Hello, ladies and gentlemen. Welcome to the Autolus Therapeutics ASCO Analyst Conference Call. 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, Jonathan. Good afternoon or good evening, everyone, and thank you for joining us to take part in today's call to discuss the data from the pivotal FELIX study of obe-cel, presented today at the ASCO conference. I'm Julia Wilson, communications consultant for Autolus. With me today are Dr. Christian Itin, our Chief Executive Officer, and Dr. Claire Roddie, Associate Professor at UCL and Honorary Consultant Hematologist at UCLH, and lead investigator on the FELIX study. 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 to the status of clinical trials and development and/or regulatory timelines for our product candidates, and our expectations regarding our cash runway. 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 until 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. On slide 3, you will see the agenda for today's call, which is as follows: Christian will make some opening comments. Claire will go over the slides that she presented earlier today in the ASCO oral presentation, before Christian will wrap up with how Autolus is building the obe-cel opportunity and next steps. We will, of course, welcome your questions. Over to you, Christian. Well, thanks a lot, Julia Wilson, and thanks a lot for joining us at this sunny day in Chicago. It's been quite a remarkable day, I think, for us at the company, you know, presenting the first pivotal study. Obviously it's our great pleasure to have Claire Roddie here to actually go through the data and frankly, give you an opportunity, who may not have had the possibility to be here at the conference, to actually get a first-hand presentation of the data. In the distance here, we have Soldier Field, and we're just actually experiencing sound waves coming over from a concert that's sort of getting ready. We're sort of seeing obviously whether the sound will sort of overpower us or not. We'll sort of do our best on our end. It's a Taylor Swift concert, you may actually sort of recognize the tunes. Yeah. With that, what I'd like to do is actually hand over to Claire, who will run us through the presentation and obviously give us a first-hand account, of the data for the FELIX study. Great. Thanks very much, Christian, and thanks for joining us. I'm gonna talk today about the FELIX study, the top-line results. I'm Claire Roddie. I'm based at UCL in London. I think we're familiar with the background here. We know that the CD19 CAR T-cell therapy really, truly has revolutionized the field of relapsed and refractory acute lymphoblastic leukemia. I think we recognize also that obe-cel is really a very unique autologous CD19 CAR by virtue of its fast off-rate CD19 binding domain. Of course, this binder was selected to really, as a reaction, to other CD19 CAR T-cells in this space, where the issues around safety and limited persistence were a problem. obe-cel really doesn't have those problems. obe-cel has got an excellent safety profile and excellent persistence profile. The clinical activity of obe-cel has already been tested in some phase I studies, as I'm sure you're aware, both in pediatric and adult acute lymphoblastic leukemia. Of course, at UCL, we've been testing it in a range of other B-cell malignancies. From the point of view of today, we're really going to focus on the adult patient population with B-ALL that we've treated on the FELIX study. Again, most of you will probably be familiar with this schema of the trial design. Essentially what happens is the patients are screened, and they go for REED. They undergo bridging therapy at the investigating clinician's discretion, and then when they have a product available, they're admitted to the hospital for preconditioning chemotherapy with fludarabine and cyclophosphamide, followed by a split dose CAR T-cell infusion over day 1 and day 10. The criteria in order to receive the day 10 dose is the absence of severe immunotoxicity in that intervening phase. There's another additional safety measure that's been implemented in this study, and that is to titrate the day 1 dose of CAR T-cells to the pre-lymphodepletion bone marrow biopsy result. For instance, patients with bone marrow blast of less than 20% will receive a higher initial dose of CAR T-cells on day 1. That's 100 million cells, patients with more than 20% blasts will receive a lower day 1 dose, and that is 10 million cells. These patients will go on to receive a dose 2, in the absence of immunotoxicity, to a total dose of 410 million CAR Ts. It's important to note that irrespective of the differences in the pre-lymphodepletion bone marrow burden, actually 94% of all infused patients received both of these obe-cel infusions to a total dose of 410 million CAR T-cells. let's focus. Oh, sorry, do you need to move on to the next slide, Julia? I just moved it forward myself. Well, we'll go on to carry on now, and we'll look a bit at the eligibility endpoints and disposition of the patients. Important to note that the eligibility criteria, this was an adult ALL study, patients needed to be over the age of 18. They needed to have 5% or more blast in the bone marrow to be eligible for the cohort 2A. In terms of the endpoint, the primary endpoint was really mainly CR or CRI by central assessment, with secondary endpoints including a duration of response, MRD negativity and safety parameters. There were 112 patients were enrolled on this study. 84% of those enrolled patients were infused with obe-cel. There were some dropouts, and that was mainly due to death and progressive disease. Ultimately, 94 patients were infused with product, and the median duration of follow-up we have for those patients is 9.5 months. In terms of the baseline characteristics, there's a lot of information in this slide. We note that the median age of the patients is 50, but we actually did treat one patient who was 81 years old. Other notable factors here, we can see that these are high-risk patients. A lot of them are heavily pretreated with 3 or more lines of prior therapy, and 31%, and 53% are refractory to last line of therapy, 38% have had a prior allogeneic stem cell transplant, and 67% have been exposed to either blinatumomab or inotuzumab. Again, this often denotes patients who've been through more lines of therapy. In terms of the disease burden of these patients, I think this is important to emphasize. At the point of screening for the trial, there were 50% bone marrow blasts. That was the median bone marrow blast burden for this patient cohort. When you look at the point of lymphodepletion, the bone marrow burden is still high, with a median of 41% blasts. We know that this is a high-risk population for CAR T-cell therapy. We also have to point out that there is a sort of overrepresentation, if you will, of extramedullary disease in this cohort, with 19% of patients having extramedullary sites. We know that this portends to a sort of a poor prognosis in the ALL field. Extramedullary disease is poor outlook. I think this makes this slide particularly important. We know that these patients have lots of disease. We know they've got circulating disease in a proportion of cases, a lot of extramedullary sites, older patients. The fact that the manufacturing data is so crisp, clean, is really encouraging to us. I think on the left-hand side of the slide, what you can see here is that 96% of products reached the target dose, that's 410 million cells, and this is irrespective of whether you've got a high disease burden. You can see that even those with more than 75% blasts reached dose. In the middle of the slide, you can see the median transduction efficiency was 72%. I think you have to look closely at this, because those results really are clustered very tightly around that 72% mark, telling us again about how consistent, this process, this manufacturing process that we're using is. The last point of this slide is about this vein-to-vein time, what you can see here is that we have a median of 21 days for that vein to release. That's really important for this patient population, in particular, because they're often in urgent need of clinical treatment, and they often have rapidly progressive disease. This is a great place to be in terms of delivery of drug to site. In terms of the disease response, you can see it very clearly marked here, 76% of infused patients achieved CR or CRI. That's in the context of an extremely high disease burden for a large proportion of these patients. It's also an older patient population, a lot of comorbid patients. This is very encouraging data for us to see. What's more, these responses are deep responses, with 97% of responders achieving MRD negative disease response, as calculated by flow cytometry. In terms of whether or not these responses are durable, Well, this graph speaks for itself. 