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spk04: highlights for the quarter. As you can imagine, we're in the process of going through the various review processes for OVCell, both in the US as well as in Europe, and most recently now also in the UK. So that's been the primary focus from an operational perspective. I think we're making good progress and are on track with all the various interactions that we have with the regulatory authorities. The BDUFA target date, as you may remember, is November 16th this year, and we're tracking well towards that timeline. We've also initiated or have currently ongoing two phase one clinical trials. One is in pediatric ALL, which is a trial that is moving very nicely, and obviously we're excited about applying and having OV-cell evaluated in pediatric patients. That's ongoing, and we'll report, obviously, in the upcoming periods on that trial. And in addition, the phase one trial with patients that have an advanced stage, a relapsed type slash refractory stage of systemic lupus. This is the Carlisle study. We opened this study in the beginning of the year, and we dosed our first patient in the second quarter, and we continue involvement in that study as we have projected. But importantly, as we went through the course of the quarter, we did focus, I would say, very much on the update of the clinical data from our pivotal Felix study, the Phase II study that's underpinning the regulatory filings that we've made with the various authorities. Importantly, we looked at a number of aspects that we hadn't actually explored to the same extent in our prior publications and presentations around the program. One, of course, is to look for the longer-term outcome. And what we do see is that we do start to see a stabilization of both event-free survival as well as overall survival in the study, and we're starting to see a plateau forming, which is obviously something we've been very keen to evaluate, and we start seeing that now actually stabilize with more follow-up in the study. What was quite interesting, and I'll show you the data a little later as well, is that Quite typically what we have in this particular patient setting is that you actually look to consolidate the effect that you could induce with a particular therapy to induce longer-term outcome. And typically what you do is you actually have the patients undergo a stem cell transplant when they are in complete remission and ideally MRD negative, which was the case for all our patients. What was quite surprising to see, and you'll see the data in a short while as well, is that it didn't appear that the consolidation with the stem cell transplant improved the outcomes for the patients, which is very different from the other therapeutic options that are currently available in the space. We also, I think, had a closer look at the role of persistence into longer-term outcome, as well as the impact of bridging therapies, and particularly also the use of inotuzumab in patients that have very high tumor burden at time of inclusion. and where we did see a very effective approach here in terms of bridging with in a to the map. Now, in terms of the operational side of the business and the governance side, we did strengthen our board. We had Mike Bonney join as the new chair of the company and Rob Rao, who's an expert in autoimmune diseases and inflammatory diseases. So broadening of the skill set on the board and obviously a sort of the next step in terms of the evolution, both from a movement towards commercialization, which is obviously where my body's background is obviously very strong, but also an expansion from a medical perspective into adjacent indications outside of oncology, where it's clearly where Robbie Rowell's particular experience is extremely valuable. Now, in addition, obviously, we've been driving through a remarkable amount of growth and maturation of the organization as we're setting up our commercial manufacturing capabilities, getting through first regulatory filings and now keep pushing through that process and are preparing for commercialization. And there is a group of very talented leaders within the company that have really risen to the challenge and have done a fantastic job and a recognition of their work and their leadership have been promoted to senior vice presidents within the organization. This includes Brian on the regulatory side, Chris Gray, site head for Stevenage, Marcus Grill on quality, Claudia Mercedes, really operations from the manufacturing technical operations side, but also actually in a broader role than that. And then Dilip Patel, who's looking into market access and obviously did a fantastic job on that side as well. So great to see this group of leaders really grow up and within the organization and having made substantial contributions that we expect to see a lot of important contributions going forward to the business. Moving to slide number six. I would like to just briefly remind you of some of the key data that we did update on at ASCO as well as at the EHA. Both meetings happened during the course of June this year. What we did focus on is actually look at the totality of the data from the Felix study. And as you remember, the Felix study has three cohorts. By far, the largest cohort are the patients that have proper relapsed refractory disease with morphological disease, so more than 5% tumor burden. And this is the vast majority of the patients that we have treated. We have also had two small cohorts in addition that we have included in the study, a small cohort for patients that had isolated extramedullary disease. That's typically a cohort that actually gets excluded from clinical trials because of the difficult nature of the disease and the challenges of managing those patients. but also a small cohort of patients that have minimal residual disease. So disease burden below 5%, but above 10 to the minus 3. So a very relatively narrow corridor of MRD-positive disease. So that's the group. We actually analyzed the totality of that data. And as you can see, this is a total of 127 infused patients. And what we're starting to see is incredibly encouraging in terms of the patients that actually are in ongoing remission without subsequent stem cell cancer or other therapy. And that is, I think, really important because about 40% of the patients that actually continue in remission without any need for additional therapy. We also have this smaller subgroup that I'll also refer to now in the next slide, then that received a subsequent stem cell transplant. There was 18 patients. They received this transplant while being in complete remission, not only in complete remission, but also being MRD negative. So no signs of measurable disease in these patients at the time of transplant. And then obviously we had also a group of patients that were moving to other therapies or have relapsed and died. So that's the status with a median follow-up of 21 months, which was the data cut that we were using for the ASCO and DHA presentations. Moving on slide number seven, we're looking actually at the event-free survival of the patients. And as you can see, the event-free survival, and we're looking here at the two curves with and without sensing for stem cell transplant, but both curves you can see are stabilizing. and actually are starting to form a plateau, which is very indicative of a substantial portion of these patients remaining in continued remission, which is also extremely encouraging in this very difficult group of patients who have a very aggressive form of disease. When you see the curve, actually, for patients that include the stem cell transplant, that's the green curve. The blue curve are the patients where we center our patients that went on to stem cell transplant. What you