19 CAR T-cell, which was used in the study, was an academic manufacturer's CAR T-cell.
The structure of this CAR-T cell was very similar to that what it has been done, what has been used for Kymriah. It had an FMC63 binding domain, it had a 4-1BB costimulatory domain, and it had a CD3 zeta signaling domain. The dose which we used in this setting was body weight based, and they used about 1 million cells per kilogram body weight, which then, based on the weight of these patients, led to about 50-60 million cells. All of these patients had heavily been pre-treated. They had a refractory advanced disease in SLE, and all of them had many organs involved related to SLE. Now, if you move to the next slide, this goes a little bit more in detail in, into the data. First of all, the treatment was very well tolerated.
From these 5 patients, there was only 3 patients who had a grade 1 CRS, and there was no ICANS reported in this patient. Importantly, these, from a clinical perspective, the clinical manifestation of the SLE rapidly ceased. You see here on the right side of the slide, you basically see that the initial SLEDAI score, which is a measure for the severity of the SLE, which was between 8 and 16. Three months after the treatment with the CD19 CAR T-cell, it really was, for 4 patients, the SLEDAI score was 0, and for 1 patient, it was 2. If you use other criteria, all of these patients reached a state of remission, for example, according to the DORIS criteria. On the other hand, which was very important, is there was a seroconversion.
Those patients, as you can see on the right side, these patients had positive antibodies at baseline, and they also had a decrease of the complementing complement. And after the treatment, the antibodies were not detectable anymore. And I think that the antibodies was not detectable anymore indicate that the autoreactive B-cell clone, which are potentially in plasma blasts, which are more potentially responsible for the secretion of these antibodies, they were eliminated. Furthermore, I think what was also important to see, as I indicated, those patients had an organ involvement. And as a sign of the treatment involvement, they had a proteinuria, and as you can see, in all patients, after the treatment with the CAR T-cell, the proteinuria normalized. What also is important, not only those patients were symptom-free, they were also free of medication.
I think what was also what is not shown on this slide is the cellular kinetic. What they have seen with the CAR T-cells is they saw the peak at day 9, and there was no CAR T-cells anymore detectable after 3 months. Importantly, associated with this cellular kinetic, there was a B-cell aplasia, but all the B cells were coming back at around day 100. And I think that's important because with these B cells coming back, there was no, the patient remained symptoms free, which basically may be an indication that the autoreactive B cells were eradicated with this kind of treatment, and there was a deep cut into the B cell compartment. Now, if you move to the next slide, the Erlangen group also treated other autoimmune disease, which are basically summarized here.
One patient who were treated with a CD19 CAR T- cell had a huge systemic scleroderma, as it was a 60-year-old man. This patient had indication of fibrosis in the myocardium, in the lung, and so on and so forth, had failed several treatments. And when he was treated with the CAR T- cell, it was very well tolerated. There was no ICANS, no CRS, and the autoantibodies normalized as well. On the imaging, there was sign that the fibrosis were reduced. Now, I think what, for me, especially for me, perhaps the most impressive was also the patient, which were treated with an idiopathic myositis, that was a 40-year-old patient, refractory disease, several prior treatments. And what happens with this patient, initially, at baseline, the myositis score was seven, but under the treatment it moved to one. It had initially had antibodies detected.
They were not detected anymore after the treatment with CD19. But perhaps most importantly, at the beginning, before the treatment, the patient was only able to walk about 10 meters, and after the treatment with CD19, the patient was able to walk every day, five kilometers. If you move to the next slide, and this is my last slide, I think what this data showed is that with the treatment, with the CD19 CAR T- cell, there was a deep reset of the immune system. There was the B cells were recovering, but with the recovering of the B cells, the symptoms, the patient was still symptoms free, and they don't need a medication, which basically indicates that there is a deep reset in the B cell compartment, and that potentially the autoreactive B cell were eradicated.
Overall, the treatment was very well tolerated, and what I haven't mentioned is when we spoke with the Erlangen group, they now have treated a total of seven patients with SLE, and they had a follow-up up to 24 months, and those patients remain symptom-free. Those patients remains don't need any further treatment for SLE. So putting this all together, I think this is an indication that a treatment with a CD19 CAR T- cell can be a transformational therapy in the setting of severe refractory SLE. With that, I will give it up to Christian.