61% of responders are in ongoing remission without subsequent anticancer therapies at a median follow-up of 9.5 months. Again, this is really important data. We can see that the duration is really impressive here. There were a few patients who proceeded to stem cell transplant whilst in remission, but these were censored for the purposes of this pictorial representation. Let's look a little bit about the subgroup analysis. Here is CR/CRI assessment, there's lots of different criteria that we've looked at here. Fascinating, to get some early insights into what factors may predispose to response or not. We identified both extramedullary disease prior to lymphodepletion and high bone marrow blast percentage, and by that I mean more than 75% blasts, preconditioning. Those both were associated with a higher risk in terms of this subanalysis. Let's focus on the toxicity on this next slide. I think we've already alluded to the fact that a lot of these patients are older, a lot of them are comorbid, and that they have limited tolerance for high-grade immunotoxicity. In terms of CRS and ICANS, I think what we can see in the far right-hand column is, of all infused patients, we saw minimal grade 3 or more CRS, despite the heavy disease burden in this group. You can see it was only 3% of patients experienced a grade-3 CRS event. In terms of ICANS, again, limited grade 3 ICANS events affecting only 7% of patients. If you track into the table, you can see that the majority of those events were quite predictable in that they occurred in patients with high disease burden pre-lymphodepletion. This is a sort of a population that could potentially be watched more closely for this side effect. Tocilizumab and steroids were used, of course, for CRS, in 56% and 17% of patients, respectively, and there were very few patients who required vasopressor support for CRS, that's 3%. The ICANS we've alluded to already, that it seems to be associated with higher bone marrow blast at preconditioning, certainly the greatest event. In terms of treatments, the adverse events, there were lots of things listed in this table, but I guess the most common things to draw your attention to are neutropenia, affecting 36%, thrombocytopenia affecting 25%, febrile neutropenia in 25%, and anemia in 19%. There was 1 death on study that was related to HLH and neutropenic sepsis, that was attributed to obe-cel. The expansion and persistence data, as seen on this slide, is particularly impressive. When we ran the ALLCAR19 study, which was the phase I test of obe-cel in adult B-ALL, you can see that we did some pharmacokinetics in this table on the right of the slide. When we compare our experience of those early pharmacokinetics with that's achieved in the FELIX study, you can see how comparable those measures are. We get great peak expansion, the Tmax is equivalent across the two studies, and the area under the curve over the first 28 days very much mirrors what we saw in the phase I study. Suggesting that effectively, we're delivering the same drug to this patient population, which is very heartening for us to see. You look on the left-hand side, you can see a nice plot of the CAR engraftment and persistence by qPCR. What most patients have achieved, that peak Cmax of around about 100,000 copies per microgram of genomic DNA, which is, you know, is an excellent initial expansion. What's really nice to chart here is essentially where the graph plateaus out, and you can see that patients, even at 6 months, and 10 months, and there's further points of follow-up here, have bottoming out at about 1,000 copies per microgram of genomic DNA. What this is telling us, in these patients that are followed up to this time point, that they have got ongoing CAR T-cell persistence. We know from our early experience on the ALLCAR19 study that this is important or has been shown to be important for our long-term responders. If we had to conclude, essentially, despite this, a patient population that we've acknowledged, have got high disease burden, have got lots of poor risk features, are older and comorbid. Irrespective of all those factors, obe-cel can deliver complete responses in 76% of patients, and not only complete responses, but MRD negative deep responses. This is again, you know, this is something really that we're very proud to be able to share. That what's more, these responses can be durable. With 9.5 months of follow-up, 61% of responders remain in remission, which again, is, you know, a very important piece of data. I think one thing that's really important for us clinicians, particularly, is the tolerability of this therapy. In contrast to some other agents that are available, obe-cel resulted in very low rates of grade 3 CRS. As you can see here, it's 3% of patients and very low rates of grade 3 ICANS at 7% of patients. I think, you know, this, again, the tolerability in these poor-risk patients is a huge factor in the decision-making about which drug to give. Let's just pay a bit of attention to the manufacturing process. Irrespective of disease burden, poor and adverse prognostic factors, actually, the manufacturing was pretty straightforward, and the majority of patients, for whom leukapheresis was received, achieved a released product through this nice, consistent manufacturing process. Of course, we've alluded to the CAR T-cell engraftment and persistence, which we believe from a kind of a pharmacologic perspective, is very important for durable responses. It's really heartening to see that parallel pharmacokinetic data with our ALLCAR19 study. With that, we'd just like to thank everybody who's been involved in the study, the patients and their families and so on, the study investigators and coordinators, the healthcare staff at the study site, who've worked very hard on this study, and also the therapeutics for sponsoring the study also. With that, I'll hand back to Christian. All right. Thank you much, Claire, for a very exciting presentation, very clear presentation. What I'd like to do now in the next few slides is really look to put the data in perspective with regards to the other therapies that are available to these patients. Moving to slide 21, what you can see here is sort of a comparison between the studies that actually led to the approval of tocilizumab, as well as Besponsa. You can see the summary of the key data that we're seeing there. If we see how if we're looking at FELIX, what you can see is that clearly, obe-cel stacks up very well, both on the efficacy with a very significant level of activity, including when we're looking at intent to treat, which is what normally isn't really calculated or shown. Our intent to treat actually is at 64%, which is an excellent outcome for a personalized therapy. When we look at the median duration of response, we're stacking up very well. Obviously, what you have seen from the curve that Claire was presenting is that we still have a lot of patients that are in the early part of the curve. With 9.5 month median follow-up, obviously we're much shorter than what we currently see as the median duration of response, which is at 14 months. We're obviously, we'll see the maturation of this curve as we go through the course of this year, and obviously expect a key update at the ASH meeting at the end of the year. This is actually looking very encouraging. Gives us, I think, a lot of confidence in terms of the ability to translate this very nice level of initial activity from a response perspective, the excellent persistence that we're seeing, that this also will translate into an excellent outcome from a durability perspective. As Claire pointed out, the safety is remarkable, and we shouldn't take safety for granted. We needing to understand that these patients are truly in a very difficult position. They have gone through a very significant set of therapeutic treatments, and they tend to be in very poor condition. When you actually have patients, particularly elderly patients, and you drive high-grade neurotoxicityicity or high-grade CRS, there's a very high risk to these patients. That is something that we shouldn't take lightly. What you can see here is that as we're comparing to BLINCYTO, that in fact, the safety profile that we've been observing in the FELIX study actually is better than what was observed for BLINCYTO. I think that is important to keep in mind when we think about the opportunity for this product, to really become a significant component, of the backbone of therapy for these patients over time. This is obviously with regards to Blincyto as well as Besponsa. We look to the approved CAR T therapy, Tecartus, what was very interesting in today's presentation or today's session, is there was a real-world data presentation as well from Tecartus, and was interesting for two reasons. First of all, what we do know from the Yescarta experience is that the actual real-world data between the original ZUMA-2 study, as well as then the real-world data, was extremely well, extremely close together. They were tracking each other remarkably. To what was quite interesting to see is obviously that this isn't the case between ZUMA-3, the approval study, and the new study, the ROCCA study, in terms of the real-world experience. What was quite obviously is different, and I think we need to keep in mind also as we're thinking about the FELIX study, is that we've done this in the same period of time, most during the course of 2022, at the height of the pandemic and under very similar conditions. Indeed, we do see an impact clearly in the numbers. The patient population is a bit different when we look at the real-world experience. About 31% of the patients actually were in complete remission at apheresis. These are patients that had either no disease burden whatsoever, so a molecular complete remission, or they might have had minimal residual disease, but they're clearly in complete remission on the morphological disease. That also is important to keep in mind, and also the denominators obviously have been shifting somewhat. Clearly, the product is active. When we do the calculation, we believe the product is showing equal or comparable activity to what was seen in ZUMA-3 in a comparable data patient pool. What was quite interesting and not surprising, this obviously was a very difficult environment, and patients were very aggressively managed for cytokine release syndrome, and that's obviously the key component there, is obviously the use and early use of steroids. In fact, that actually that was helpful. It reduced the overall grade three/fours to about 6%. The flip side was that it actually did lead to very significant levels of high-grade neurotoxicityicity, which in fact, when we look at where they occurred, which appeared to be in patients with higher disease burden, would suggest that every other patient, more than 50% of the patients, have experienced high-grade neurotoxicityicity, which obviously is very challenging to manage. In fact, 