see when you look at those two curves is actually a picture which is the opposite of what you would normally observe in these studies. Normally, we'd observe that patients that actually with stem cell transplant would do better and would actually give you a better, eventually, survival. What we're seeing here, it looks like the inverse, certainly not doing better, possibly doing a bit worse. if they actually receive the stem cell transplant after receiving OV-cell. Now, when we look on slide number eight at the overall survival, we see a similar picture. Certainly no evidence that a patient receiving a transplant provided them a survival benefit. And so very interesting in the sense that clearly the product on its own appears to be able to deliver a longer-term outcome and may actually be able to serve as a standalone therapy for a subset of the patients. So these are two of the key findings that we were presenting at ASCO and DHA, which we move on to slide number nine. What we're evaluating there on the left-hand side is the impact of CAR-T persistence in event-free survival in the patients. What you can see on the blue curve on the top are patients that have actually ongoing CAR-T persistence, and you can see that teeth tend to do very well, again, with the stabilization of eventually survival. Patients that lose CAR-T presence at 12 months, you can see that's the median curve, the green curve, and patients that would lose CAR-T persistence already at six months if the red curve is tracking below, indicating that indeed longer persistence of the CAR-T cells appears to be associated with a better performance on an entry survival. And just as this other surrogate to look at sort of the impact, we're looking at B-cell eplasia, and you can see also there the same type of stagger, but less differentiation between the patients. So persistence seems to be a better readout and a more reliable readout, if you want to understand the potential impact for longer-term outcome. Now, in summary, on slide number 10, quick takeaways from this pooled analysis. First of all, 40% of the responders are in ongoing remission without any subsequent therapy, and this is now with a median follow-up of 21.5 months. We clearly see evidence of a plateau forming, both in event-free survival as well as in overall survival. it does not appear that stem cell transplant-based consolidation provides an advantage for the patients and does not appear to improve event-free survival or overall survival, which is certainly an important outcome consistent with the effects we're seeing, but certainly unusual in the field so far. And clearly, we do see an interesting correlation between online persistence and improved eventually survival in these patients. With that, what I'd like to do is actually move to sort of more the operational side. And so they're getting to commercial launch readiness, move to slide number 12. As you remember, we sort of have been already very active in the preparatory steps to get ready for commercialization for quite an extended period of time already. And a lot of that, obviously, was really focused on a key area of activities. Clearly, it's creating awareness around the medical affairs activities, as you would expect, building the value stories for market access of the product. But then what's very involved is certainly the onboarding of the treatment centers. And that onboarding process is very involved, not only from a company, but also from a center perspective. That's a real effort that actually has to be put in. That goes across quite a wide range of activities that we need to sort of integrate in, whether it's related to apheresis, to the actual delivery of the product, the handling product of the product at the center, as well as additional support that we're looking to provide both to the centers and downstream to the patients as well. So it's quite an involved process, including everything related to the cell journey from the collection of the cells at the center to the manufacturing process and back. And the IT systems required to really be able to track the product and to ensure that we have a a very clear chain of identity throughout the entirety of the process. So a very substantial amount of work that's ongoing there. We're on track to have between 30 and 36 centers ready for activation by the time of an approval and are going to move once we're getting to that point would expect to be within the first year of launch at a level of about 60 centers onboarded and active with the product. So we're moving here in a very significant way as well as you know at a significant number of centers even for the initial startup phase. Now what we're particularly focusing on where we are at this point in time is really looking at the integration of the workings and testing, frankly, of all the systems required to deliver the product. So there's a lot of activity going on, making sure that all the interfaces are working between the different processes, the different systems. And that's a very involved process that we're actually engaged in in the third quarter and leading into the fourth quarter to make sure that all elements required to deliver this therapy are fully operational and tested out and actually have achieved the level of robustness required for a commercial operation. Now, on the next slide, it's just a brief view on kind of where we are and what some of those activities are that we actually need to think about at the time point when we actually do get to an approval. Obviously, we talked about the path there on the prior slide. We eventually, get to a point where hopefully around the target date, we do receive an approval for the product. Once that happens, there are several activities that need to take place. On our side and driven from the company side is really kind of the activities that are defined by the label itself. And there are certain aspects of training and activity that only can actually be finalized and run through at the time when the label is fully set and determined. And that actually has to do with a set of trainings that have to be consistent, obviously, with the approved label, as well as obviously administering a REMS strategy and training that needs to actually be implemented at that point in time. So those are elements that, from a company perspective, you'll be able to complete once an approval is in. Now, the centers themselves need to run through quite a range of activities at that point in time that really make sure that they're internally ready to be able to actually manage this type of a therapy, both from an administrative perspective as well as from an actual physical operational perspective. And you see quite a set of those activities that sort of will actually have to be worked through on the center and the inside of the center. And you can see that on the right-hand side. spell that in a bit more detail. Now, when we think about what that means from an overall timing perspective, you can see the blue curve or blue arrow up there is actually quite a range of time that we actually see where from that time point where the center actually can get activated until it actually would enroll the first patient. And we will see certainly a variability among centers in terms of the time it will take to be on board and be enrolling patients. To look at that in a bit more detail, we will go to the next slide and just look at sort of in a relatively simple way of what are some of those key activities and timelines. So completing the site accreditation, we expect will take anywhere from two to 12 weeks with the centers that we have prepared for you through the onboarding process, but are now from the time point where you can actually initiate the site activation will have take anywhere between two and 