Thanks a lot, Edgar. Much appreciated. We're moving forward to slide 25. You've heard before from Dr. Leandro that there's a significant amount of patients that actually do experience SLE, and particularly in this earlier time window between teenage years and up to 40 years, as sort of the peak of the activity, quite a significant bias towards female patients. And also having, particularly with the severe patients, as were treated in Erlangen, those types of patients tend not to function or have an ability to function in normal life. They may not be able to work, they may not be able to go to school, and they're incapacitated to a very significant degree.
And to see those patients, and I've seen actually the data as well as pictures of the patients in Erlangen, is quite remarkable, the transformation that these patients actually underwent, and frankly, being back and being able to lead normal lives, which is just absolutely stunning. But as you can see in the chart on the right-hand side, there is a significant proportion of patients that we believe actually are addressable with CAR- T therapy. Obviously, there's going to be a big question, as Dr. Leandro pointed out, is obviously affordability at some level, which is why, you know, cost of goods and sort of the economic range and price elasticity will certainly be an area to look at very carefully as we move forward.
But if we look at a sizable population that could actually be addressed with a CAR- T therapy, and we believe actually would certainly, you know, substantially change the outlook for a product like obe-cel going forward. Moving to the next slide, these are just a few views on how we believe that this obe-cel could actually work in this setting and why we believe that we have such a unique position with the product, and I started articulating that at the introduction as well.
I think the first one is certainly that I think in autoimmune disease, much more so than in cancer, there is much more sensitivity towards adverse events and actually having a good benefit risk profiles from a safety and with a particular focus on safety. I think that is important. And obviously, as you remember, one of the key things in terms of the design of obe-cel is really focused on the ability to engage in a very physiological way with the target cell, avoid overactivation, deliver the kill, but avoid overactivation. And as we had shown in a number of different, both preclinical as well as clinical settings, we actually do get deeper responses.
We get more actual activity, but we avoid the overactivation, we avoid a lot of the adverse events that are seen with many of the programs. I think it's worthwhile remembering that, as we started developing obe-cel, we started in pediatric patients in the CARPALL study, which was published in Nature Medicine, with from Sara Ghorashian as the first author. What we have seen in that study is, and this was done alongside pretty much the ELIANA study or right after, so with the same type of patient management, et cetera, that the patients that we were treating did not experience high-grade CRS, which certainly was a major adverse event. 47% of the kids in the ELIANA study, the approval study for Kymriah, that actually did experience high-grade CRS. Massive difference in the behavior.
We saw that that was actually going alongside with obe-cel having somewhere between 3 and 5 times the number of CAR T- cells formed in vivo, although the dose that was used with obe-cel was identical to the dose that was used with Kymriah. You remember, based on what Edgar just told you before, the dose for the pediatric patients is weight-based, and it was 1 million cells per kilogram, as it was 1 million cells per kilogram for Kymriah, as it was 1 million cells per kilogram used in the SLE study that was conducted by Andreas Mackensen at Erlangen. So we know actually on this like for like, in the same patient setting, we have a different profile with our product, also against Kymriah.
Obviously, we've shown that certainly on the adult population, we have a remarkable safety profile. I don't think I need to go into that. We've also demonstrated that in the non-Hodgkin lymphoma patients that we have treated, where we have no high-grade CRS, no neurotoxicity of any, of any kind that we have observed in these patients, which also gives us a very strong understanding of the overall profile of the product. So safety, I think we're doing really well with an ability to make a very deep cut into the compartment.
And when you think about the most stringent test that you can actually have to measure the cut that you can actually do into the B-cell compartment, that is, looking for minimal residual disease in the bone marrow, in acute lymphoblastic leukemia patients, where you can pick up cells down to the 10 to the minus 6 level. This is more sensitive than anything else we can measure in B-cell-mediated diseases, and obviously, what we have demonstrated, using various methodologies for MRD, testing across our patients in the pivotal study, that we do actually get patients below 10 to the minus 4, depending on the cutoff, that was used for the technology applied, that we had very deep, MRD- negative, results in almost all patients that responded to therapy.
So we know that the product actually does an exceptional job of making a very deep cut into the compartment in probably the most challenging setting, where you have the largest hurdle with regards to, B cells that are available. But also, remember, we did treat patients that had low disease burden, that had MRD- negative, MRD positive disease. Even in, also in those patients, we could demonstrate we could convert those patients in MRD- negative status, which is much closer to what a situation in an autoimmune patient is, that has normal B cell counts, and you need to be able to then still make a very deep cut into that compartment. So we've demonstrated that, I think, as extensively, I think, as anyone has demonstrated that type of an activity, on the oncology side.
