Cellectis — Call Transcript 2025

You said also that the event will end up at 10:30, Charlie. With that, I would like to. So B-ALL is definitely on that medical. First of all, there's roughly 10,000 patients worldwide, not worldwide, in the U.S., EU, and the U.K. on a yearly basis. And most of the time, these patients are treated by chemotherapy as a first line. As we just said before, you have the heavy relapse rate for adults, essentially. ADCs have definitely an effect, but it's limited effect as there is a lot of relapse, especially using certain types of agents. And CD22. CD19-directed therapies have 50% relapse, so they can't do it. And all these therapies based on patient T cells, as I said before, where the T cells can be unfit or scarred, have no solution. This is where it's important to come with healthy donor T cells to try to treat this patient. This is what we're going to share with you, so why allogeneic T cells? First of all, the quality of this T cell can be very, very stable on this side and healthier, less exhausted T cells coming from healthy donors, pre-selected patients, can give the same chance to every patient. If the patient doesn't have T cells, we're missing. The patient has plenty of T cells, we're also looking at them. The speed of the therapy is not the shelf therapy. They allow every day count. We're not talking about monthly sometimes. We're talking about weeks, sometimes days, so it's very important. It's also one thing that is really important in this field is to standardize the product. Repeatable quality of the product is one of the selected missions in the way we design these products. And finally, CD22 complements also preempt, for example, for CD19-negative or post-CD19 cells, or even engaging CD22, potentially less than CD19. You will see also that some people who are treated with product partly with CD22 potentially take them up with an allogeneic therapy. So one of the things we can try to select this is our manufacturing. People tend to forget about this. I've been talking about the importance of manufacturing for allogeneic T cells, usually autologous therapy. Most of the time in cell therapies, the product is the most important thing because this is the thing that is going to make the change in the patient. Also, at the time of the approval of the BLA, the quality of the production and the way to master the production is often what's most important. This is why we decided in 2018 to integrate inside Cellectis all manufacturing. I would say from A-Z because we do the buffers, we do the electroporation machines, we do the messenger RNA, the plasmid DNA, the antibody vectors, up to the final product. And also what we have is that our Raleigh manufacturing plant that makes the final product, where we have integrated all the supply chain and the logistics. So we have one in Europe and one in the United States. We're ready to go commercial today with the quality of the product we have. And we master all the details of the biochem. I think Adrian will walk you through P1 and P2. P1 is the process one that has been made at the CMO. It's helped us a lot this time. Since then, it's been required by Novartis and things changed. You cannot, if you're cell therapy competent, give your manufacturing to someone else because they're not going to treat it the same way you will treat the cell. And you will see the difference between P1 and P2 is essentially the fact that Cellectis just manufactured a process that we invented, and we make products that have no comparison. And at the end, you have an allogeneic T cell. It can be scalable. We do hundreds of doses per batch. This can also be scaled up more than this. And then finally, we have controlled costs. This is in the presentation of Arthur, which is really important because if you want to have a product that is pharmaceutically valuable, product means not this negative gross margin, then you need to control the cost to make a very valuable product. We believe that we have this product. So like this cell, we're developing this first indication as a bridge transplant that we will be presenting. HSCT, so hematopoietic stem cell transplant, is currently the gold standard in acute lymphoblastic leukemia. This is what's going to give the best long-term chance to every patient. Long-curative disease and the patient will come back to the hospital with disorder. The patient is considered as cured. It secures, so like I said, we'll secure a window. We'll see how we secure this. It makes patients eligible for an HSCT. You need to be MRD negative, not only CR. This gives a clear path forward with an HSCT and long-term remission. Also, I will show you that it's a very malleable safety profile. Much more. With that, I would like to hand the presentation to Adrian Kilcoyne and Professor Nitin Jain that will walk you through all the data of BALLI-01 and the way BALLI-01 works. Adrian? Thank you, André. Thank you all for being here today, and a special thank you to our three investigators who have supported this trial for being here to talk to us through the data, but also discuss it during our panel. Why I'm opening this session up is really to create an element of better. This is an incredibly important meeting for us. This is us transitioning to phase II, which is why we're focusing this day on UCART22, the National Center. Now, just so that people are aware, this shouldn't in any way be interpreted that we're not fully committed to our other program. We absolutely are, but given the importance of this event, we wanted to focus on that. But I will give you a little bit of a snippet of, sorry, wrong way, where we are with UCART22, which is now 87. These are where we are at the current dose level. Now, there will be more data shared at ASTCT this coming year in terms of the update on the program. We can talk about it more then, but I just wanted to reassure those of you who are in the audience and online, we remain committed to this. Dr. Ramakrishnan is an investigator on the study. He is here today as well. But what we're seeing right now is response rates that are very encouraging at 57% complete response rate, partial response rate at 86% based on the seven patients at the current dose level. Now, I know you have lots of questions about this, but please, if we could hold that till we get ASH in our rearview mirror, that would be very good. But again, we just wanted to reassure you that we remain fully committed to this program. Right. I also want to contextualize the data you're about to see because what we have seen over the last few years, there's been advances in ALL, but what we've seen is increased access to targeted therapy. So if we look at frontline, second line, third line, fourth line, and beyond, what becomes very clear is some of these targeted therapies are