6 patients died with ICANS and infection. What it suggests is that clearly controlling this type of a profile in a real-world setting clearly is challenging, and I think is something that I'm sure Claire can comment on in the Q&A section as well. As you can see, again, subsequent stem cell transplant, quite similar to what we've seen before. Overall, I think it highlights the fact that safety of managing safety is difficult in these patients, and I think it puts in perspective, I think, the remarkable safety outcome and activity outcome that we've seen across the FELIX study. When we look at sort of the commercial opportunity, we also do realize that in fact, the safety profile is the key enabler for BLINCYTO to actually grow the way the product has been growing, and it has been growing remarkably. We currently expect that BLINCYTO will reach approximately $800 million in sales this year. This is really to do with the fact that the program is well manageable, and patients can actually be managed not only in the academic transplant centers, but also in non-academic transplant centers and non-academic hospitals as well. I think that is important because it actually allows patients to be treated closer to home. It takes away risk, and particularly the risk that we've seen during COVID and risk related to travel, exposure to infection, et cetera. I think it is an important component. Given that in fact, obe-cel actually has a safety profile that is better than Blincyto safety profile based on the studies that we have now to compare to, would suggest that we're very well positioned to actually have, provide a broad access across not just the academic transplant centers, but beyond for a product with the profile that obe-cel has. With that, I'd like to spend a little bit of time talking about manufacturing, and I think you heard from Claire before, and you saw the data that we obviously had a very remarkable robustness on the manufacturing side. I think I'd like to sort of allude to that and move on that a bit further. First of all, when we think about product supply, and we think about the critical success factors in a personalized cell therapy, one of the real challenges that we have with these types of therapies is that we have to have a very reliable, timely delivery of every batch with a consistent quality. Every batch we do not deliver either on time or do not deliver to quality, we actually have a patient at risk that will not have an opportunity to benefit. This is very different from any other therapeutic modality where your manufacturing is dissociated from treatment. Here it is integrated and integral connected. That is the challenge. What that requires you is to actually develop a manufacturing process that can perform consistently with a very wide range of patient material. As you heard from Claire before, one of the challenges we have with these patients, particularly as they have high tumor burden, is that there is in many patients, effusion of leukemic cells from the bone marrow into the blood, and when you collect then the T-cells from the blood, you also will collect, obviously, the leukemic cells. The majority of the cells you do collect are actually leukemic cells. That's a very, very difficult starting point for any manufacturing process, because not only do you have to extract and isolate your T cells to in the first place, but you also actually have an environment that really is challenging for T cells to be active in, and that actually is a very, very difficult starting point. The second aspect is clearly turnaround time, and I think it's important to note, though, that we did manufacture for 24 centers in the U.S., we manufactured in the U.K., and we were able to actually have a vein-to-vein, median vein-to-vein time of 35 days. This compares to the real-world study, the ROCCA situation, with commercial manufacturing established in the U.S. and only U.S. centers involved for 31 days. I think it points out to the fact that we're highly competitive in terms of our manufacturing turnaround time. As we'll talk about a little later, obviously, we're actually on track to massively reduce that time. When you actually think about the importance of product consistency, but also economies that you have to achieve to actually get products manufactured at reasonable cost, you do actually have to sort of get to a manufacturing process that at least is in part automated. This is one of the core principles that we're using, is to actually have a level of automation. The other component, which is really critical with these types of manufacturing processes, are people. It starts with the leadership team where that we have in place at Autolus, which is really outstanding on the product delivery side and gives us really a level of attention, drive, and continuous improvement, which are absolutely critical. You do need a highly trained and motivated workforce. In fact, we had to operate and set up an actual training center to train our operators because the people with the skills we need for this type of manufacture do not exist in the workforce. That's an investment of about a one-year investment in every single operator. That obviously becomes a key value and a key element in terms of the success. You have to establish a culture of that really focuses on continuous improvement, and that sort of requires you to really put in place an operational excellence program. The final bit I wanted to talk about, which is scale of operation, and this is critical for in two dimensions. When we look at the CAR-T experience, and I think the challenge that a lot of the centers have that deliver CAR-T therapy, is that it is often difficult to get access to CAR-T therapy because the manufacturing capacity isn't there, that you need to actually be able to reliably deliver. There's also quality issues which actually make the matter worse. Capacity is important. What we really need to do is we actually have to put in place a capacity in terms of its size, that matches the target population that this product is looking to address. That's one parameter. The second parameter is, you have to put that capacity at the right level to serve the population, but also make sure it's at the right level to not actually overbuild the capacity, because if you do that, your overall economics on the cost of goods actually goes down the drain. You actually have to find the right balance between capacity and the actual size. When we think about the study that we've just conducted here, obviously what we have done is that we really had to execute in an extremely difficult environment, and that in essence, allowed us to pressure test every aspect of the product supply part. It started obviously, with the semi-automated manufacturing process, which was critical, that we optimized to manage this wide range of apheresis materials. We were doing a lot of work in fine-tuning process controls and release analytics, a training center already mentioned, which was absolutely important to establish and maintain the workforce. We also operated it with a commercial model with two shifts, seven days a week, and that gives you actually the type of operation that is also the commercial operation. The excellence program was very important, and it actually has allowed us to continuously improve our overall operations and with that, our operating cost. The final part, which was really challenging, was that the logistics part, we have 24 centers in the US, we would have to deal with all the COVID restrictions. We had transatlantic flights that were down to 5% of normal, and we're able to deliver product for each one of these patients, and I think that is absolutely important. What it did really, this environment, is it really allowed us to look at every individual component of the product supply chain and pressure test it and ensure that we actually have a very robust overall setup. It does show very nicely in the data that Claire just walked you through in terms of overall performance. I'm sure you do realize that those type of data are not often shown. This is every individual batch shown on this depiction, and that's normally not done because typically this is difficult to actually show consistency and tightness of data. The commercial manufacturing facility, the Nucleus that we set up, is designed to actually serve 2,000 patients in its initial build-out, which is two-thirds of all relapsed refractory ALL patients in the U.S. and Europe combined. The sizing allows us to actually fully deliver and serve this market and be able to actually capture the opportunity in full. The challenge that we were dealing with was that we actually had to start this set up for this facility as we're actually gearing up to start the phase II portion of the FELIX study. This was, therefore, had to be done in a quite unusual way and in a much shorter timeframe than any other facility that actually has been pulled together in our space. We could do it because the design was such that we had a modular build, which allowed us to build most of the components of the building offsite, 70% built offsite, and it actually allowed us to actually reduce the build time by 60%. To put this in actual dates, we had groundbreaking on November 8, 2021. In 22nd of November in 2022, we actually did take our first clean room into operation. Had our first Prodigy machine that you see here on the right-hand side, the suite and actually full during the capacity challenge. The first machine got online December 14, 2022. By May this year, we actually had the capacity to. This is where we are. This is on track, it's robust, it's reliable, and it's at the right scale. With that, just a few words in terms of outlook and next steps. Obviously, we just went through the great presentation of the data for the FELIX study. We'll have, obviously, this type of presentation at the EHA in just a few days in Frankfurt. Obviously, what