Now, the manufacturing base, we've already mentioned briefly, twice in this presentation, is really critical. It is critical because number one, you need a manufacturing process that is highly reliable, that actually ensures that for every patient you take a leukapheresis from, you have an ability to deliver product back to that patient. And secondly, you do not only have to do this reliably, but you also have to be able to do this at scale and economically. And this is really where we spent the last more than two years, working out an extremely robust manufacturing process, but also have established now a commercial manufacturing facility, which will allow us to launch a second or third indication over and above the ALL indication that we're gonna be launching as a first indication from the facility.
And that infrastructure, that ability and capability is really core and obviously one of the key differentiating factors in as we're looking at the opportunity here. We'll also be able to obviously leverage the fact that we're going in and file for a BLA at the end of this year and expect to get to an approval by sometime second half of next year. That is important because it means that we're the product will have a BLA, and there is an opportunity to actually move forward and consider an application in SLE to be actually moving through an sBLA pathway as well. So leveraging a lot of the information, the CMC package, which is complete, and so on and so forth as we go forward. So it's a massively risk-reduced approach that we can take.
And then the final part I want to just highlight is that the remarkable results that you've just seen before, presented by Edgar, where you have not just a small differential of SLE scores that are improved, as you would typically with a monoclonal antibody, you would develop on top of a standard of care backbone, as sort of a standard of care plus/minus antibody. In those settings, you typically look for a 4-point improvement, and as you remember, with many of these studies, you just about eke out a statistical improvement after about a 1-year period. So this is a very small effect that you actually ultimately will see with those antibodies, obviously not leading to a reset of the B-cell compartment. If you stop treating, the disease is coming back.
Now, what you've seen with—from Edgar's presentation is that these results actually were not just a four-point improvements. Most of the patients went back to baseline.... and actually had no symptoms whatsoever, no scores whatsoever. And now with one to two years of follow-up in these patients, are still free of autoreactive B cells and autoreactive antibodies, and they're free of disease in the absence of any other therapy. So what that means is that you have a level of treatment effect that is comparable to a sustained complete remission in oncology. So it's a sustained effect, and that actually allows you to consider a clinical approach and design of a clinical study here that actually is much more compact than what you normally would do in autoimmune diseases.
It looks much more like the types of approaches that you would take in the oncology setting. The problem that that actually creates is, you will be able, on the positive side, to create, to actually demonstrate the clinical activity. But on the negative is you're probably not gonna have enough data points to, and patients in the study, to actually discharge the safety signals and the safety risks. And that is where we have a very big opportunity because we can supplement, because we're using the same product, we can supplement, obviously, our safety database and safety information using the oncology data, the ALL data that we have on the program, which will obviously even be more expanded by additional clinical study downstream, but also by the capture of safety data on the commercial patients as well.
That's gonna be a very significant advantage, but will actually help us to drive an accelerated path in terms of development. I've touched on slide 27 just briefly on design bit here on the product, and obviously, that we have a physiological engagement, very different binding properties, and with that, different actual mechanism of action that we can build on. We briefly talked about it on slide 28, the fact that we obviously have conducted the FELIX study. We've are on track for the regulatory filings, and we obviously do get a very significant amount of activity.
What's important, of course, is that when you think about even thinking about moving forward into larger trials, we will obviously be present in a large number of centers commercially with obe-cel by the time we consider to actually run a pivotal study in an autoimmune disease settings, which will also will be extremely helpful to be able to start up the study and actually build on experience in those particular centers with the product. When you look in slide 29, just as a reminder, this is a summary of the key findings of the FELIX study as presented at ASCO. We've shown that we have a very high level of overall response rate, 76%. Almost all of these patients, 97%, had MRD- negative status of at least 10 to the minus four or below, four or below.
Then we look into the table below there. You do see kind of the key immunological safety signal, CRS and ICANS. As you can see, we have very low level of high-grade CRS in these incredibly difficult to treat patients of about 3%. Remember, we have more than a third of the patients with enormous amount of tumor burden, of more than 75% tumor burden in the marrow, which is an incredible amount of B cells that have to be removed to convert these patients into complete remissions. But also on the ICANS side, we have a low level of high-grade ICANS, about 7%. Only 23% have experienced any form of ICANS. And in fact, almost all high-grade ICANS happened in patients that have more than 75% tumor burden.