moving earlier line. Blincyto, for instance, is up at frontline consolidation. Second line, there's a lot more response auto CAR-T. By the time we get to third line, things have changed because most of these patients have already been exposed to at least one targeted therapy. And as you go down multiple lines, many of them have been exposed to all of them. So all of these salvage therapies also have an impact on the response rates. And the mere exposure to many of these target therapies also changes the response rates to following target therapies. So let me look at our trial, and Professor Jain will go through this in a lot more detail. We know that the patients that we've recruited for this trial are very limited. And we know that many of them have been heavily exposed, not only to chemotherapy, but multiple. So for most of our patients, the real next line for them is yet again, salvage people. And the only real chance they have of getting a long-term admission based on what's currently available is to achieve the transplant. But what we can see from these data here is that getting to deep responses with MRD negative is very challenging for the most of them. But we also acknowledge that our phase I program is very complex. And I wanted to make sure, just to give you a quick overview of how this program was run, so that you can understand it as you're seeing the data that will allow you to interpret it a little bit more accurately. So as André already said, we needed to answer a few questions. One, can we make better products from expertise? We needed to answer that question. What is very topical at the moment is an anti-CD52 antibody necessary to optimize response? We have looked at this. Of course, we want to know what the opportunity is, and Professor Jain will share that with you. And of course, touching on what André said, in the context of these very heavily pretreated patients, what is the best outcome measure? What is the best viewpoint to reflect clinical value for patients? And we will share with you, after you see the data, all of the clinical trial design and timelines. So you'll be very clear about the pathologies. So this is the trial design. Now, there's a number of questions to be asked. Now, forgive the simplicity, but all the dose interchange is in the bottom top left-hand corner. Dose level three is the relevant dose here, 5 by 10 to the 5 millionths of kilo. But as you can see, we started off with dose test one. As André said, that is our external manufacturing. And we did do dose escalation by particularly three. But then we internalized our manufacturing for a number of reasons. And to André's point, nobody knows better how to make these living cells that we need. So we fundamentally believe that cell therapies, like allogeneic cell therapies, should be brought in house. But what you will notice as we transition from P1-P2, we don't escalate it. Why did we do that? Because it was very clear from our in vivo data that our product appeared to be more efficacious. So in the spare response, maintaining safety, we de-escalated and re-escalated back up to dose therapy. That's the first one. So throughout the data, you will see at the bottom P1 and at the 17th. Also, you'll see on the bottom, we have FC versus FCA. Now, this is very topical. FC is fludarabine standard conditioning and lymphodepletion. FCA is fludarabine plus alemtuzumab. And we will. Okay, sorry. I'm going to, I need to keep the microphone closer on that. So when we looked at FC versus FCA, we have looked at both to see what the responses were and what the depth of the responses were. And you will see that we very quickly transitioned away from FC alone. We understand that alemtuzumab is important, and we will share that data with you. And beyond that, all of the usual stuff, efficacy rates at the dose optimization, including what our target phase II population is. So hopefully you will find today informative, but this data is not for me to present. It's actually from Professor Jain, who's been a really key contributor to this trial, not only from delivering patients, but also the strategy behind it. I'll give you a sneak peek of the response rates between P1 and P2 with advance of what Professor Jain will show. Hopefully, it's very clear to you that there's a significant difference between P1 and P2, reinforcing the importance of us internalizing our manufacturing process. So without further ado, I'd like to welcome Professor Jain, who is the chief investigator on this study from MD Anderson. Thank you. So everything you. Right. Oh, sorry. We're going to add this thing up. Oh, just read. Oh, hold on. Got it. All right. Good morning, everyone. As we just discussed with slides, as it's kind of shown here, we started the study with the FC process, then dose level one, dose level two, then we added alemtuzumab, went to dose level three, then the process changed to P2, then we just discussed, and then we had three dose levels, DL2, DL2i, and DL3. You can see the actual dose in cells ranging from 1 to 10 × 10^5. Right now, our DL3, which is our current dose, is 5 million cells per kilogram. That's what overall the study design has been for the course of last year. So in terms of the key inclusion criteria for this trial, patient age 15-70 years, so we have some pediatric population to say, between 18 years of age, good performance status, and obviously CD22 CAR, so CD22 expression more than 70%, at least more than two prior lines of therapy. And obviously, these patients were transplant ineligible, getting into the study because they had active disease with the eventual goal that any of these patients hopefully will go to transplant in completion. The key secondary key outcomes included obviously the safety of the product, investigator assessed the clinical response when phase II dose, and also the exposure of alemtuzumab. And then we had several exploratory objectives looking at the RT expansion, persistence, and also immune responsibility. So this shows the overall demographic of the patients. So if you look at the rightmost column, there were 40 patients. So overall, the study, we have treated 40 patients over the course of the last several years. You can see the median age for all 40 patients was 27 years. But I would also like to highlight, if you look at the median number of prior therapies, it was four. So these are commonly treated patients. And again, if you look at the entire group of 40 patients, you can see 45% had prior allotransplant, 55% had prior alemtuzumab, 80% had prior blinatumomab, and actually half of the patients had failed a prior CD19 cell therapy, which they had failed. And then I also want to highlight the bone marrow blast count, which you can see is upwards of 60%, which is a high amount of disease these patients had. Now, what we