12 weeks of the patient screening, look at freezing schedule, then having that completed anywhere from one to two weeks at that point in time. And then obviously the anticipated range of delivery time of 16 days. So when you think about that and you think about it, a target date, a Purdue for target date of middle of November, and as well as sort of year-end holidays, it is reasonable to assume that the first patient dose will be happening in the early part of 2025 if we're operating on those timelines. So I think that sort of, I think, hopefully gives you a sense for what it means to start up and what are sort of reasonable assumptions around when to expect kind of first patient's dose, and then obviously it would gear up from there as we go through the course of the year. Now, with that, what I'd like to do is switch gears and just briefly talk about sort of the OB-Cell product family on slide 16, Franchise Opportunity. This is the slide you've seen before. Also, we continue to work not only on the current activity on the adult ALL side, but also working on the pediatric side as well as the autoimmune side with OB-Cell. And we'll continue to actually work on auto-122 as well as auto-8. Auto-122 mostly on the pediatric ALL side where we do additional work with the UCLH and GOSH, our partners for that program for a long period of time. And we're also obviously with Auto-8 continue to work on the multiple myeloma side, but we're also looking to sort of expand the opportunity for that program going forward as well. and we'll update you as we go forward and initiate next studies with that program when that actually happens. So with that, just a quick word on the environment on the autoimmune side of this space that many of you have watched very carefully. We had one major conference that happened in Q2, which was the ULAR conference. Interesting data set presented during the course of the conference. I think what we're starting to see is some differences that appear between programs still early days in terms of understanding what is contributing to some of the differences that are being observed, to what extent are those product driven, to what extent are those factor variability in the patients that are being treated. But certainly very interesting development that we're seeing, but also overall I think also very nice cooperation of the initial observations that we have seen with gerakshet in Erlangen that indeed there is very profound impact that can be had in those patients using CAR-T approaches. When we look at the next slide, just to remind you obviously that we have a program that has a remarkable set of similarity in terms of the clinical properties to the program that's used in Erlangen. We have, but also not only do we have a high degree of similarity in terms of the efficacy, the persistence on the pediatric ALL side where we can compare the programs directly. But also, obviously, we do have a very substantial amount of safety data, which also is an area where we can see differentiation to the program in airline, but also the differentiation to any of the other CAR-T programs that are currently commercially available. And what you see is just a summary there on the right of the table on the various key outcomes that we have seen across the various studies that we've conducted with OVCEL, and I think give you a very good view on the level of activity that we're seeing and the ability to achieve those levels of activity with a very attractive safety profile. Now, the study on slide 19, the Carlisle study, our phase one study in SLE, as I indicated, The study obviously started up, happened during the latter part of Q1 and into Q2. First patient dosed in Q2, and we're continuing to enroll in the study. We're planning six patients at a 50 million cell dose level, which obviously is a level that we know to be highly active in pediatric ALL, giving us molecular complete responses, and also a level of dose that is also highly active in the adult patient population, where, as a reminder, we're using as little as 10 million cells to induce complete remissions in patients with high tumor burden in that setting. So overall, I think we're at a very interesting stage. We're starting to sort of get first insights from a data perspective, and we'll also continue to collect that data with a plan to have an additional update on clinical data late in the year. Now, other pipeline programs on slide 21, as you remember, there's a number of other programs we're working on. I think with regards to AutoAID, I already indicated that we're looking at potentially expanding the program into additional indications. So that's something that's ongoing and will update certainly by the end of the year or the next year on sort of the trajectory we're going to be on. And then just as a quick highlight, because we haven't actually talked about that in a while, is Auto6MG. That program also is enrolling patients, and first patient actually has been treated as well in the second quarter as part of the progress that we were making during the quarter. So overall, progressing well, and we also expect additional publications to come out during the second half of the year related to our clinical programs that we've been conducting. With that, I'd like to hand over to Rob, who will then lead you through the financial results.
spk03: Thanks, Christian, and good morning or good afternoon to everyone. It's my pleasure to review our financial results for the second quarter of 2024. So I am on slide 23, where we see at the top our cash and cash equivalents. At the end of June 2024, totaled $705.9 million. That's compared to $239.6 million at the end of last year, December 31st. Our total net operating expenses for the three months ended June 30th, 2024 were $58.9 million as compared to $44.4 million for the same period of 2023. For research and development, These expenses increased from $33.2 million to $36.6 million for the three months ending June 30th, 2024, compared to the same period in 2023. This change was primarily driven by increases in operating costs related to our new manufacturing facility, employee salaries and related costs, and OB cell clinical trial and manufacturing costs. These were partially offset by a more favorable UK R&D tax credit reimbursement for the period as well. General administrative expenses increased from $11.1 million to $21.9 million for the three months ending June 30, 2024, compared to the same period last year. This increase was primarily due to salaries and other employment-related costs, driven by increased headcount supporting our overall pre-commercialization activities. And finally, for the company, net loss was $58.3 million for the three months ending June 30, compared to $45. 0.6 million for the same period in 2023. Autoless estimates that with its current cash and cash equivalents, we are well capitalized to drive the full launch and commercialization of ObieCell in relapsed refractory adult ALL, as well as to advance its pipeline development plans, including runway to date in the first pivotal study of ObieCell in autoimmune disease. I'll now hand things back to Christian to wrap up with a brief outlook on milestones. Christian.
spk02: Okay.
spk03: Let me, I'll jump in here. We're waiting for Christian. Maybe moving to slide 25, just again to hit on some of the anticipated milestones through the year end. We've got the target action date on the FDA side with the PDUFA, as Christian mentioned. That's November 16, 2024. And we'll have updates certainly at the end of ASH. You've seen some of those with the ASCO data and EHA. That'll be further advanced and presented towards the end of the year. And then as Christian mentioned on the SLE Phase 1 study, we expect initial data from that program later in the year.