So they also, they're indicating that we have an exceptional safety profile with the product, and obviously, that was also corroborated with the non-Hodgkin's data as well. I mentioned the commercial manufacturing facility. This is a depiction. It's a 70,000-square-foot facility. We were extremely fast in its build. We will have gone from groundbreaking to BLA filing in just a bit more than the two years' time, including full validation of that facility, which is obviously key data that will have to go into the BLA. It's a very unusual approach, frankly, possible through an extremely high level of offsite building, a high modular nature of the, of the design.
And what you see on the very right-hand side is the capacity challenge that we ran, in the first clean room, which basically is designed to put everything to the breaking point, in terms of intensity of use of the facility. And what you have to be able to demonstrate is that, in fact, the system, the product, nothing breaks. You can actually demonstrate, you can get high-quality products in all of those runs, as well as obviously sustaining control over manufacturing all around, during that period. So it's been very successful. This is a true pressure test, and it's only possible because we have a highly automated manufacturing process, and we have extremely well-skilled and trained operators that we do actually train up ourselves.
We expect to be... Obviously, this facility is designed in its initial build-out for ALL to have at least 2,000 batches worth of batches that can be produced per year. There is fallow space, and we actually can exceed that amount of batches per year, which gives us ample room to launch in autoimmune disease from this facility, which obviously, again, takes an enormous amount of risk out, but also reduces cost and investment required. The manufacturing performance on slide 31 is just one of the things we wanted to highlight, and we have sort of actually shown that as well at ASCO. But the point is that if you look at these four charts on the right-hand side, we do have obviously a very high...
ability to deliver product at the right quality, even if you have very high levels of tumor burden, as was shown in the more than 75% tumor burden window in the left upper panel. The right upper panel looks at the median transduction efficiency, which is around 70% and very nicely packed. We had going to re-release time of 21 days in the trial, and we expect to be at 16 days with some of the improvements we have put in place at the end of the trial and a depot model for the ALL setting. This is ALL. Now, the improvements that we will be able to do for SLE is that we are, can, can operate at a lower dose level in SLE. We're going to use the pediatric dose level.
Remember the CARPALL study that we already have demonstrating works extremely well. That actually translates into a fixed dose, this weight-based dosing that you use in children because they have a wide age range and, you know, going from 2 years of age to 25 years, obviously, a huge range in terms of weight. So this is why you use in kids a weight-based approach. And when you translate that back and understand that the majority of the patients are female, you end up with in the range of 50 million as a fixed dose level, which we're going to be using going forward. This is substantially less than we use in ALL.
In ALL, we use 410 million cell dose, so this is a fraction of the cell dose, which also means that the manufacturing process can actually be shortened, and that will be helpful in the overall going to release time, and give us, obviously, I think, a very nice process to work with. In addition, these patients are in much better shape than an acute lymphoblastic leukemia patient, although they've seen cyclophosphamide, as you've heard before, that may have been given up to 6 months. They're still in a much, much better shape than patients who've experienced high-dose chemotherapy for extended periods of time, as ALL patients do.
So their starting material, the leukapheresis, actually are in much better shape, and this will obviously also further improve the quality of the product and obviously will ensure that there is going to be a very, very high success rate on manufacturing. So moving to slide 32, this is just a quick look at the path that we're going to take going forward. As we indicated, we're going to start with a first dose confirmation study, which is going to be a small study beginning in the early part of next year.
The goal is here to confirm the dose and then take the data to the regulators to review the design of the pivotal study, which we expect to be able to sort of have that conversation, if everything goes according to plan, somewhere in the, towards the end of next year. In addition, what we want to do once the dose is actually confirmed, is also to consider a basket study. In other words, include a range of autoimmune diseases and understand the signal that we can get in further indications, and from there, also obviously, choose opportunities beyond the SLE, based on that data. So those are kind of the fundamental sort of overview in terms of the approach that we want to take.
In terms of additional immune, autoimmune indications, you already heard, both, Dr. Leandro and Edgar talk about some of those. I think there's quite a range. There are a number of parties also on the commercial side that are starting to talk about a range of indications going all the way, in fact, through the entire range, of B-cell- mediated approaches, including, obviously, very large indications like rheumatoid arthritis, or MS, sort of, areas that people are considering at least, to evaluate and explore. So when we look at the slide 34, just to give you a brief sense for why some of the infrastructure actually is going to be very helpful.