have done is in the first two, we specifically were looking at DL3P2. So this is the dose level three at process two, where we have treated 12 patients overall. And also, we want to specifically highlight the nine patients who were less than 50 years of age, which is kind of the focus of the trial. And we'll talk about that in a few slides down the line. So in that group of patients, you can also see still a high amount of five parallels of therapy for this group of patients. And again, you can see the bone marrow blast count of our server was 60%. I think that point remains that these are very heavily treated patients who have failed most of these standard therapies, which are available, and then we have to start next step of therapy. The same thing is kind of exemplified here in this kind of figure here. Again, heavily treated patient population, 4-5 lines of therapy, 80% had prior Blincyto, 55% had prior inotuzumab ozogamicin, and then half of the patients had CD19 CAR cell therapy either T-cell or CAR cell. So what were the responses seen? So this kind of, again, goes through, and you saw a snapshot briefly. So P1 is listed first, then the entire P2, so this takes the RP2D patient cohort, the total patients we treated. And as Adrian had shown you, I think we're already, you can see that the P2 process appears better. And then we also separated the response rates for the 12 patients in DL3, and then the 9 patients who are less than 50 years of age, which is the target population for the phase II study. The response rate here is the strength overall response rate, which includes CR/CRi, as well as what is called MLFS. The bullet point you see there, the recommended phase II dose for this product is dose level 3, which is the 5 million cells per kilogram. And the target phase II patient population is at dose level 3, less than 50 years of age. Now, the patients who achieve CR/CRi, so this is among those group of patients who've achieved their remission, especially the CR/CRi, we are looking at the MRD negativity within that group of patients. So the dark part of the curve here is within the CR/CRi population, how many patients are MRD negative versus MRD positive. As you can see, the majority of the patients who achieved their remission were also MRD negative. Again, this kind of shows the kind of the same data, kind of in a similar way. Again, we have split by phase I-II, specifically targeting those 12 patients, and then the nine patients who are at the target phase II kind of patient population, and again, among the CR/CRi or overall cohort, high rates of MRD-negative remission in these patients, so next, we wanted to really specifically look at the nine patients. We talked about the nine patients who were at the target phase II population, so again, to remind everyone, these are phase II, dose level three, less than 50 years of age, so we happen to have nine patients in the study who we have treated with this, and this shows the kind of the similar plot going through these patients in more kind of detail. What you see here is the red triangle is the patients who achieved an MRD-negative response. Anyone which is censored is a patient who had a transplant, and then the arrows, which are for the three patients who are still alive and they are censored at that time, so as you can see, I mean, in this cohort, all actually nine patients had a response. Again, response means either CR/CRi or MLFS, and many of these patients, as you can see, have gone to transplant, and then there are a couple of patients who are still in the process of being evaluated for that, so this kind of shows you kind of the spectrum of the patients here then. The patient number one, or top patient who has an office follow-up, had a transplant and then doing well now, close to 14 months in the transplant, so now this shows the overall survival. This is not censored post-transplant. So we look at the first patient with transplant. And you can see the summary at the bottom here, that the median survival for patients who achieved the MRD-negative remission was 14.8 months. And again, you can specifically at the kind of graph on the right side there, overall for P2, the median survival was 1.4 months. But if you look again at the dose level three patients or the less than 50-year age group patients, the median survival, again, this is a group of patients who had four or five parallels of therapy, the median survival was about 40%. Now, one of the important aspects here was to get the patient to transplant. So, this is because we know that for these patients who are multifactorial, at the end point for them is to get to a transplant and hopefully they can achieve a long-term remission post-transplant. And to get to a transplant, we really need to be in remission for patients with DLF. So the goal here and what we are going to mention here is that at the phase II target population, which is those nine patients we talked about, all of them either have received or are eligible to get a central transplant for this patient population. And then again, it's kind of shown here in a graphic that if you look at the last bar here, which is the nine patients, 80% had proceeded with the transplant, and the remaining 40% are the kind of what's the more recent data for these patients. So I think the majority of the patients are able to get transplant kind of the cohort. And the transplant does seem to improve the outcome. Certainly, patients who are able to get transplant, they are doing better than versus patients who are not. Kind of makes sense because then they derive long-term benefit from the transplant. So you can see the curve. The top curve here is patients who agreed with the patients who received the dose level three, process two. So these were the 12 patients, and then patients who were able to go to transplant versus one. Now, as we're thinking about designing kind of a phase II part, one of the things we also wanted to look at is the number of parallels of therapy. Certainly, when we split the number of patients by four or less lines of therapy, there doesn't seem to be a big bit of a difference in terms of the survival seems to be the same with less than four versus four or more lines of therapy in this patient population. Now, as was mentioned before, right, in these days, everyone, at least moving forward, getting Blincyto in the first-line setting because of approval of Blincyto in the first-line setting. Obviously, inotuzumab ozogamicin is approved in the later-line setting. So most patients who come to the trial have certainly received Blincyto, have received inotuzumab ozogamicin, and many times they may have received CD19 CAR-T cell therapy as well. Because inotuzumab ozogamicin is also CD22-targeting drug, and we published CD22 because of target CD22, we wanted to