spk04: So Rob thanks a lot for jumping in. My headset was basically given up. So what I actually wanted to say in addition to the news flow is really that we're going to be obviously laser focused on getting the program through the registration for first approval and getting the launch off the ground with the product. That will be the primary focus of the company. Looking forward to the data update, absolutely. But operationally, that is what we're really going to be having our eye on. And we're looking forward to keeping you updated on the progress there. And now we're happy to actually go into Q&A.
spk01: Thank you. At this time, we will conduct the question and answer session. As a reminder, to ask a question, you'll need to press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1-1 again. Please stand by while we compile the Q&A roster. And our first question comes from Gil Bloom with Needham & Company.
spk08: Gil Bloom Hi. Good morning, everyone, and thanks for taking our questions. So, first one, as it relates to the launch, I'm sensing here maybe something of a rolling launch. Would we see sites coming on, you know, over time, basically?
spk04: Hi, Gail. That's actually not what it is. What we're trying to do is just explain that the actual activation at the centers is ultimately a decision or, frankly, a process that's governed by the centers. And the timeline that we're seeing, anywhere from about two weeks to 12 weeks, is pretty much what we see across the space with centers that are ready to actually get activated and then the actual time of activation. A lot of time it is actually also driven in the centers by, frankly, patients that are in need of therapy, and that usually actually accelerates the process and the final stretch of the activation. This is not a rolling launch by any stretch of the imagination. Being able to be out of the gate, you have 30 to 36 centers ready to activate at that point, which has been all, you know, the internal part of the centers, um that compares very favorably to almost all launches that actually have been done in aerospace and could you go from there to 60 centers within a year will give us more than 90 percent access patient access uh in this indication uh which is obviously a very very rapid build much more rapid than i think we've seen across the across the competitive programs thank you for the clarification um and maybe moving to the
spk08: autoimmune data. So probably the top question is, what level of data disclosure should we expect at the center? Are we talking mostly safety, or will there be some follow-up to suggest efficacy as well?
spk04: I think that most of the update will clearly be on safety and short-term impact. or shorter term impact of the therapy. As I indicated, we treated the first patient in Q2, so that gives you the maximum observation time that you will have. And obviously the rest of the patients will be at a shorter time period than obviously a Q2 to end of the year timeline. So there's going to be initial data that will indicate activity, but obviously will not be a substantial amount of follow up yet on most of the patients.
spk08: Maybe a bit of a in the weeds question. So we saw data updates for parties that include for one BB coast them versus CD 28 coast them. And historically, people have talked about how CD 28 tends to, you know, have very high ramp up in cells, but also leads to maybe higher toxicities and for one BB can link to, you know, really long aphasia. Maybe there are AID autoimmune indications that are more amenable to one versus the other? I'm probing your thoughts here.
spk04: So what you're basically referring to is that the co-stimulatory domain has sort of an impact on the initial activity that we see of the cells, and particularly the cell expansion of the CAR T cells that we're seeing. And that is certainly been generically true that most programs would show a faster onset of proliferation of the CAR T's with the CD28, somewhat slower in 411BB. But then 411BB would give you longer persistence, and the CD28 typically gives you very little persistence. And that also then has an impact, obviously, on the longer-term, you know, B-cell aphasia, et cetera, you'd see, because you frankly, in one case, you have no active agent. In the other case, you have active agent. What I think is worthwhile remembering, certainly for OB-cell, is that actually the peak expansion that we're seeing with our product exceeds that of the CD28 CAR. Okay? So the story certainly is a bit more complex than just post-simulation, so we actually see have an excess level in terms of maximal expansion of the CAR-Ts, which are beyond what the CD28 cars were able to do. And that combines, in addition, with a very long persistence. So that gives you a very, I think, unique set of properties that we do have with OVCell that is quite different from the rest of the commercially available CAR-T programs. Now, in terms of the type of activity you may need, depending on the indication, That's an interesting question, and I think I would probably answer it from the position of what is the mechanism of action. And the mechanism of action, obviously, that we have is the removal of B cells, C19-positive cells, and also plasma blasts. In the case of autoimmune disease, what you have to get rid of typically are clones of cells that actually drive the autoreactive antibodies. And so you need to actually have a complete depletion of those cells if you want to get to a reset of disease. And that, I think, sort of should be the expected outcome for a CAR-T therapy, which is obviously very moral therapy for this type of a disease. So that mechanism is shared across the board. And I think what you need to ask then is, what are the properties that you need to have to achieve that goal? And in my view, what you need to have is, because it's a cell-based mechanism, you obviously need to have an ability to actually have proper cell-cell engagements. In other words, your CAR T cells have to find those particular cells that drive autoimmunity and then actually have to be able to take them out. Because it's a cell-based process, you need to go through cell migration, distribution, et cetera, to do that, and you need to get all of those cells eliminated that have that ability to drive the autoimmune reaction. And that means there is a certain amount of time required to actually do that. What we do not know is we do not know what's the minimal amount of time to actually achieve that goal. What we do know is that the time that actually the program had in the airline study was sufficient to do that. So the importance of the message that I was looking to give before in the prepared remarks was that our product actually shares all of those properties. to the resale compartment and sufficient persistence to actually achieve that goal shares that with the airline program but has a better safety profile. So that's, I think, the way I would answer the question. How short you can go, that's frankly a thing that none of us knows at this point because we haven't seen enough data from other programs with different profiles from the airline product to get a feel whether something else might also work. But what we do know is that that profile that we had seen in their lungs does work.