we're focusing on internally is really getting ready to file for a BLA towards the end of the year, and also are planning to file with the European Agency and the MHRA in the first quarter through the first half of next year. The manufacturing, which is talked about, I think it's important, We're exactly from a time and execution perspective, we want to be. We expect to receive a GMP license from the MHRA during the second half of the year, and with that, are gonna be in a very good position to support the BLA filing and other regulatory filings there on forward. From a commercial perspective, obviously, with clinical data in hand from a pivotal study, that's a good time to actually go out and talk to physicians about the profile of the product. Medical affairs is obviously a key set of activities we're engaging in, but we're also actually articulating the value proposition to the payers, to the hospitals, the physicians, but also obviously, to the patients, and that's obviously a key part of what we're engaging on the commercial activities. Finally, we're starting the work to actually onboard centers so that when the product gets through to approval, the centers are in a position to actually deliver the therapy to patients. Those are kind of the key activities that we have lined up, and we believe that puts us in a very interesting spot. From a execution perspective, we have a fantastic data set from the FELIX study. We're actually in a position where we can supply the product, and we can do this reliably, and we're now in a position to actually gear up to go through the regulatory process and prepare for commercialization. With that, I think we're at the end of the formal presentation, and we're happy to take questions. Certainly. Ladies and gentlemen, if you have a question at this time, please press star one one on your telephone. To remove yourself from the queue, simply press star one one again. One moment for our first question. Our first question comes from the line of Kelly Shi from Jefferies. Your question please. Congrats on great result of FELIX. I have a question regarding the safety profile. The neurotoxicityin is particularly very outstanding. On your cellular kinetics chart, obe-cel was observed with rapid cell expression, expansion and a great persistence relative to other CD19 CAR Ts. Regarding the cause of the neurotoxicity, besides tumor burden, I think in the past, it has been proposed that the frequency of neurotoxicity occurrence was somewhat associated with the speed of cell expansion. Clearly, this is not the case for obe-cel. What plays the magic for achieving such a clean safety profile, especially on neurotoxicity? Thank you. Hi, Kelly. Well, first of all, really good question. You know, obviously, neurotoxicity is a type of toxicity that's sort of been, I've sort of been dealing with probably for 21 years by now, having seen the first neurotoxicity in 2002 with Blincyto and, you know, working with my old team to figure out how to manage it, how to better understand it. What is interesting about obe-cel is that obe-cel obviously leads to very, very significant expansion. The growth of the CAR T-cells in vivo is very, very significant. That growth is driven by the actual kill that is occurring and the actual removal of target cells, and it goes alongside that. What we have observed, this is work that goes back almost, actually goes back a good 20 years, is that what we see is that CAR T-cells actually do repeat cell killing and go into serial killing mode, that they actually do stop producing cytokines, and actually, their profile starts to shift. In other words, you can have a lot of high level of activity and very minimal cytokine release. That's something you can see, and typically, when you looked at that, if you were taking a BLINCYTO for that, you would see, you know, significant cytokine release on first kill. If you then actually take those same cells on the second kill, your cytokine release goes down to about 10%. If you take the cells again and run another kill, you actually have virtually no measurable cytokine release. You actually have adaptation. One of the hallmarks that we're seeing with obe-cel in its design is that it is really designed to give you very efficient serial killing. Because it actually does not get stuck on the target cell once the kill is delivered, the cell can actually recycle, going to productive next kill. What that allows you to do is really get through that adaptation, and with that, actually get to a mode where the cells are active, but they actually stop producing a lot of these immuno inflammatory mediators, cytokines, obviously being an obvious one category, but other categories as well. I think that is really at the whole market, goes very much back to the actual design of obe-cel, which enables the product to actually behave in a much more physiological way, much more like a normal T cell engages, and with that, avoids this very high level of induction of neurotoxicityicity. Very insightful. I also have a follow-up here. I'm curious, how is the enrollment in the morphological cohort ongoing? When should we expect the data, and how are you planning to use the data in extending the patients which can be treated with obe-cel? Could this data be included in the label? First of all, I think what you were asking was related to the MRD cohort, not the morphological cohort. Oh, yes. Uh. Sorry. Yes. Okay. RD cohort, what I meant. Obviously, the key activity, obviously, and the focus on this presentation, and also the focus from a data perspective to submit for a registration, is all on the morphological cohort. Any data that we have on patients with low disease burden is supportive, but actually will not in of itself, support the actual approval. We'll provide an update on those activities as we go through the second half of the year. One of the things that certainly we're starting to look at also much more carefully in the current data set is, to what extent tumor burden actually impacts, the activity, the toxicity, as well as long-term outcome. There's quite a lot of work and a lot of data, a very rich data set that we have, even with the current cohort, that I think will give us a lot of information in that regard. Thank you very much. Congrats again. Thanks a lot, Kelly. Thank you. One moment for our next question. Our next question comes from the line of Eric Joseph from JPMorgan. Your question, please? Oh, hey, guys. Thanks for taking the questions, and very encouraging to get an update. Can you talk a little bit about the duration of response among patients that entered with baseline extramedullary disease, and how sort of the activity in that population compares with outcomes seen with CAR T currently in a similar patient setting to the extent it's been studied? I have a follow-up. Well, thanks for joining, Eric. In terms of patients with extramedullary disease, as you've seen, we have about 19% of the patients that have extramedullary disease. We're starting to actually collect that data. I don't think we have sufficient patients that are far enough out to really, I think, analyze the questions that you're asking. I think they're very interesting questions, definitely some areas that we're gonna look at, you know, with quite a bit of intent, and we'll certainly communicate around that. We do need more follow-up on these patients, I think, to have a good understanding of how the data is tracking and also how it compares to patients who do not have extramedullary disease. Okay, got it. Just maybe just one on the manufacturing side. I wonder whether there's a minimum transduction threshold that would need to be surpassed as part of the release criteria. Particularly sort of in the commercial setting for products that qualify as, you know, suitable product, I guess, actually as reimbursable product. How does that relate? If those, that criteria has been defined, how should we be thinking about that in the context of the 72% transduction efficiency that you're showing here? Right. So first of all, yes, you know, you do have a minimal level of transduction efficiency that you need to have, as you have a minimal level of dose, as well as a few other parameters in terms of actual, you know, cell kill activity and so on, that are all constitute release parameters and release criteria. You're correct, those need to be met. Now, what I think was really important in the presentation is that you can see that the transduction efficiency actually is very tightly packed, and they're very tightly packed, you know, squarely above 50%, and with just hardly any product actually that was below that level. The minimum level of transduction efficiency is substantially lower than 50% that you need to hit, and in fact, just around, you know, 15%. That gives you still, at that level, an active product. One of the things that we're also doing, and this is also one of the more detailed analyses that will be shared with the regulators, is obviously also what is the outcome of patients that have across the range of transduction efficiencies? Obviously, as you can see from the data as it is summarized here, it is highly consistent. We're, we're in really good shape with that regard, and you know, we'll, we believe that we're gonna have a very high percentage of the products that will be in specification, or to put it differently, very, very few samples or products that will be out of spec. Great. Okay. You can see the current study was 94%. We're in spec. Okay, great. You're good. Thanks for taking the question. Thanks a lot, Eric. Appreciate it. Thank you. One moment for our next question. Our next question comes from the line of Gil Blum from Needham. Hello everyone, thanks for taking my questions. I'd like to add my congratulations. Very interesting presentation today. Maybe to start, just to give us an idea of how much more follow-up do you expect will be required to give a