specifically look at the outcomes of patients who had prior inotuzumab ozogamicin. And again, as you can see, it appears to work in patients who had prior inotuzumab ozogamicin as well. Obviously, for these patients, before study N3, what is the correct therapy set in person? CD19 CAR cell therapy. This again shows the CR/CRi for the same. So this is the CR/CRi rate. And among the CR/CRi, how many were MRD negative? And again, as you can see, high rate among the patients who had prior inotuzumab ozogamicin. Now, we also wanted to look at the group of patients who really had all target therapies. So obviously, these patients have chemotherapy. We look at everyone who gets ALL these days, patients who had inotuzumab ozogamicin, patients who had blinatumomab, and also patients who had a prior CD19 CAR cell therapy. So the number of patients becomes relatively small here. But if you just focus on the P2 dose level three, five, and then at the target population four patients, again, these are the patients who had received all three approved target agents in the context of R/R ALL. They had appeared to be responding to this therapy. And it shows here the same kind of a patient population. Again, the numbers are small, but these are all patients who have received inotuzumab and CD19 CAR-T cell therapy. And again, just to show the CR/CRi rate, these patients are responding, and they're MRD negative. So for example, four patients at the target dose three or four responded with CR/CRi, and they were MRD negative. Obviously, we talked about the efficacy part. The next part is the toxicity part. I'll just show how this cytotrophic is doing. And this shows the CRS and ICANS, first for the overall population or in 40 patients who have been treated. And that's specifically for the 18 patients at dose level three, which have been treated. So as you can see, in general, I mean, most of the CRS events were grade one and grade two. Similarly, same thing for the ICANS, grade one and grade two. You can see that grade three, 2.5% of the overall population for CRS, and then 5% for ICANS in the overall population for grade three. And then the right part shows specifically for the 18 patients at the L3. And overall, low rates of grade three or higher toxicity. Now, one of the other things which have been talked about is the IEC-HS, which has been associated with some kind of seen for different targeting agents. But in this, we had one patient who had IEC-HS, which was called the NF-11, so-called. And so we haven't seen a higher incidence except just one patient who had the IEC-HS. This shows these are specifically the related cytokine adverse events which were reported for CRS and ICANS and others which are kind of listed here. Again, overall, if you look at the 40 patients, these are again only the serious adverse events we talked about, the overall CRS and ICANS, single incidence. Only two patients were reported as serious SAEs for CRS as well as for ICANS. In terms of other adverse events of special interest, you can see here. One thing to highlight is graft-versus-host disease. There's only just one patient, which was at the dose level one, who had a grade two graft-versus-host disease of the skin. But we haven't seen that with GvHD process one. Now, obviously, the product uses a CD52 antibody, which can be at the risk of infections. And this shows all grade three or higher infections which were related to CD52 exposure. So this kind of shows the process one or the dose level they were noted. And in the next slide, we'll talk more about the CMV reactivation, which is something common we see with the CD52 exposure. This shows specifically the CMV reactivation, which is, let's see, there were six patients who had CMV reactivation, again, at the dose level and the process that they had. And the investigator assessed the relation to alemtuzumab, cyclophosphamide, or fludarabine. Now, as we mentioned in how the study started very early on, initially, we were only using FC without the blinatumomab. This is when the trial started with process one. Then we moved process one with FCA, and then process two with FCA. Five patients were treated. The first five patients in the study were with FC alone. And at that time, we really didn't see any response in these five patients, making a point that. I think that is my part of the study. So I'm now going to talk you through the next steps as we're transitioning to our clinical phase II program. I'll give you an overview of what we've done thus far. So for those of you who have been following us, you'll be aware that we have already completed or in the phase I and scientific advice meetings with both the EMA and the FDA. And these were very encouraging meetings. They both agreed that this was an area of specific front-end need. And they also agreed that transplant represents a very positive clinical outcome for these patients. And this is an important step for us based on the data you've seen where all patients were able to get to transplant at our chosen dose. This is, again, gives patients the opportunity of some durable remission and, in some cases, hopefully cure. Equally importantly, we got agreement on our end points of our trial. And I will take you through the design of the program so that you're aware of what that is. And given that there is very little other option for these patients, the regulatory authorities have also agreed that this will be a single-arm trial. And that's important for us in terms of patient numbers. But we will have an external control arm supporting it, which we are designing. But nonetheless, what is clear from all our regulatory interactions is we have a registration path for this program, understanding the importance of achieving a transplant for this particularly difficult-to-treat patient population. So let me talk you through the single-arm study design. Now, for those of you who are used to interacting with the regulatory authorities, they will always want us to have a traditional endpoint. And indeed, we have a traditional endpoint, which is CR/CRi rates in the three months between day 28 and day 84. You will notice from Professor Jain's presentation that our phase I program covered patients 15-70. Based on our observed responses, we lowered the upper age limit. So our move forward phase II pivotal program will be looking at patients age 12-50. And this does two things. One, it gets us a registrational data, but it also satisfies a significant portion of our pediatric investigation path, which we're also working on right now, and we'll talk about that in a couple of slides. Now, this is a CD22 targeted therapy, and within our phase I, we had a cutoff of 70% of CD22 expression. Now, we think that's important, but given the way mode of action of a CAR-T, do we need higher levels of