spk08: All right. That's very helpful, Christian, and thanks for taking our questions today.
spk01: Thanks a lot, Gil. One moment for our next question. And our next question comes from with Truist.
spk06: Hi. Good morning. Good afternoon, guys. Thanks for taking the question. So congrats on the progress as well, Christian. I'm going to add on to Gil's questions on the centers here. And I'll maybe ask something related here. Among the 60 centers targeted, how many centers require an approval in hand to even begin the qualification process? And just to give some color here, All in, how long does it take for a center to become an ATC, including the whole qualification process and site activation required? And then I got a couple of quick follow-ups.
spk04: So there's sort of two steps to that. First of all, the center has to be interested to actually onboard the program. That's the first road we have to take. We had remarkable success in having the centers interested in actually taking the product onboard. hits the very bullish guidance that we're giving of 30 to 36 centers ready to be activated at time of approval. So that's a very significant involvement. Just to put that in numbers, the centers do cover about 65% to 70% of the ALL population of the US. So that's the magnitude we're talking about. And that's right out of the gate. So that's the level of interest to actually even engage. That's a first few things. Second is you need to actually go through all the preparatory steps so that you can get, when you get to the level you can actually activate the center. That can take anywhere from six to 12 months. So that is a very involved process that has a lot to do on the IT side. There's contractual pieces that you have to put in place and so on. So it's a very involved process and typically takes in that order of magnitude of six to 12 months. This is why we've been working on this for an extended period. time many of the centers that we expect to get ready for activation after an approval is in are already now in the onboarding process just to be clear so that's a continuous process and most of these centers actually are in are ongoing in terms of process already at this stage so those are kind of the key things but then the final bit is obviously you know, we can go with these 30, 36 centers as far as we want to go, but there are obviously the final steps do require the actual label in hand. And that is sort of the final, that's then the step that actually gets you to that, into that, you know, between two weeks and 12 weeks max time to actually get the centers fully activated and enrolling pensions. So that's sort of that stretch. And obviously the, The vast majority of the centers they're working with, obviously, have made the decision to actually put all the work into the onboarding process ahead of actually having the label in hand. There's some, obviously, that would actually want to wait until the label is there and would sort of actually engage the higher workload of the activity later on. But those, obviously, will be beyond the 36 centers and will be at that end. But the overall majority of the centers actually have been, you know, remarkably engaged and willing to actually proactively work on the actuation.
spk06: Thank you, Chris. That's really helpful. Then maybe bigger picture, with the recent deal with BioNTech and the RAISE, you know, you've got a good, nice pot of cash that you can kind of dispense. for clinical development here. We see a lot of, obviously, a lot of prioritization done for commercializing OB cell as well as doing the autoimmune study. Maybe it's a good time to also revisit what comes next. What's next when you're really high on the priority list after these two top two priority items?
spk04: Right. So, look, we're very keen, obviously, on sort of, you know, committing to the next biblical study. So this is, you know, very much a workflow that is in full swing at the company. Obviously, at the same time, we don't want to distract from what we need to do now, which is a very heavy lift for any organization going through the first time. an approval and a launch so um we want to be mindful that you know the one hand that we're having the focus required to execute and execute with what we hope to be a vested class launch um uh at the same time obviously we're preparing for that for that significant engagement and uh into the next typical study so that's what we're working on um and grossly we'll update you know the from a public perspective at the right time around that. But that's also where there's a lot of activity in. We're also very excited about the interaction we're having with BioNTech. There's really great chemistry between the teams, a lot of good engagement, broader discussions that are going on. And I think that's sort of also a key activity that obviously doesn't have yet that level of visibility in terms of news flow, but it's an area I'm very excited about, and I think will create additional opportunities as well that are not necessarily visible at this point from an overall company perspective. So I'm excited about those next steps, but first things first, get the approval, get the launch off the ground, get into the next pivotal study, and then we're going to move from there. but very excited about kind of what the end of the year and then also the next year will bring.
spk06: Great. Thanks so much for taking my question.
spk04: Thanks a lot.
spk01: And one moment for our next question. Our next question comes from Kelly Shee with Jefferies.
spk05: Hi, congrats on the progress and thanks for taking my questions. As we are very close to the first launch for Atlas, Curious, just a quick question. Maybe, like, it's too early to comment on the price of Abicel, but I'm curious if the split dosing regimen would add additional cost compared to a single dose of Abicel therapy.
spk04: Hi, Kelly. Really good question. So, first of all, obviously, on price, you're right. That would be too early to actually give any specific guidance. I think we can only reminds of the car price levels that we see with the Carters, which is around $462 in the US, Thousand, and Convio, which is around $582.
spk00: There's an overlap.