better understanding of comparable long-term remission as it compares to, let's say, something Tecartus? I know we're going to have another data readout at ASH, is that time point sufficient? Thank you. Gil, thanks for joining. It's a really good question. I mean, normally, what you'd like to be at, to sort of actually have, I think, a good understanding that the numbers that you look at on duration of response, et cetera, are really solid and are not moving anymore. You try to go to about 1.5 times the time of that median in terms of follow-ups. In other words, if you want to have 14 months of follow-up and when I say, and this is median follow-up, and it's solid, the data is solid, you would have to have at least a median overall follow-up in the study of 21 months. That's when it gets really robust. I think we start to get a very good level of understanding as we're sort of getting towards the end of the year. We see the trend and, you know, it's not unusual that you then actually see those numbers actually continue to move further back and actually give you sort of an increased level of outcome over time. We've seen that with other programs as well. Given where we are, 9.5 months follow-up, we're already at, you know, if you want to call the median at 14 months is quite remarkable. Obviously we have a significant proportion of the patients, as indicated, 61% of the patients that actually had no event whatsoever, no other therapy, and you can actually see those patients continue over time. I think this is a very good opportunity to sort of see that data mature and sort of, you know, will give us certainly by the end of the year and then by ASH next year, I think, a very solid view. Thank you. Very helpful. just maybe to kind of reiterate this, although I know you've discussed this, just to put in context the importance of the reduced rates of ICANS, especially when compared to what you saw with the real world Tecartus. I thought it was interesting that one of the panelists who presented that data, basically said that that would be a reason to pick one treatment over another, if you can elaborate there. Yeah, I think I probably would like to hand that over to Claire Roddie, because you're the treating physician. Yeah. you're dealing with those decisions. I mean, I think I do sort of speak on behalf of myself and a lot of my ALL colleagues. You know, these are really tricky to treat patient population, and they're already quite, you know, they're quite comorbid by the time they get to us, and I think toxicity is sort of like a really top priority for us. I think that ICAM data from the real-world experience would put a lot of clinicians off. I mean, I think we already understand the toxicity profile of Tecartus. We understand the kind of low durability of responses, and as a clinician body, we are really looking forward to obe-cel being more widely available. I speak certainly on behalf of all my colleagues in the U.K. We discuss this quite frequently, and I think across the U.S. also. We've got two big advantages here. We've got the toxicity profile across this high-risk group, and we've got the persistence profile as well. I think those two things really make the decision incredibly easy for us. I don't know if that answers your question, but I think that's the clinician's perspective on the data we heard today. Definitely helpful. Maybe kind of a last one on that angle for the ROCCA study. Just from what you've seen, were there any clear manufacturing challenges in the real-world setting of Tecartus? This is just particularly interesting because it was also done during COVID, so it might give you a better reference point for obe-cel. Thank you. It's a good question. I don't think we have information. What we do know from the ZUMA-3 study is that the 77% of the patients that were at-risk got dosed versus the 84% that we had in the FELIX study, that obviously was pre-COVID. There was no information actually given how many patients were intended to be treated on the real-world study. There was actually no information that was provided. What was clear is that the vein-to-vein time was highly comparable with our vein-to-vein time, although obviously this is a commercial setup. You know, at this point, I think certainly the best supply chain on the CAR T side. All right. Thank you for taking the questions, and again, congratulations. Thanks a lot, Gil. Appreciate it. Thank you. One moment for our next question. Our next question comes from the line of Yanan Zhu from Wells Fargo. Your question please. Hi, thanks for taking the questions and also wanted to add my congratulations. The neurotoxicityicity profile, when presented in the same session with Tecartus real world, it really stood out as being a better profile. I think I have a couple of questions for Dr. Roddie. Um. In terms of, you know, we are trying to compare efficacy from the FELIX study with that of Tecartus. What should we keep in mind in terms of baseline severity of the patients or prior treatment? Anything Anything that you would highlight for us, you know, in terms of the baseline characteristics of the patients from those two studies? Well, I think. I'm sorry, carry on. If I may, just mention the second question is with regard to the single case of HLH or neutropenic sepsis that was deemed related to obe-cel treatment. I was wondering, you know, is that really an obe-cel effect, or is that a lymphodepletion effect? How what have we seen in the FELIX, sorry, in the ZUMA-3 study? Has a similar case or cases happened with the tisagenlecleucel studies? Thank you. Well, I guess in terms of answering your first question, I mean, you're asking really sort of what were the differences in the demographics between the patients recruited to ZUMA-3 and the FELIX study. I think we can sort of quite comfortably say that there was more extramedullary disease on the FELIX study. Again, a really high-risk group of patients, we accepted onto the study. We certainly had older patients on our study compared to ZUMA-3. I guess, but beyond that, you know, the cohorts were broadly similar. I think in terms of the therapies that were permitted, sort of pre-FELIX versus pre-ZUMA-3, obviously ZUMA-3 excluded those who had been exposed to blinatumomab, thereby taking out that population that might be at risk of CD19 negative relapse. On FELIX, we accepted those studies, maybe we had a more permissive eligibility or entry criteria. Those would be the sort of the differences as I see them between the two studies. I think we were more permissive, and we probably had maybe potentially some higher risk patients in our cohort. In terms of the HLH, I mean, HLH is obviously a well-recognized side effect as or associated with CAR T-cell therapy. It's more commonly seen with CD22 CARs, it's well recognized in the CD19 space also. It happens as a sort of like a sequely following a prior CRS. It's sort of like at a CAR T expansion in the absence of antigen. It's not that... You know, it's, we're not unfamiliar with this. We see it in patients, and it seems to be more concentrated in patients with high burden disease, as well. In some regards, I'm not, you know, I'm not surprised that we saw a case of HLH. I think probably the kind of what precipitated the grade five event here was the neutropenic sepsis. You know, in the context of, you know, profound neutropenia in an HLH, I think that's, I think that's quite commonly observed. Unfortunately, I think this probably was related to the sort of effect of maybe the cumulative effect of the lymphodepletion on CAR T, but it is certainly a CAR T-associated phenomenon, if that answers your question. Got it. Super helpful. If I may add one more question. The real life, real world data for tisagenlecleucel does show that tisagenlecleucel seems to be effective with the CNS disease patients. Obviously, CNS disease patients are excluded, have been excluded from any of these trials for tisagenlecleucel or obe-cel. I was wondering, first of all, do you think obe-cel might also have that kind of property in CNS-positive patients? Also, you know, obviously, we know the, you know, neurotoxicityicity of obe-cel is obviously much better than tisagenlecleucel, but would that you know, have implications of efficacy in a CNS? I guess, are the two things somehow connected? Thank you. Again, in the context of CNS involvement by leukemia, I mean, there's a precedent through the pediatric data to show that CAR T-cells traffic very nicely to the CSF, and they can eradicate leptomeningeal disease. I don't think that that is, you know, something that's new. I think that's something that's appreciated. Obviously, studies have been designed to be, to control, to exclude those patients just because of concerns regarding a heightened risk of neurotoxicityicity. I think the bottom line is on the ALLCAR19 study, which is a study I ran at UCL of 20 patients, we routinely checked the CSF on those patients at day 14 and day 28, looking for CAR T-cell infiltration into the CSF. Consistently across the whole cohort, we saw really nice trafficking to the CSF, and sort of like high CAR T cell expansion within the CSF. This is across the board. This is patients who didn't have any neurotoxicityicity. I don't think there's any question CAR T-cells can traffic, and obe-cel can traffic to the CSF. I guess the next question will be, you know, it's trafficking and can it eradicate disease? And potentially that's something that could be the subject of further study or an extension cohort on the FELIX study, potentially. I mean, it's an area obviously, that we also had sort of seen in the context of the pediatric work that we've been doing, also actually in the context of AUTO1/22, where we had children with CNS involvement. It's interesting, it doesn't necessarily actually drive neurotoxicityicity in these cases. Mm-hmm. Which is, typically, you think at first glance, those things are associated. They