What we're just highlighting here is the fact that we're obviously putting in place the whole product delivery set up for a large number of CAR T centers. And that obviously will help us a lot when we're also conducting clinical studies, that commercial set up and backbone, because there will be a high degree of experience with the product and obviously an ability to engage with the company, where we can leverage in part, obviously, the infrastructure that we have built, including the cell orchestration platform, as well as many of the other components that are required to have a seamless experience for the centers and the patients in engaging with us. And this is slide 35. Just a brief view, if you just sort of compare the competitive landscape here.
Obviously, as I indicated, the idea of depleting B cells and changing hopefully the course in autoimmune disease is one that's been around for a long time. As you can imagine, as a consequence, there's also a lot of people who've been thinking about it and start to being active in the space. We believe we're very uniquely positioned. If we look against some of the pharma companies that are moving into the space, those are actually those approaches are based on heavily modified programs compared to what was used in the oncology settings. In fact, modified to a point where we expect those products to be considered new products.
And with that, obviously, you do lose some of the benefits of having an existing product that you can move into, around the use of safety information, which is also limited to your ability to show comparability between products. We don't think that will be possible. And then there's also, obviously, significant impact with regard to just the investment that you have to make, in order to get the manufacturing base ready for the new process and the new products, and sort of build that up from scratch as a complete new package. A lot of the newer entrants obviously come in with products and CD19 CAR approaches, which are completely new, without any clinical data, none of the infrastructure, none of the capabilities that we have built up with obe-cel.
We believe that that is going to be an enormous advantage, as we're here, because we know that we're ticking the box on tolerability and clinical profile and infrastructure, as well, both on manufacturing as well as commercial. And this is why we believe we're in a very good, very good position, not just to start the race, but actually to win the race, in this particular disease setting. So with that, what I would like to do is actually open up for Q&A. I'm looking forward to your questions.
Thank you. As a reminder, to ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question comes to the line of Mara Goldstein from Mizuho.
Great. Thanks. Can you hear me okay?
Yes, we can. Hi, Mara. Thanks for joining.
Hi. My pleasure. So I have two questions. One is a clinical question, trying to understand the perhaps ideal candidate and the feasibility of cell therapy in autoimmune disease. And so I'd love to hear your clinical view on that. And then, I'm curious, you know, the plans to look at obe-cel and autoimmune disease, you mentioned sort of a basket type approach, and I'm curious as to, you know, the scope of how many patients you think you will need to be able to determine true signal and what, you know, what the benchmark will be in following those patients to arrive at that point?
Yeah, very good questions, Mara. So, Maria, if you would like to take kind of the first question around kind of what is the ideal candidate and for these types of studies in terms of patients, SLE patients, and how do you see feasibility for to sort of deliver CAR- T therapy to those patients, given the speed of disease, et cetera?
So, thank you for the question. I'll answer that question with, in two stages. So I think it depends first, now, when we're exploring it, and the patients that we will be considering for this are the patients with refractory disease, active disease, severe disease, for which we have, at the moment, no other options or very little options. And there's clearly a small number of those that we see in a year. So that is, that would be the first thing. Then it all depends on how safety and efficacy, what we see about that in the studies.
If we were to imagine that we'll be able to reproduce the initial results, then I could see this moving forward to including the population of patients with severe disease. But even if we're, at the moment, controlling it to some extent, where we know that their prognosis is worse, and they have risks of morbidity and mortality over time, that exceeds the other population of patients. So I think that initially will be the sort of patients where we can't control their disease. Their disease is severe, but in the future, it all depends on the how what happens with the studies.
Mm-hmm.
What data do we get?
If I can just ask a follow-up to that, and do you believe there is a difference from a potential treatment effect for patients who have had disease for a long period of time versus those that have had, you know, severe intractable disease, but for a shorter period of time?
So certainly, we would like, if the results are reproducible, then we would like to offer them to the patients to start with, but still have it available for the patients that have long-standing disease but are still not well controlled. So I think that it would change the way we would approach a cohort of patients that we see in clinic, particularly the young ones. It's interesting to note that most patients were all young. I do the adolescent and young adult clinic, and we do have many severe, you know, severe patients. So I think it would cover both.
Certainly, we would be hopeful that if the results are reproducible, we would be able to change the prognosis of the patients to start with, but, you know, we'll need to wait.
Okay. Thank you.
Thank you. So, Edgar, do you want to briefly talk about the basket study and how we would sort of think about signal finding, in this study?