spk04: There's also an age range. We know Felix Tuttle was from 18 years onwards. When you look at the labels, for the two commercial products. One obviously goes up to 25 years, which is Camarilla, and the second one, Picardus, goes above 25 and older. So that's sort of the range that's currently in the market. I think we can give more guidance in that and just actually basically point to the reference prices that we have here in this phase. In terms of the cost or the added cost related to dosing, What we do, obviously, with OBCL is we do a tumor burden adjusted dosing. And that actually has proven to give us an enormous amount of robustness in terms of the safety data, which is driven on the long half of the design, but also takes into account, obviously, the tumor burden. And remember, these are very particularly older patients, tend to be fairly frail patients. And a lot of these patients certainly cause a lot of issues lead to actually treatment-related mortality. We've seen that in some of the real-world data as well, that being a real issue. And as you may remember, our median age in the study actually was about 10 years older than some of the other studies that were done in the space. And despite we did that whole thing through the pandemic, which also aggravated a lot of the safety-related challenges further. So the dosing that we have in combination with our profile, gives us a very substantial improved safety profile. The primary cost that actually you see for the delivery of the current heat is not the delivery itself. It's not the administration, because that's pretty uneventful. That's literally an infusion in that staff that tend to be very short infusions. We're talking maybe 50 minutes or something like that. So it's a very short infusion. That doesn't actually add a significant amount of burden. What actually adds burden and what really drives cost is related to the management of the patients where they actually do experience hybrid CRS or they experience hybrid ICANN. And in fact, the ICANNs are almost worse because they tend to take a substantially longer period of time to actually get under control. And also often are associated also with long-term steroid use and a combination can lead to sepsis and treatment-related mortality. So that's where the real cost actually comes in. to be able to reduce the number of events massively, but also shorten the recovery time, which is both elements we've seen with OBSEL in the Felix study, actually reduces massively the cost, and is actually one of the key attractive elements for onboarding the product, which is that the product actually will be less intense to manage, because it's less intense to manage, actually the profitability goes up for the centers, And that actually is one of the key drivers that, from a financial perspective, is attractive for the centers, why the onboarding also is going as well as it does, and what is also recognized not just as a clinical improvement as well as the longer-term outcome, but also an immediate financial improvement that I think is visible and quite well understood within the centers that we're engaging with.
spk05: Super helpful. And thanks very much. And also have follow up on autoimmune. Follow your comments from opening remark. So although we saw better tolerability of CD19 CAR T cell therapy autoimmune indications when compared to heme-on-cure trials from Dr. Sheth's pioneer work, we started seeing neurotoxins from other ongoing trials in lupus. So curious if you could share your insights on if the patient baseline difference as more like a dominating factor or card design or maybe other reasons regarding the impact on safety. And also another important question here is how Obicel achieved much better neurotoxic control in the hem-oncology indications generally speaking, and also whether this is transferable to autoimmune trials, in your opinion. Thank you very much.
spk04: Yeah, very good question, Kelly. So what we're also seeing is, in general, what we're seeing is that there's several parameters that drive immunological toxicity, and this is both actually CRS and neurotoxin. And the parameters, on the one hand, are the number of target cells that have to be taken and have to be removed. Obviously, that defines the number of CAR T cells that get activated. And with that, depending on the design of the CAR T cells, gives you a base level of activity, potential cytokine release, and also the risk of neurological toxicity. So that's one element. So it's the number of cells. When we look at the autoimmune indications, we do not expect to see significant variation in terms of the number of cells that have to be removed. These are patients that have overall normal immune system. They are lucky in the sense that they have individual clones that recognize structures in the body and drive autoimmunity as a consequence of it. But it is not a proliferative disease as we would see in lymphoma or leukemia. So we see a pretty steady level of pretty much a normal level of B cells and plasma blasts that need to be removed. So that sort of basically becomes a constant. But then actually it becomes a variable, and that's the second element that can drive toxicity, is really the design of the CAR-T product. There are two key components there. We already talked, and I think Asti was mentioning that before, which is the The cost inventory elements have the impact that the cost inventory elements can have. They do have an impact in terms of how quickly the cells proliferate and how much nitrogen release they actually do. That's an element that is sort of in part coming from the cost inventory domain. But what we have proven with OVCell is really that the primary driver and probably the most important parameter that we're dealing with is actually the way that the CAR T-cells physically engages with the target cell. And what you do remember about the design of OviCell is what we're looking to do with OviCell is create a product that behaves as physiological as possible while obviously being a canary antigen receptor, but trying to be as close to a normal T-cell engagement. And what's characteristic for a normal T-cell engagement is that the engagement is short-lived. So detail actually recognizes the target cell, forms the CyMAX, delivers the cytopoxic content, which drives the cell death or the apoptotic process in the target cell, and then actually disengages rapidly. We're talking minutes in terms of the engagement max. And that short engagement is really characteristic of a normal physiological engagement. And it is that engagement that actually is clearly different for the first generation of CD19 CAR T programs in the space, but also will be true for most of the products currently being developed for all new diseases. And that is that most of those designs use antibodies fragments to CD19 that are high affinity in nature, which means they have a fast down rate and a very slow off rate. And next, if you then think about thousands of CARs on the side of the CAR T cell, thousands of CD19 molecules on the target cell gives you basically an enormous amount of high affinity interactions between the cells and very, very long interactions between them. Now, those long interactions do not actually help the kill. That already happens within a minute or so. But what they do is they drive an over-activation of the CAR-T cell. That over-activation drives the cytokine release as well as actually drives exhaustion of the cells. And ultimately, it's really contributing in a very significant way to toxicity. And that toxicity is unrelated and unnecessary to get the activity. And so what we designed with OviCell is really obviously a product that has the ability to be specific, but disengage rapidly after delivering the kill. And we do that by having about a hundredfold faster off rate. from the target than any of the other products out there. And that gives us a very different behavior of the CAR T-cell and fundamentally changes the toxicity profile. That difference will be relevant in any setting and will give you a substantially better safety profile in any setting you would actually apply the CAR T-cell.
spk05: Really appreciate your insights. Thanks, Christian.
spk04: Thanks a lot, Kelly.
spk01: One moment for our next question. And our next question comes from James Shin with Deutsche Bank.