may not be associated. We clearly saw activity, in addition to the trafficking, that Claire just mentioned. Got it. Very helpful. Thanks for all the answers. Congrats again. Thanks a lot. Thank you. One moment for our next question. Our next question comes from the line of Matthew Phipps from William Blair. Your question please? Hi, thanks for taking my questions, and congrats on the updated data. I was wondering if I could ask a question for Dr. Roddie. When you're looking at data sets, just generally or talking to patients, I guess, what do you emphasize on the efficacy side? Things like median DORs or landmark DOR or PFS, you know, so maybe a landmark that focuses on the tail of the curve. Just curious what you look for there as kind of highest priority. I mean, yeah, I think there's lots of different, you know, there's lots of different hurdles to jump over here in terms of your efficacy. Your efficacy can be whether or not you can generate a product. That's efficacy number one. Efficacy number two is whether you can get that product into your patients in a timely way. The next binary assessment is whether or not you can achieve a response, so it's the day 28 assessment. These are all important factors that we consider when we're looking at the possibility of a, you know, a product to take sort of more broadly into patients. We've got our kind of assessment at day 28, and, you know, that's the binary yes or no. Then we sort of get into the nuts and bolts of whether or not we've got event-free survival and overall survival. I think those are two really important pieces of information as well, and we look forward to being able to analyze those in more detail and potentially present towards the end of the year. Those are, you know, very sort of meaningful, clinically meaningful pieces of data that are important to patients and their families as well. We're not in the position yet to be able to, unfortunately, present that data for this cohort. I don't know, Christian, if you've got anything to add here. Well, I think that part of what I think, if I understood the question correctly, Matt, was that you wanted to understand, I mean, what parameters really matter and give you a good understanding for the performance of the product? One of the interesting things when we think about the old CAR T study was obviously we had sort of a clear early indicator for longer term outcome, which was persisting CAR T cell. Actually we did see, obviously, you know, the decline of event-free survival over time, but then a stabilization from 12 months onwards. That was actually, in our case, at 46%, so technically or below the median. Yeah. The median was what it was, but the actual story was not the median. The story was that we have a proportion of patients in long-term remission, which ended up actually being 35% of patients in long-term remission. That actually is what was ultimately really the key element in those patients that, you know, did not receive any additional therapy. I think that is sort of, I think, a key parameter. It's both medians, if you just assume it's a straight decline and a straight line decline, then the median is meaningful. But what certainly becomes more meaningful if you see stabilization of these curves, and you actually have a true long-term benefit in some of these patients. Thanks, Christian. If I can ask one more quick one. Are you seeing similar rates of cause of relapse, such as maybe CD19 negative disease? Just thinking about if we're hoping that the persistence improvement drives that long tail, just obviously making sure there's no kind of differences in reasons why these patients might be relapsing. I mean, we have got some sort of, you know, early binary data on the cause of relapse from the FELIX study. I mean, it's between a half and two-thirds of patients from CD19 negative relapse, so of the relapse events. I guess that stands to reason. I mean, what we're talking about here is, you know, we're essentially putting a kind of selection pressure, if you will, on the leukemic blast here by virtue of the persisting, highly proliferative CAR. Again, this is something that we saw in the phase I data set and that the pediatricians also saw in the phase I ALL study in their hands, is CD19 negative relapse is seen on this study more so than CD19 positive relapse, as would be the case with Tecartus. I mean, the other parameter we were looking at is how the product was performing. The studies were performing at a 6-month time point, where we obviously with, you know, 9 and a half months of follow-up, the 6 months data, we believe is firm. What we can actually see is that the data tracks extremely well between the various studies. We don't see any differences between them. If you look at those parameters where we have solidity in the curve, actually we do see that it matches very well, including, as you've seen, the data on persistence, which is actually matching very well. We have everything we see at this point appears to tell us that we're really tracking to what we have seen prior. Great. Thanks. There's no more questions. Thank you. One moment for our next question. Our next question comes from the line of Asthika Goonewardene from Truist. Your question, please. Hi, guys. Thanks for taking my questions. I would also like to add my congratulations on a good-looking data set and also executing on the study here. I got a two-part question for Dr. Roddie, and then, Christian, I got one for you afterwards. Dr. Roddie, when do you typically expect to make the decision to give a patient on remission a stem cell transplant? The other part is that you reported that at this data cut on FELIX, about 61% of patients remain in remission without further treatment. Related to the earlier part of my question, what proportion of these patients in remission have gone past this window when the decision to put them on transplant is made? Yeah, I mean, this is something that we debate amongst ALL physicians the world over because it's not an easy decision to make. I think that allogeneic stem cell transplant, as you know, has got huge limitations in terms of treatment-related mortality, donor availability, et cetera. I think in our own practice, usually what we would do if a patient is transplant naive and hasn't had a prior transplant, then in that setting, we would counsel the patient after they've received CAR T cell therapy. If they were ongoing, in ongoing remission after their CAR T cell therapy, but really importantly, if they had ongoing CAR T cell persistence, then I think the argument is that in the context of sort of a very sensitive MRD assay, and the ability to track your CAR T cell engraftment, our usual practice is to watch and wait, and that's made more attractive if you have, say, another available line of therapy that you could potentially use, should they require it, should they relapse, and you wanted to bridge them to a transplant. That would be our usual practice. On the other hand, if you've got a patient who has lost their CAR T-cell engraftment, then that's perhaps, and they've got recovery of their B cells, then that's maybe a slightly different clinical situation. You could look to the We take guidance from the pediatric data, and the pediatric data would suggest that the patients who tend to relapse, even with the loss of B-cell aplasia, is often those who've had high baseline disease burden. You know, in the patients who came in with high baseline disease burden and who lost their CAR T cell quite early and their B cells, that would probably precipitate a decision to do a transplant in remission. I think that that would be a sort of like a, kind of a, you know, a sort of a summary of, of a very practical approach to allogeneic transplantation in patients who are in remission post CAR T in the adult setting. On the other hand, patients who have a prior transplant, I think the data for second transplant is still abysmally poor. There was an EBMT study that was published in 2019, with Arnon Nagler as the main author, and the outcomes were absolutely abysmal. Five-year overall survival is around 7%. You know, again, that's a population who you would just continue to watch and wait. Okay, if you were to make a guesstimate here about what proportion of the patients who are remaining in remission right now, may be considered for stem cell transplant, or could you maybe quantify how much of that do you think you could keep in this, you know, just watch and wait setting? I'm not sure that I have an ability to sort of answer that question, what proportion could be, would be, could be transplanted. That's something I probably need to go away and look at and get back to you. Because there's lots of different factors at play here, not least patient age, donor availability, baseline disease burden, like I say, and the ongoing CAR T cell persistence and ongoing B-cell aplasia. There's multiple factors here that we need to consider. I think it's fair to say, Asthika, though, that when you look across the various, you know, studies that were conducted in the space, that most of the transplantations actually happened early and not late. Mm. When you look at where we are with the study, obviously, there's still a few patients that are in the early segment that are, you know, within, you know, 2 months to maybe 5 months away from the original treatment. There, there may be a chance that maybe, some few patients might still actually experience a transplant, but everybody that's sort of further out, the probability of those patients to going on to a transplant is relatively low. Overall, we see the same dynamic in terms of transplant that we've seen in the other studies, and we don't expect the numbers to actually differ in a significant way. Got it. That's very helpful, guys. Then, Christian, something for you, please. I'm kind of checking my notes here, and it seems like 32% transduction efficiency is quite