expression like we've seen in the NCI trial, etc., where there seems to be a cutoff of 70% below which efficacy starts to reduce? But nonetheless, we think it's important to answer this question, so there will be another cohort. Yes, the pivotal cohort will be with CD22 greater than 70%, which is the overwhelming majority of the patients, probably 85% and above. If you're CD22 positive, you're very highly positive. In the NCI trial, for instance, I think the median CD22 positivity was in the region of 98%, so we know that there will be some patient attrition from this, but we will still capture them in Cohort B, where we're going to specifically look at patients with lower level of expression, so we will be capturing all comers within this trial. An important part of this program is also the first part, which is the dose optimization of alemtuzumab. This is a requirement, and we will be looking at two doses: the dose we already have investigated and one other dose, and it will be randomized in terms of the exposure to alemtuzumab, and at the end of 40 patients in each arm, 40 patients overall, we will do our first interim analysis. And that will allow us to decide what is the optimal dose of alemtuzumab to take forward into the remainder of the trial. Now, just to be clear, this is an essentially seamless design. So the patients in the dose optimization of the chosen dose will also form part of the pivotal patient population. So it reduces the burden of recruitment on us for the remainder of the study. With that, we will have another interim analysis at 50% of the pivotal cohort recruitment. And for the primary analysis for BLA, we'll be based on CR/CRi at three months following full recruitment. You will note that we have a follow-up analysis for overall survival, which will be up to two years. Because as you've seen from Professor Jain's presentation, we believe that one of the challenges we've had in recruiting our phase I program, it's not recruiting it, but actually analyzing it, is interpreting response in the context of durability of response. What we found is once patients got to MRD negativity with a deep response, they were immediately going to transplant, and therefore by three months, most patients had already had a transplant, and because we were censoring for transplant, it's very difficult to show durability of response. Moving forward, because we won't be censoring for transplant, we will be able to show much more clarity around duration of response for these patients, so based on our phase II plan, as I already said, we are currently working on a pediatric investigation plan. The current phase II program will capture patients from 12-50, but we will also have almost parallel pediatric plan looking at patients from 0-12, so we are capturing the majority of patients from 0-50 years of age. That's not to say we're abandoning the patients above 50. We will look at those, but not just yet. We believe our first indication will be in patients up to 50 years of age, and again, once we have an update on how we're going to address the remainder of the patients, we will share that with you. We now have. Our protocol has been submitted to the regulatory authorities. We are now opening. We are now setting up our study, and because we want to accelerate this, we have increased the number of sites we're using when we're opening. So we're going to globally open sites, 75 centers across North America and Europe. The numbers for each of those countries are there. Apologies to the Italians. I forgot to shade in that one, but we will be going to Italy as well. But 75 centers will give us what we consider reasonably brisk recruitment to give us these timelines. These are the timelines we are working toward. We are, of course, hoping that we can beat those timelines, but we anticipate toward the end of this year, we will have our first patient recruited. Based on our recruitment projections, we will have our first interim analysis at Q4 2026. Now, because we will continue to recruit, we will not be pausing recruitment at any point in time. And at that time, we will have all centers active and recruiting. The second interim analysis comes fairly quickly after, in the second quarter of 2027, and that will be at 50% of the pivotal cohort. By Q3 2027, we anticipate we will have completed enrollment, and then we know that we have our three-month follow-up for CR/CRi. We should have our primary analysis complete, allowing for that in the first quarter of 2028. Now, assuming all of that, we should be submitting for the second half of 2028 our BLA. Now, I just want to reiterate one thing that I haven't probably made clear enough. When we're submitting this BLA, we're actually submitting two BLAs, because throughout this, we have two investigational products. We have the UCART22, but we also have alemtuzumab, so by the second half of 2028, we will be submitting not one, but two BLAs. Now, that's all I'm going to cover. Hopefully, the timelines and our plans are clear. But I'd like now to invite our three investigators. I'm delighted to have them here. We've been introduced to Professor Jain already, who's the chief investigator of our studies and a huge supporter. I would also like to invite Professor Boissel to join us from the Hôpital Saint-Louis in Paris. And again, he's the head of young adults and adolescents. And your insight is going to be really important. And very important also is Dr. Ramakrishnan from San Antonio. Sarah Kim. Oh, sorry. Excuse me. Sorry. But he's particularly important today because he is the only investigator who's running both our studies. So he is doing 22 and 20x22. So his insights are really helpful to us. So what we want to really do now is just, you've seen the data. And it would be great if we could really start thinking about the, as we look at the data, just for the audience and for those online, what is the level of unmet needs that we're addressing? Maybe we can start with you to get a European perspective, Professor Boissel, to talk about the unmet need of these particular patients. Start with your point of view. So we're not so far from what we're hearing in the U.S. doing for the patients in children and adults. We are, of course, now exposing our patients to Blincyto frontline. So all the patients, including in first or several relapse, who have been exposed to Blincyto, we can treat with targeted inotuzumab ozogamicin. So CAR T cells. So it may be surprising to speak about first-line ALL because it's not something that has been usual in prior study, but that's the reality now. So a lot of drugs we propose to our patients, and mostly CD19-targeted. What is probably also changing now in Europe is, because of the use of Blincyto frontline, we will postpone allogeneic stem cell transplant to several months, so we