Yeah. So Mara, the way we think about this is not in a fixed number of patients per indication. I think the way we would design this basket study is more in an adaptive trial design way, which basically means, let's say you would start, let's say, with about 10 patients in each indication, but depending on the sake of the efficacy signal or the safety signal, you would then either have the possibility to stop when you don't see any efficacy, you would stop this indication or this type of an autoimmune disease. If you see a strong signal, you would maybe also already stop earlier. If you see a signal in between, you have the possibility to expand until you have some more confirmation about the activity and safety in this specific indication.
It is not driven by a fixed number of patients more. This, I think what we need here, since the activity may differ in all kind of different indications, that we use a more adaptive patient design for this basket study, if that makes sense.
... Okay. Thank you.
Thanks, Mara.
Thank you. One moment for our next question. Our next question comes from the line of Gil Blum from Needham and Company.
Hello, and good morning, everyone. First question for Dr. Leandro. Given the conditioning, you know, especially in the younger patients, that includes fludarabine, do you consider that an issue for you know, using a larger population, especially if these patients are younger?
So fludarabine is not a drug that we use. Usually cyclophosphamide is. I don't think so, so if you're thinking about the risk regarding infertility and all that. So for example, with the cyclophosphamide, a single dose as the one that is included in the conditioning regimen, we wouldn't necessarily think about protecting and decreasing the risk of that. We do that if we do courses of cyclophosphamide. So I don't think we expect that the doses used in the conditioning regimen to be a major issue. The main question will be the cytopenias, but not other issues as such.
Thank you. Maybe a related question to the company here. Is there any thinking around, I don't know, adjusting the conditioning regimen to this type of patient or just going with tried and true here?
So first of all, Gil, thanks for the questions. I think they're really, really good questions. When we think about the conditioning regimen, it's really a regimen that's been designed and frankly worked out, you know, over probably by now many decades in for preparing basically patients to accept cells in the marrow and for cells to be able to engraft. That mechanism, I think, has been enormously optimized, and what we see with regards to the risk here is I don't think we see any significant risk to the patient. Obviously, as Dr. Leandro pointed out, the cyclophosphamide dose is a fraction of what you would use for just standard therapy in this setting, so that's completely not a non-issue, and flu is obviously only used in pretty small doses.
So we don't think actually there is a good rationale for changing the conditioning regimen. And if you were to do that, you would probably have to run a very sizable study to work out whether that change what the impact of that change actually would have been. It doesn't make sense as far as we are concerned, to actually make a change there. We're gonna use, as you pointed out, the true and tested, given that this is frankly where we've now, over quite a few years now, as a field, have coalesced, understanding that this is a really excellent conditioning regimen to induce IL-7, IL-15 in the marrow, and with that, actually support the engraftment of the CAR T- cells.
All right. And one other follow-up. How much does the vein-to-vein time matter in SLE? I would expect it to be different than a B-cell lymphoma. Thank you.
Well, first of all, the vein-to-vein time is gonna be relatively short because we're obviously, number one, we're gonna have a shorter manufacturing time on the product. But we're also will post approval, even on the ALL side, we're planning to implement a faster release on the sterility side, which will actually further collapse the time. So we expect that to be at around 10, 11 days on the SLE side. Obviously, when you think about these patients, this is a much more chronic type of disease. This is not the type of disease where you have explosive growth as you have in acute leukemia, and so time is actually much less of an issue here.
And clearly, if you sort of be able to actually turn around the product within the time periods that we are turning around products in ALL, that certainly is manageable. And when I talk to Andreas Mackensen as well, on his experience, you know, clearly that was not an issue for them because even in these refractory patients, you know, there is... You can manage the patients appropriately. And the flaring of the disease, actually is not something that he actually has seen as a concern, as the patients are waiting for the CAR T- cells to be ready for infusion.
All right. Thank you for taking our question.
Thanks a lot.
Thank you. One moment for our next question. Our next question comes from the line of Sebastian van der Shoot from Van Lanschot Kempen.
Hi, team. Thank you for the valuable insights and taking my questions. Just one from me. I believe there was a recent report from the Schett group that one patient had still circulating autoantibodies against double-stranded DNA, and this was suggested to be cause of CD19 negative B cells. Can you maybe expand on what contributes to, or, or to what level CD19 positive B cells constitute to the disease? And whether you're also considering going into space with a bispecific CAR-T approach.