high for CAR T manufacturing. What's enabling you to do this and to get you there? Then related, when you get high transduction efficiency, are you also getting a higher vector copy number? Related to that, does the higher vector copy number also give you better avidity? Really it's an interesting set of questions. First of all, the transduction efficiency is something actually that you typically look to dial in, and you want to dial in at a level that is in the, you know, above 50%. You know, clearly we felt strongly that the range that we're in is actually really good. You also want to make sure you not actually overdo it, because if you overdo it, you may then actually have multiple insertion copies per cell, and you may actually get sort of more distribution. In order to actually get, you know, basically single insertion copy per cell, but actually, almost all the cells are a very, very high percentage of the cells, expressing the CAR T, the chimeric antigen receptor, sort of the sweet spot where you want to go. That you don't have a huge variability in expression across the cells, but actually keep it relatively tight, but at the same time, go to the upper end of the range, where most of the CAR T-cells, most of the T cells that you actually have in your product are indeed expressing CARs. That's the sweet spot you want to go to, and that's actually what we're dialing in from a process development perspective, to actually go with a level of transduction that gets us exactly to that point. I think that's a key parameter also for the consistency of the outcomes that we're seeing. Just to speak to the VCN data from the phase I study, essentially it was less than 5 for all of those, despite the high transduction efficiency. I think the, you know, the transduction efficiency is partly because we select in this manufacture process, we select for T cells. I think we also have a nice stable CAR. You know, some of the constructs that you see out there are quite unstable on the cell surface, but we have a really stable expression on the cell surface, and we have a nice modality for staining for the CAR expression as well. All of this, I think, feeds into that really nice, tight transduction efficiency you see. Great. Thanks for taking my questions, guys. Maxwell, how's it go? Thank you. One moment for our next question. Our next question comes from the line of Mara Goldstein from Mizuho. Your question, please. Great. Thanks so much, excuse me, for taking the question. There's been a lot of questions asked, but I guess this is for Dr. Roddie. I know we talked about, obviously, the differences between Tecartus and obe-cel, and some of the demographic differences. I, I'm curious, though, you know, when you look at the two products together, how in a real-world situation do you make a determination, given the differences in the adverse event profiles, you know, to use Tecartus over obe-cel or obe-cel over Tecartus? I'm wondering if you can comment on that. Well, I'm just wondering, I mean, you've obviously heard the data. What would you choose if it were you? If you were a patient or a patient's relative going into the clinic room and you saw those presentations, what would you ask for? Right. Well, I guess that's my question. Yeah, no, I know. Well, the point is that you've heard the data as well. I mean, I think I've made my position on this really clear. You know, one of the most difficult things in the hospital setting is having a treatment that is so incredibly toxic that you have to give to a load of very elderly patients, often very frail patients, often. You know it's going to land them in the intensive care. That you know that it's going to land them on a whole load of immunosuppression, and it's going to then engender a load of in infections that may well, you know, end up with a grade five event. That is just not a scenario that I feel comfortable with. I feel, you know, patients... When we counsel patients about Tecartus, and in the UK, that's up to date, it's been in the context of mantle cell lymphoma. We're very frank, I mean, it's a 10% treatment-related mortality associated with Tecartus in the mantle cell lymphoma setting. We have limited experience in the B-ALL setting, yet it's only recently been approved in the UK. You know, it's not really feasible to deliver that to elderly patients. What's more, is because of the toxicity profile and this high incidence of neurotoxicityicity, and the protracted courses of steroids and all the infections, you then end up with patients who are sort of essentially occupying a hospital bed for what can be sort of weeks to months at a time. They then become really disabled, and there's a protracted period of physiotherapy that's required to get them back home again. All of these features, you know, all cumulatively, sort of impact quality of life and impact the feasibility of this as a therapy. You know, I just think that we really sort of need to completely swivel here and change our perspective and make toxicity really a top priority. You know, managing toxicity, having a therapy that potentially, if you come in with a sort of a limited disease burden, you know, you could have your therapy potentially as an outpatient. You know, you don't even need to be in hospital. These are things that are really appealing to patients. They're appealing to the patient's families, they're appealing to physicians, they're appealing to sort of economists, et cetera. You know, having a product that you can deliver safely with minimal toxicity, potentially also as an outpatient, is I just don't even feel that, you know, this, there's a competition whenever you look at it from that perspective. Then I think coupled on top of this, and I know I sound like a broken record, but having a product that's associated with persistence, that in a phase I study, you can correlate the persistence with long-term durable response rates, you know, which is clearly not apparent with the alternative agent you mentioned. I mean, I just don't see where there's a competition here. I just really don't. That's why I ask you, just because you're coming from a less sort of enmeshed position on this. You know, you're seeing the data fresh. That's why I was interested in your perspective. Well, I appreciate it. Thank you very much. Thank you. One moment for our next question. Our next question comes from the line of Rajan Sharma from Goldman Sachs. Your question, please. Hi, thanks for taking my question. I just had a couple left, actually. Firstly, just could you provide any more visibility on the 11 patient deaths between enrollment and infusion and what the drivers may have been there? Secondly, just on the vein to delivery, I think you talked about the median of 21 days. What was the range there, and what could have been driving kind of a faster or slower delivery? Thank you. I think I'll take the second question. I think you go for the first. Sorry, do you mean the 11 patients, when you're talking about the patients who enrolled and those that fell out and didn't receive their product? Yeah, exactly. Yeah. I think there was... Yeah. 112 enrolled, 18 discontinued, and then the 11- The majority of those patients had progressive disease, and they, and basically, they had progressive disease, and unfortunately, it was impossible to continue and treat them. This is something that we see, again, in the CAR T space quite a lot, because as you're aware, you need a good performance status to be able to receive a product. You know, whenever you've got a performance status of two or three, and potentially you're bedbound, you know, it's just not a safe option for you. In those sorts of settings, you know, whenever the performance status falls out, and it's often in the context of progressive disease, it's refractory to bridging, that's, well, often a major reason why patients don't proceed. I just, I think we have a slide. We can maybe go back to it, and it can illustrate in a bit more detail to you. There were a few other causes, sort of an N equals one for, other reasons why patients didn't get there. Okay. Within those 11, do you know what proportion actually received the bridging therapy? I can, again, we can probably dig that data out for you. I don't have the granularity of that, but our study patients will be able to do that. I mean, most of the patients obviously do receive, across all the studies that were conducted in this phase, do receive bridging therapy of some sort. Yeah. This is a very, very aggressive form of disease, very rapidly progressing. The patients that obviously did not actually get a chance to get those, are basically patients you have to move on palliative care. Mm. They're at a point where therapy didn't make any sense anymore. Yeah. I think to put it in perspective, this is a true difficult patient population that are in pretty horrible condition. That is why you do lose a component there. Mm. You obviously linked the question to the turnaround time. First of all, range of delivery, we did show the exact, for each patient was shown. If you looked at the chart, you had every single patient, delivery time actually on that chart. What you see it is actually amassed around 21 days, and it goes between about 18 days and about 25 days. Part of the difference there is logistics, depending on whether there are any issues on actual air travel. As I indicated, we did this study during the height of the pandemic, where air travel actually was significantly disrupted, not just domestically within the U.S., but also transatlantically. That had some impact. I think what's important to understand, and this is what I was highlighting before, is that our vein-to-vein time, so the time from taking the cells to infusing the cells, was virtually identical with the real world study conducted by Kite, which also gives you a very, I think, good appreciation that first of all, what we've been doing, what we've been