spk09: Hi, good morning, guys. I had a question on the onboarding activity. The range of two to 12 weeks for accreditation, are the sites that would fall into the two-week range centers that have existing CAR-T programs and those that fall in the 12-week range are centers that are CAR T-naive? That's question number one, and I have a follow-up.
spk04: Okay. Hi, James. Good way of thinking about it. It's suggested that that could be the case, but I don't think actually that's true. I think it has a lot more to do with the workflow at the centers. There are currently probably four to five programs for many of the centers that they're onboarding, so there's a very involved process for many of the centers, so there's a capacity component. And I think ultimately it will be very much driven by, frankly, patient needs as well. So I think that's going to be a big driver of actually how quickly that final stretch on the activation will occur. So I think there's a lot more to do with that. Most of these centers, though, are active CAR-T centers. We're talking about the top centers in the U.S., which, frankly, all of them tend to have multiple CAR-T programs already on board.
spk09: Appreciate that. And then on the P&L side, are we pretty much at full commercial run rate for the commercial activities? On the spend side, that is.
spk03: Hi, James. It's Rob. Yeah, so we are still going to be building towards the end of the year. We haven't fully built out the team yet in the U.S. I wouldn't necessarily project kind of a flat run rate from Q2. Thank you very much.
spk02: Thanks a lot, James.
spk01: One moment for our next question. And our next question comes from Matthew Phipps with William Blair.
spk10: Hey, Christian. Thanks for the update and taking my questions. Following on a little bit with what Kelly asked on earlier, but with Cabaletta reporting a grade 4 ICANN this morning from their lupus trial, they said they're implementing some protocol modifications, including some seizure prophylaxis. Wondering if that's something that you guys have used or thought about using. And then I realize you are very early in your trial, Faradami, but maybe you can just give any kind of comment on
spk04: the safety profile is reflecting uh the you know kind of felix and other experience with themselves so far yeah um good to have you all met and thanks for the question um so i think probably the best surrogate here obviously we're going to indicate where we're early on in our in our phase one study so um you know not seeing something in in that early stage doesn't really you know get you to give you a clear-cut answer. So I think the better part of looking at it, the better way of looking at it, is really in the old CAR-19 extension part of the study where we had about 40 patients with various forms of non-Hodgkin's lymphoma. And what we did observe in those patients is that without prophylaxis, so just normal conditioning and dosing, and prophylaxis, also no steroid prophylaxis and no seizure prophylaxis in these patients, we actually did not observe neurological toxicities in these patients. So we didn't observe the VICAMs in these patients, which I think is giving us a lot of confidence around the overall product property. And similarly, our patient with low disease burden in ALL also had very limited neurological activity and, in fact, no grade 3s even in those settings. So overall, I think The product profile is obviously what's really different here for OV-cell. And what we know from our product is that clearly that we do have a different behavior that we're seeing. And we're based on the non-hospitalized data, which is probably a good way of sort of comparing. Although we do have, obviously, localized high tumor burden in these patients, there's not a lot of, bone marrow burden tends to be very low or normal, and normal circulating B cells, that in that setting, obviously, we have not seen neurological toxicity in the patient. So it gives us a lot of confidence that we are obviously in a good space, but, you know, it's early days and autoimmune, and I think there's a lot to be learned.
spk10: Great. One quick follow-up. I don't think you discussed this, but when do we get an announcement on, I guess, the next autoimmune disease beyond lupus that you guys might explore?
spk04: I think we're, you know, obviously we're going to go through kind of the launch process. I think, you know, kind of the next trajectory and update we're probably going to provide in Q1 in terms of next steps. And, you know, that's sort of what we're working towards. But at this which is really on getting through the regulatory process and getting way into the launch before diverting in a broader way, diverting focus.
spk10: Great. Thanks, Christopher.
spk01: Thanks a lot. One moment for our next question. Our next question comes from Yanan Zhu with Wells Fargo.
spk07: Great. Thanks for taking our questions. On the autoimmune side, I was wondering, you mentioned the three centers are enrolling in UK and Spain. I'm just wondering, are all these centers also Felix centers? And have you enrolled patients, SLE patients, at all of the three centers? The other question related to autoimmune is, I was wondering about your thoughts on the recent cell publication regarding allogeneic CAR-T and demonstrating some efficacy in some autoimmune indications. As you look into that data, what is the learnings and takeaways regarding the prospects of allo-CAR-T in autoimmune? Thanks.
spk04: Thank you, Adam. First off, with regards to the centers, the answer is all three centers have been Felix centers. So there's experience in all centers, and they're all evolving. So that's, I think, the first part of the question. The second part of the question is related to just different modalities that could be giving you deep remission, the deep responses in the B cell and plasma Also, there's sort of three basic categories that are sort of under investigation. You have the autologous CAR T-cells, which is what we talked about mostly on the call. We have allogeneic CAR T-cells, which is what the question is. And then also there are bispecific T-cell engagers, which are sort of the three categories of at least T-cell mediated approaches to reset the B-cell compartment. What we do know at this point is obviously that with the autologous programs that we do get very deep responses. You know, if you look at the original data in the airline, I think the indicative that we can get to transformational outcomes, what we know in pediatric ALL or in adult ALLs, we can get extremely deep responses being, you know, MRD negative at a level of beyond the 10 to the minus six. It's the frustration where you can test it and the ultimate test is the activity of these products. We do know that the LMA programs can make a cut into the compartment. To date, all the data we have on the oncology side is indicative of the fact that that cut isn't as steep or as consistent. And I think that is certainly going to be true, I think, also in the autoimmune settings. But you do expect that when you do make a cut in the compartment that you see an impact. And even if you do even much less of a cut, as we've seen in the contentious use work with Blinzaito in the trials that were published earlier in the year, you could see that actually, at least temporarily, you could actually have a reduction of D-cell cans in those patients and see an improvement, a clinical improvement in those patients, doesn't appear to be actually sustainable, but you would see an improvement. So I think what we've seen so far is consistent. I think with what we know, what these products can do, the fundamental question is going to be, is there going to be a differentiation between D-cell engages and other genetic programs? And do either one of them is actually get you to a place where you can get a sustained outcome. And I think we just don't know at this point in time. I think we have a really pretty good feel that if all of these programs, if any, will have probably the best chance of actually giving you a transformational outcome. I think that's sort of where we are at this point. Obviously, it'd be interesting to see how these other programs evolve over time. And we'll be carefully watching the space.