were traditionally more consulting patient frontline than how it's here in the U.S., but we will come closer to the standard practice because of the use of targeted alemtuzumab therapy frontline, and so obviously, the patient will have built in terms of relapse or refractory status will be exposed to CD19-targeted therapy with two different profiles who will lose the target, so it will be CD19-negative, and those who are not completely identified so far are those who have an immune system that is unfit to either respond to Blincyto or to provide it to CAR-T. That is something that is still unclear. So I think there's always a question about the likelihood of the T cell patients for frontline or advanced patients. I think that, yeah, the first surprise about this, the results of the patients were exposed at a high rate of prior exposure to immunotherapy. I think none of the studies or pivotal study were done for ALL in relapse or refractory disease for this kind of profile or prior target. It's clear that frontline and 80% of Blincyto, the number is up to 55% or 60% binding to Blincyto in high rate of transplants, something that medicine wants, and so clearly, these patients will require to have an innovative strategy as presented. Reports. So of course, I think that the agency is required to move to relapsed or refractory disease, but when you are addressing the question of unmet needs at different stages, including frontline patients, we are trying, we are now identifying patients that are also refractory to CD19 targeted therapy, so it's still not well described. It's the E1910 study that led to the approval of blinatumomab frontline was for MRD negative patients, so they were MRD negative, good responders, and then received blinatumomab, so there are good responders. But we know also from limited studies, and if you consider the overall population of patients, we will identify very rapidly patients that are refractory to primary positive blinatumomab, and that do not convert to MRD negative, especially with the high sensitive MRD tool that we are using now. In this patient, we know that they have quite a high risk of progression. And that in this situation, it's not the option to treat them with allogeneic stem cell transplant with this MRD-positive cell. So it is clear that also this kind of appropriation for early phase. So any tool that helps me convert my patient standpoint within curative intent, especially if we can stage the advancement regimens, we have very good outcomes in getting them into MRD negative stage. Regarding that, patients we're seeing now are also exposed to all these targeted therapies. So it's much harder to get them to that point. I mean, I think when I see the data and look at numbers this high for MRD negativity, actually activity is very, very encouraging. I think the other thing, I've worked with allogeneic CAR T therapies for some years now. And I want to highlight what André said, that the manufacturing is very critical of this team. And I'm looking at, do we get reproducible CAR T expansion and response? And I think that's also been very reassuring with this product. And I think that distinguisher. So I mean, the critical thing we often see is patients coming in, they have refractory disease. With the standard CAR T, how are you going to collect T cells on someone while maintaining their disease at a state, controlling them, getting them to transplant? This product provides a lot of advantages. Ready to go. We know it works very well. We have a very good target. And we have high rates of MRD negativity. So we're typically planning a transplant while they're probably. So it's been very encouraging. I think I will just say on the same point. I think one of the things which I, so I treat ALL, but so I think one of the challenges with the outlook of CAR T cell therapy which has been great that we run into issues with these patients who are cytopenic from the disease. So their white count is like 0.5, 0.3, and there is no T. You cannot collect. There is nothing to collect. There's no T cell getting T cells. So I think that's a challenge especially for B-ALL. Maybe not so much for NHL. I mean, maybe, but because B-ALL is a disease. So I think that's also a point that I think for specifically for B-ALL, allogeneic CAR T cell therapy will have a point because you don't need to worry about blood counts. Your results are pre-made. So I think that's another important point we used to be really running into issues in our department trying to say, "Oh, let's do a CAR T cell therapy," but, "Oh, the white count is 0.2." They talk about all those CAR T cell therapy and, "Oh, we're going to do that." The results are below. So I think that is a potential challenge for a B-ALL. What was really interesting, I met with you a few weeks ago. All three of you asked me the same question, which was, "Tell us what's happening with prior CD22 exposure." And it would be great to get your view on the data you've seen because I was a little surprised when I saw the response, to be honest. So maybe we'll start back with you, Professor Boissel. Yes. So the question was, I think, obvious because of the disappearance of the CD19 and repeated CD19 targeted therapy, so blinatumomab, like you said. And we now know that this will emerge from real-world experience here in the U.S. where we know that prior blinatumomab exposure may have an impact on early response, but also on the risk of progression of their response to CD19 targeted CAR T. So the mechanisms are a little bit different in terms of CD22 expression modulation between CD19 and CD22. But we know that, and also from daily experience, that exposure to CD22 with inotuzumab ozogamicin may modulate sometimes transiently the expression of CD22. So we start to have some data, but I think it was very important to have the analysis done. And so yes, I was a bit surprised by the results you showed me yesterday. It was certainly a surprise. Remember, I write small, but yes, people hear that, but there is no clear evidence that prior exposure to inotuzumab ozogamicin will modulate the response to the cells. So it's something a bit encouraging. Dr. Ramakrishnan. Yeah. So I would concur, I think, with a lot of Blincyto usage where you see a downregulation of CD19 and those patients are no longer eligible for CD19 CAR T if we can't affect the target. So I was a little surprised with prior inotuzumab ozogamicin. A majority of patients are getting it. Perhaps the mechanism of resistance is a little bit different. The target is still, I mean, it is a different type of approach. It's an ADC versus a T cell redirect agent. But it's very encouraging that I know that I had patients with heavy ino exposure that went into an MRD-negative position. They're very encouraging. Yeah. And they're doing the same