able to do, is highly competitive. What is driving in terms of the turnaround time, the two components that drive that, one is the time that you need to manufacture, and that obviously doesn't change much once you actually lock in your process, and that is in the range of 6 to 7 days of actual manufacture. The remainder of the time actually is related to product release, and that is analytics. A lot of that actually is linked to the determination of sterility, which at this point still requires you to actually run plate-based assays. That is likely gonna change over time. What our current estimate is based on the changes that we have implemented on the analytical side, which is in actually conversation with the agencies, will get us to a point that at the time of launch, we're gonna be in the range of about 16 days from vein to certification. About 6 days less to what we had in the study, five to six days less of what we had in the study, and we expect that to be further reduced with improvement on the sterility testing. That should get us actually between 10 and 14 days. That's where we're gonna be. This is gonna be highly competitive and very well manageable. Okay, perfect. Thank you very much. Thanks, Ronald. Appreciate it. Thank you. One moment for our next question. Our final question for today comes from the line of Sebastiaan van der Schoot from Van Lanschot Kempen. Your question, please. Hi, team. Congrats on the presentation and results today. Thank you for taking my questions. My first one is on the correlation between the high tumor burden and the grade three CRS and ICANS. Can you maybe comment on the possibility to later in the real world for obe-cel treatment stratify patients for treatment in the in or outpatient setting based on the tumor burden at baseline? I think a really good question. I think what we have quoted on the slide, and I'll let Claire answer some of the more specific points. What we've indicated in the presentation is that we had 7 patients that experienced high-grade ICANS. 6 of the 7 patients had more than 75% tumor burden at lymphodepletion. In other words, this is that even with bridging, could not actually be brought down at all. This is a very extreme portion or a very extreme end of the spectrum of tumor burden, and obviously gives you, before you dose, gives you a very clear indication that if the patient has this very high level of tumor burden at the time where you make the going to lymphodepletion, that you actually have a patient that you want to watch more carefully. The other proportion of the patient obviously, had very, a very infrequent, just about 2 or 3%, or probability of developing a high-grade ICANS. That obviously gives you an ability to, you know, have a place this patient in a segment of the hospital, which would be, in the U.S., often be considered a hospital outpatient type of setting. As we go forward, obviously, we'll learn more about, I think the how this the adverse event profile evolves. I think what we're gonna be seeing or be looking at, to your point, is also look at the start tumor burden at inclusion. The much more predictive one that we're seeing is not at inclusion, it is the tumor burden at lymphodepletion, because the trajectory that a patient is on, how fast the disease progresses, can vary quite a bit between patients. You can have patients that go from minimal residual disease to full-blown disease within three weeks. You can have other patients that come in with, you know, a medium level of tumor burden, and they're still at the same medium level of tumor burden at the time of lymphodepletion. The real determinant here that we find is really the tumor burden at lymphodepletion, which is also the time when a physician actually needs to make a decision, where you actually talk to the patient, we can prepare the patient. It actually gives you a very good handle, to actually prepare, also think about the resources you may need, et cetera, and plan from a hospital utilization, resource utilization perspective, actually do the planning accordingly. Maybe, Claire, you can maybe give a bit more color around that. Yeah, I mean, I just would concur with that. I think that's where this product really has, you know, huge potential, and that is sort of in terms of in versus outpatient stratification. I think it's, the data is pretty much as clear as it could be, that high disease burden is the risk factor for the sort of grade three ICANS in this cohort. They just need a, you know, more scrutiny, and they need maybe a bit of closer follow-up. What that means is that the other patients, you know, potentially can have a less invasive, post-infusion monitoring experience, which would be ideal for them. I mean, we're talking about patient experience and quality of life measures here as well as economics and so on. Great. I was also wondering regarding the step dosing, for clarification, can you just mention the number of patients who did not receive the second dose? What were the reasons behind not receiving that second dose, were those specific patients also taking along in the efficacy and safety analysis? Yes. Those patients were included in the efficacy and safety analysis, and there were 6 patients who only received one dose. 3 of those were due to immunotoxicity. There was a couple of ICANS cases and 1 CRS. There was 1 patient in the cohort who received only 1 dose, who had frank progressive disease, unfortunately, after the 1st dose, and it was felt to be inappropriate to dose them with a 2nd dose. There was 1 death, 1 early death, and 1 manufacturer issue. I think the bottom line is that there were only 6 patients. Remember that we're talking about almost 100 patients here. It was by far and away, the minority of patients only received 1 dose. The majority, the reason for that was because of immunotoxicity. obviously, the immunotoxicity- Very helpful. the very reason for designing this particular approach, to make sure that you know, the physician stays in control of the therapy and what's gonna happen to the patient, and you not basically just get into an overshooting activity. Obviously, with the excellent safety profile we've seen in the product, actually this is much less required to be used. Obviously, it's very helpful if you have patients that have extreme conditions. You could still give you the safety to actually manage these patients and give you the tools to do that. Great. Very helpful. My final question is, maybe a little bit naive, but I saw I was kind of intrigued by the, how older age correlated with higher overall response rate in the sensitivity analysis. Can you maybe elaborate on whether this is typical in adult ALL, or what the possible explanations are behind this effect? Do you want to go? You know, I mean, I think the bottom line is I think we've got to recognize that, you know, adolescent patients are sort of 18 through 24-year-old patients, often have quite aggressive disease phenotypes, and they are traditionally quite a difficult patient group to treat successfully and to get into remission. Often with teenage, young adults, we do encounter problems in the relapse refractory setting. Often with the older patients, you know, again, they're a carefully selected population in some ways. You know, you take, we have treated an 81-year-old patient, but that patient had a performance status of 1 in order to qualify for the study. you know, I think that's my take on it, is the biology often of the younger patient's disease is actually quite difficult for us to manage with any therapy. That's my interpretation of what you see is the inverse of what you might expect. It's also consistent with, you know, what we had seen, in the development for BLINCYTO as well. I think the background that we experienced at that point was that the young patients or the younger adults, are patients that actually have a start of their disease as kids. Mm. They go through hell, lots of lines of therapies, and they're really at the very end of the line by the time they actually make it to their twenties, and they end up actually in a study like this. They tend to be very, very heavily pre-treated. Conversely, the adult patients or older patients actually tend to be treated much more with much less intensity. Mm. The story of ALL, is that the old patients or adult patients couldn't take the toxicity the kids could take. Actually, you have less intensity of treatment, and with that, the immune system of these patients is actually still in better shape. The cells are less selected out by the other therapies, but also the T cells in these patients still actually are less damaged. Paradoxically, that leads into the situation. You actually get a better product and a more responsive for a more responsive disease in older patients. We've seen very similar outcome with BLINCYTO back in back in that development. It's paradoxical at first glance, but actually it's linked to the intensity of treatment. Thank you very much for clarifying, and again, congrats on those results. Thanks a lot. Thanks for joining. Thank you. This does conclude the question and answer session of today's program. I'd like to hand the program back to Dr. Christian Itin for any further remarks. Well, first of all, thanks all for joining. It's been obviously a fantastic day for us. These are kind of days we're kind of working towards for years to sort of we actually get the type of data that we have now with obe-cel. We think we have a real differentiated product. We have one that addresses the need in this particular indication. We're looking forward to keeping you updated as the program evolves and how we're driving towards filing for registration. You know, exciting day, great place to be. You know, thanks for all the support from all of you as we're on this journey, and you've been following us as we went through that. Thank you very much. Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day!