spk07: Great. On the oncology side, I was just wondering your confidence about delivering the 16-day length to delivery time and also your sense of manufacturing failure rate and how do these compare with Tokars? Because that's something when we talk to some experts, these aspects of reliable delivery seems to be one of the factors that could drive the shift from one product to the other. Thanks.
spk04: Yeah, really good question. So, you know, this is a patient population we're in where you need the therapy to actually be delivered. These patients don't have extra time. There's not a redo typically possible. So you have to have very high levels of reliability on the delivery. What we're able to show in our clinical studies to the clinical studies with each other and, you know, remind you we did ours through the pandemic with a lot of limitations, we actually have a higher intent to treat. We have actually a higher level of intent to treat that was seen in the prior study, right, 84%, and that clearly was a very good outcome overall on intent to treat. So we can show, we can look at it from that perspective. We can look at it from the perspective of and we're at 21 days across the Felix study and one of the things that we have included and sort of implemented in the course of the Felix study is a set of faster analytical methods that would actually allow us to accelerate the release of the product. So a big chunk of the time you actually have in the event of delivery time is not your manufacturer, but it's actually the analytical testing to sort of achieve the release. And then the final part is related to the logistics. And one of the things that were implemented for the commercial delivery, this is part of the collaboration, the deal that we have with Cardinal Health, is that we are shipping a product before the release is completed to the U.S. so that the product is already close to the site. It's on our custody and will then actually be released once the product release is through. But what that does is it basically takes that element of the turnaround time out of the equation. So between the logistics element as well as the faster analytics, we'll be able to calculate six days out of the event delivery time. And so what we're guiding is currently 16 days at time of launch. with an opportunity to reduce, and that time is pretty much in line with what the best competitive data looks like today.
spk07: Very helpful. Thanks, Christian.
spk04: Thanks a lot, Gerhard.
spk01: One moment for our next question. Our next question comes from Sebastian van der Schoot with Van Lounschot Kempen.
spk00: Hi, Tim. This is Chiara Montironi. I'm on behalf of Sebastian. Congrats on the progress. Thank you for taking my question. So I was wondering whether you could provide your thoughts or some insights on the recent approval of Blinsito in the consolidation phase of the multi-phase chemotherapy of the first line ALL. So what do you anticipate the effect will be on the number of patients in the relapsed refractory setting of this disease. Thank you.
spk04: Thanks a lot for joining. Pleasure to have you on. So this is a question related to the recent approval of FlintSight and the frontline consolidation. Obviously, this is data that sort of has been, you know, first of all, known about for quite a while and presented over the last two to three years, both in consolidation of both MRD positive as well as patients as well as patients that are gone through the initial induction and the initial consolidation with chemotherapy but then irrespective of status are exposed to wind cycle. What's been very interesting about that part of the data is that when you look at the data more carefully, you realize there's a subset of patients that appear to benefit. There's another subset that does not appear to benefit from that consolidation. And the group that did not appear to benefit actually were patients that were a bit older. And that's a very interesting kind of observation. And I think this is certainly something that I think we're going to need some follow-up and I think better understanding. But it was clearly, you know, certain patients that did actually benefit whereas others actually did not benefit at all. And so that's, I think, interesting just when you look at that part of the data. Overall, we think that most of the impact, actually, of the study has already been pretty much in the space, given that the data actually has been well-known. It was an ECOG study, so there's a large number of centers involved. There's a lot of patients that actually will be managed in sort of using BlitzSight in the frontline setting. And in that sense, also, it's baked in. And you can see that also when you look at the trajectory of BlitzSight for sales is that Clearly the sales upswing actually went ahead of the approvals, although it was driven off exactly that data that was driving and actually ultimately was the basis for the approval. So we think most of that is actually baked in, and we do not expect to actually have a major impact of the Velastri factory setting. And, but certainly, you know, would expect that there's some delay of some of the patients actually becoming refractory. So buying some time, but we also believe that a lot of that actually already starts to be, you know, realized that many of these patients actually start to get back to the point to relapse, given that the consolidation has actually been used for an extended period of time, certainly in the US.
spk00: Okay, thank you. Very helpful.
spk04: Thank you very much.
spk01: And this concludes the question and answer session. I would now like to turn it back to Christian for closing remarks.
spk04: Well, thank you very much for joining. A real pleasure to have you all on. Looking forward to keeping you updated. And obviously, as we said, you know, all focus on getting to the final stretch and hopefully get to approval later in the year and be in a position where we can get this to our patients, which is really something that we've been working towards for many years now and I think would be fantastic to be able to transition as we get to the end of the year to that stage. Thank you very much and looking forward to keeping you updated.
spk01: Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.
spk06: What happened, Christian, when you dropped off?
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