thoughts. I think, as was mentioned, I think for CD19, it's more of an issue because it was not of the Blincyto and obviously after CD19 targeted therapy. I think for CD22 with inotuzumab ozogamicin, yes, there could be some loss, but it's not as frequent as the CD19. So I think in that sense, I think it's very good because you're preserving your target immunoprophylactically for inotuzumab ozogamicin. But also the fact that, which is encouraging, is that, yes, you had prior inotuzumab ozogamicin, but all these patients are still sensitive to never see that Blincyto targeted patient. And I think moving forward, I think it's quite likely that, I think, at least in the U.S., certainly a lot of patients will have prior Blincyto for sure. And I think a lot of these patients that we saw in the study will have prior inotuzumab ozogamicin before they go into the targeted therapy. So I think we also have to address the inotuzumab ozogamicin issue. And we have seen that inotuzumab ozogamicin appears to be very important in achieving results. So it would be great to get your insights on the management of your patients with alemtuzumab. We've seen the toxicity profile, which I think is reasonably reassuring. But just get your view on using it. Maybe we can mix it up with. So when I first took on this study and alemtuzumab, I heard that I was like, "Really?" But that being said, now we're actually using it. I think the advances in infectious prophylaxis have made it more safe, particularly with CMV. We've had a big advance with alemtuzumab here for prophylaxis. And that's pretty much not been that issue for the most part. We also have other drugs. So I think the key aspect there is having those anti-infectious prophylaxis and being on top of that so that you manage that with your patient with antithromboprophylaxis that comes on other drugs. And I think it can be safely delivered. And clearly, it seems to be very important in the expansion of the T cells and activity of the path. Yeah. So I think my previous we use alemtuzumab for infectious disease T cells B-ALL at a much higher dose for much longer. And they are certainly. You're not going to see immediate activation and all these things. It's an issue, it's a challenge. But here, as we've kind of discussed, we're using much shorter duration overall, much lower than what we use for B-ALL. And again, with the infectious prophylaxis, monitoring the patients closely. I think, thankfully, the infectious issues. That's not been a major issue with alemtuzumab. And it appears, as we just discussed, at least for this product, that the use of alemtuzumab is quite important. Choosing to have the OBR, also using alemtuzumab for some transplants that can be used to manage this infectious disease that are not that aggressive in terms of viral levels in the infectious patients here. Of course, the organization of this is really important to explore this to those levels, and I think it was described by the agency that it seems wise, and I'm happy to go forward with this kind of questions. I suppose I have maybe one more question. I'm mindful of time. When we look, and I know the numbers are really small, we have to contextualize. We have to interpret the case on the small numbers. We have those really heavily pre-exposed childhood therapies getting those level of MRD negative responses, which I think are very encouraging. But it would be great to get your insight into, based on your practice, what really would be the likely response rates for those patients with what's available to them beyond the next available salvage therapy, if at all? So maybe we'll start with you, Dr. Ramakrishnan. So I think we're talking about patients who are still on trial lines of therapy and who have failed, obviously, chemotherapy, BlinCyto, and maybe a CD19 targeted therapy. I think that we are really, there is no proven available agents. I mean, chemotherapy at that time will have a less than 40% chance of response, additional chemotherapy, I mean, to say. And really, I think we're relying on some kind of a clinical trial, new drugs. And I think we're talking about, again, response rate. So hopefully, 20%-30% response rate where we hope, then we'll get MRD negative, and then they'll be transferred. So I think if we go, I think, and that's an important point. I think also I think the ALL, I think if you go four or five prior lines of therapy, these are really. I don't think there's anything standard here. And we're talking about really very reasonable outcomes for the project. I would concur, I think. I typically, when I see these patients, do not recommend chemotherapy because the rates of response are going to be so low. We're always looking for a clinical trial for these patients. Usually, we don't have anything that's called NIPTN. And then the patient then try to get them on some sort of clinical trial. And that's. I can't emphasize how refractory this population is. And often, they're very young individuals also. So it's heartbreaking stories. For example, a 23-year-old girl with a 22-year-old. And just imagine sitting in front of that person and telling them, "Yeah, we got nothing else." And to be able to take that type of individual and give them a product that gets them to MRD negative, gets them to transplant, it changes their life. She's now going to be able to raise her child. That's sort of, I think, why we all here do what we do. It's to make sure we make sure we have people. Yeah. It's a good question. But I'm not surprised because other studies have shown that when you read the median of four lines and you compare less than four lines and more than four lines, you don't see any difference. So it's important for this group, of course, to move forward. And particularly, I come back to the MRD positive population of patients first, or also with several lines, because we have also this kind of patients in several lines. And we'd be very happy to see the results of this kind of study. I think they're built also for this kind of patient that, of course, we also use in a third of all of our patients right now. Well, thank you all for your insights. I'm going to ask one cheeky question of you, Dr. Ramakrishnan, because I know we didn't want to focus at all on 2022. But maybe for the audience, at least, just give your own view of how your patients are doing with it. What's your experience of it thus far. Again, the experience has been very positive so far. I think we are seeing more targeted therapies in lymphoma as well. We're seeing that clinical trials coming earlier in the line of treatments. But there is an unmet need there for patients who relapse. And again, I think one of the things about T-cell fitness, you kind of wonder in those patients whether how good were the T cells that we started off with for the CD19 CAR. And