So first of all, thanks a lot, Sebastian. Really good question. So one of the surprising findings in the original work from Erlangen was that all of these patients had an immediate and complete drop of autoantibodies, which suggested that the producing plasma cells were CD19 positive plasma cells, which meant they're in the earlier part of differentiation of plasma cells. That was a surprising finding because that was actually not known going into the study, that this would be something to expect. So what they're reporting now is that there could be instances where over time, there may actually be a recurrence or a leftover of a plasma cell that actually over time may actually add to autoantibodies coming back.
You would have to assume that those are CD19 negative cells because they're at least one of the explanations. And for that, you would then actually have to use another antigen if you wanted to go after that. The problem is, if you're gonna go after those cells with a BCMA targeting, as an example, as we have in AUTO8, which will provide data, obviously, on the multiple myeloma side at ASH, on that program. You obviously do a very profound resetting. You reset both the CD19 and the BCMA compartment.
The cost of that, though, to the patient, is that the patient will lose all normal plasma cells, and with that, will actually basically lose any of the vaccine protection and the antibody protection that you would actually have built up, and you would have to sort of regenerate that later on as the compartment regenerates. So there is risk in that. And I'm not sure you want to vaccinate or do extensive vaccination with these patients once the B-cell compartment comes back. So there is a trade-off there. How much you would see that as an event, I think, is unknown, and we'll have to see.
We now obviously have 1-2 years of follow-up, and the patients being disease-free at this point in time, we'll have to see, obviously, what happens with the particular patient that Garrett reported on. But that's going to be an interesting trade-off, and one of the key questions, obviously, to whether there is what level of patients or number of patients, percentage of patients, might actually have a recurring, a recurring clone or a clone that actually was not actually targeted with CD19. At this point, I think this is just we're at a point where we don't have enough data on that as a field. And the, you know, the larger study will start to get us that type of insight.
Okay, got it. Thank you. And then maybe a quick follow-up. I know it's still early, but I'm just wondering whether you have any idea or any insight on what a pivotal study would look like in our communities with similar therapies. Would it be a two-arm study against the current standard of care, or how would you envision that?
I think that will be, frankly, a conversation with the regulators. That's too early to actually predict. What we are clear about, whether it's a single arm or a controlled study, will be a very compact study. Because the treatment effect that was seen, if we can reproduce that, which is obviously what we expect to do, actually would be a very compact study because you have a very profound effect that was observed in these patients. And that would allow you to actually run a study that would not be dissimilar in size to what we've just done in the FELIX study. And whether there's an element of a control in there or not, I think that's gonna be, frankly, a conversation with the regulators.
That's too early to predict.
Got it. Thank you very much.
Thank you, Sebastian.
Thank you. One moment for our next question. Our next question comes from the line of Yanan Zhu from Wells Fargo Securities.
Hi, thank you for the very helpful event. I have a couple of questions for Dr. Leandro and also a follow-up for the company. For the doctor, I was wondering about the contribution of lymphodepletion regimen to the treatment effect. Is there any possibility that the Cytoxan used in the lymphodepletion portion of the study could contribute to such impressive response rate? If, appreciate any color on that. The other question for the doctor is, what would success look like in these upcoming clinical studies in SLE?
In your mind, do we have to achieve kind of a near 100% response rate, as shown by the first German study, or is there a lower success rate or response rate that could also be acceptable, for a product that could be widely used? Thanks. I have a follow-up on persistence for the company, too, but I'll stop here.
Okay, Maria?
So thank you for your question. So, regarding the cyclophosphamide, in my experience, you wouldn't expect at all, a long-term effect like this. So we use it often. We're limited to using around two, three, three cycles because of its long-term potential for toxicity. But if you, if you use one dose, which we do, before continuing with the next cycles, you would... In my experience, I've never seen such a response.... So, usually we use six cycles, six infusions as part of a course, either lower dose every two weeks for three months, which is considered the Euro-Lupus regimen, or higher dose, with a big, a larger interval, up to six months. So in my experience, I've never seen that. Regarding your second question, I think it will all depend on safety and then cost.
I think that, I'm of the view that I think it's unlikely that we'll see long-term remission with no need to start medication in all the patients that we treat with CAR T-cell. So the disease resetting and induction, inducing long-term remission for a significant period and with possible then a mild flare, easy to control, with lower doses of drugs that we, the patient tolerate and we, would be, for me, a very good result.
So yes, you know, having spent a lot of my life, you know, arguing for more profound B-cell depletion and that, and possibly targeting some plasma cells, and that's particularly the profound B-cell depletion, and that being able to induce long-term remission and reset the disease, it would be wonderful if the results are reproduced to this extent and continue over time. But I think that, they don't need to be exactly like this for it to be a very valid, treatment strategy for, several of our patients.
Got it. That's, that's super helpful. And then the question for the team is really on persistence. What's the team's expectation for persistence of the CAR T-cell in the SLE setting? I think it was mentioned on the call that the German group's studies T-cell I don't think they persisted longer term. Would that be an outcome that could also be expected here for obe-cel? And what's the implication of persistence to safety, such as B-cell aplasia, et cetera? Could lack of persistence actually be a feature that could help? Thank you.
Hi, Yanan. Well, a very good question. So one of the interesting things, and we had extensive conversations also with the Erlangen team about that. One of the interesting things is that in their experience using their academic CAR T program in pediatric ALL patients, which they're also doing, they do see in those pediatric ALL patients long-term resistance in patients that achieve CRs, very similar to what we have seen. So they can see persistence 2 years, maybe even 3 years out at times. So they have a very similar persistence profile in ALL patients as we do. What is interesting was that the observation that they had was that that same product, at the same dose given, in the SLE patient, had a limited persistence.
As they are pointing out, it was 3, 4, maximally 6 months, depending on the patient. And what you then saw is that as the persistence basically was lost, that you would also then see basically a repopulation of the B-cell compartment from the stem cells, and you would have first the classical early forms of antibody forms, the IgDs, and then IgMs, and we eventually get the IgGs come up. What they did not observe in that recovery phase is the recurrence of autoreactive B cells. That was very important because it really goes to the reset.
The benefit of it is, if you do actually see eventually, sort of a repopulation of the B-cell compartment, obviously, it's then you sort of reconstitute, you know, basically the B-cell, you know, immunology and, and protection that you can actually derive from that. So, if you look at that profile, that profile looks actually attractive. What we would expect based on what we know about our product and what we see, what we have seen, on the Erlangen product, is that we also expect that obviously we'll have an impact on persistence, and we have shorter persistence in these patients. That would be the expectation. Similarly, as we have seen, by the way, in patients that had non-Hodgkin's lymphoma, where we have different persistence profile than we had in acute leukemia.
So you would expect a shorter persistence as well, but obviously what we do have is amongst the products, is we do have that have been evaluated, we have a very, very good persistence with our product, which I think ensures a very deep cut in the compartment. So I think the probability for autoreactive B cells to escape recognition, I think is going to be minimized, which is really what the persistence helps with, because it gives multiple chances of actually finding a particular autoreactive cell and actually eliminating it.
But I also would expect that after persistence sort of actually peters out, as we still see also, by the way, in a portion of the ALL patients, that we then actually would see the B cells coming back, as we have seen in those patients as well in our prior in the oncology setting. So we expect that we'll see this kind of a profile. We may have a somewhat longer persistence than what was observed in the Erlangen study, but generally, I would expect the same overall profile. But I think overall, I think we're going to be in a very nice spot in order to put pressure and clean out the compartment, and then have an ability to, for the patients to recover their B cells.
... Got it. Great. Thanks for the great answers.
Thank you, Anant. Really appreciate you joining.
Thank you. I would now like to turn the conference back over to Christian Itin for closing remarks.
Yeah. Well, first of all, thank you all for joining today. This is an exciting field. It is something we're really excited about for quite some time, but we frankly also didn't want to dilute our messages around what we're doing in ALL, and that we're on track for the BLA filing. But we felt this is the right time now to introduce you to those activities. We believe we're uniquely positioned with our product, and I think very nicely differentiated to anyone else, with our ability to be able to move forward with a product that's headed towards an approval.
And with that, actually leveraging all the benefits of the investments we've made in the program and being able to translate that into the next disease setting, and really looking forward to getting the patients dosed, study up and running, patients dosed. And obviously, we can build here also on the great experience that we've built up at a large number of centers already with Obe-cel, who had Obe-cel in their hands. And that also gives us, I think, a very nice ability to get moving and actually develop a momentum here. And with that, I'd like to thank you all for joining. Obviously, we'll keep you posted on progress that we're doing.
Next, up will be our Q3 Earnings Call, which is coming up next week. And then, obviously, we're all gearing up for ASH, and the presentations, obviously, and updates that we're planning for ASH. Thank you very much for joining, and speak to you soon.
This concludes today's conference call. Thank you for participating. You may now disconnect.