lymphoma is also, I think, a little bit different than ALL, where maybe we don't use the same duration of T-cell persistence maybe a couple of months. And we get a good response. We get rid of the lymphoma and get durable remission. So again, I think the product so far, we've been very happy with cell expansion and responses. Everyone I've treated has responded, which is very encouraging. Again, durability is, I guess, what we see in its early days, but also encouraging. All right. Thank you so much. It's a very short time. I would say thank you to our three investigators. Thank you for your. I'd like to hand over to Arthur Stril, Chief Financial Officer and Chief Business Officer. Thank you, Adrian. Good morning, everyone. Thank you so much for being here. None of what you've seen today and will see in the coming months would be possible without your support. Thank you so much for being here. I think as we have our BLA in line of sight, as Adrian has explained, it was a good time to discuss the commercial opportunity for UCART22. What are we talking about in terms of sales and commercial opportunity? Now, if you have to take two takeaways from my presentation, the first one would be that this is a meaningful opportunity from a peak sales perspective, as you will see. But the second thing is that not all peak sales are created equal. There are peak sales from autologous therapies with razor-thin margins and individualized complicated therapies to scale. And there are peak sales coming from allogeneic therapies, which are true pharmaceutical off-the-shelf products that benefit from all the economies of scale that you've been used to in the antibody or small molecule world. And it is this kind of peak sales that Cellectis is bringing forward today. So you've heard a lot about this molecule. I'm not going to repeat too much. But the differentiation of the CD22 approach, the fact that this is an allogeneic off-the-shelf therapy, the fact that we have truly internalized manufacturing, which will be highly beneficial for a fast uptake upon potential BLA approval, and of course, the highly attractive margins linked to the off-the-shelf allogeneic approach are key differentiators of this product. Now, we've talked a lot about the competitive landscape. Today, as you know, if you accept chemotherapies, the vast majority of therapies are targeting CD19, and there is a desperate need, we've heard it many times from our panelists, for another target. The only other product targeting CD22 is Besponsa, an ADC, so it doesn't truly benefit from the T-cell mechanism of action that you can see with CAR-T and T-cell engagers. And of course, the other therapies are leveraging the patient's own T cells, which can be really problematic, whereas UCART22 would be the only product to leverage off-the-shelf donor-derived T cells. So thinking a little bit when we start building the peak sales opportunity about the landscape, again, we heard it today from our panelists. Today, the majority of frontline patients are treated with chemotherapies. There's, of course, the arrival of Blincyto. We heard about its importance in the frontline consolidation, especially following the 2024 label expansion. In the second line, there's often multiple classes. We've heard about Blincyto. We've heard about, again, rounds of chemo. We've heard about Besponsa and auto-CD19. And physicians would generally alternate between these therapies. Starting from the third line, it starts breaking down, and efficacy is going lower and lower. And of course, if you're going fourth line and beyond, as we've heard, especially from Professor Ramakrishnan, everything is becoming clinical trial. So really, the focus today, when you think about the first opportunity for this molecule, is going to be this third line and fourth line and below patient population. Now, how many patients are we talking about? So here, we're looking only about U.S., EU4, and U.K. And so we start with the incidence first line treated population. And this is projected to 2035, which is our year of expected peak sales. So we have about 9,200 patients, of which 5,100 in the U.S. and 4,100 in the EU4 plus U.K. Now, from these patients, we estimate that about 45% will go into the second line, mostly adolescents and adults, given the good outcome of treatments in children in the first line. So that brings it to about 3,900 patients treated in the second line setting. Moving from that second line setting, we expect that about two-thirds of patients will require further therapeutic intervention, which will bring you to about 2,700 patients in the third line setting. This is, of course, annual. And then finally, we apply a last cut-off for CAR-T eligibility, which would be about 70% based on the outcome we've seen with Auto-CAR-T. And this is mostly to take into account the patient fitness and comorbidities to account for eligibility for CAR-T. So our core target population in the U.S., EU4, and U.K. for the year of peak sales would be about 1,900 patients. Now, of course, this is the addressable market. And to get into peak sales, you have to have an estimate of what is going to be the preference for this molecule. So as you have heard during the panel from Adrian and our physician experts, we think that UCART22 will be a very promising opportunity for the third-line and above market. UCART22 is an alternative target to CD19. It benefits from the convenience of the one-off dosing. It's obviously an off-the-shelf availability, so no need for apheresis, no need to bring them to manufacturing, no need to have patients to go through bridging chemotherapy. It can be immediately available from the hospital pharmacy. And of course, as you have heard, we benefit from the deep MRD-negative responses in this therapy. So we estimate, based on oncology precedents, but also interviews from physicians, preferred market share of about 65% for this line of treatment. We think that the other therapies, be it because they target CD19, they're leveraging the patient's own T cells, or they have very limited efficacy and a high toxicity profile, the case for chemotherapy, as you have just heard, would not be the prominent therapies once UCART22 is approved. Second, we think that UCART22 has high pricing potential due to the unmet medical need it is going to solve. In Europe, we're being a bit conservative. So we're using the anchor price in 2025 of the average price of the approved therapies that's CAR-T and Kymriah. And we project a flat pricing until year of peak sales to 2035. So we have an anchor 2035 expected list price of about $365,000 for the EU. In the U.S., we have looked at what has happened with the price of Kymriah, Yescarta, and the CAR-T, the three autologous CAR-Ts that were approved. The current anchor price for 2025 has been about $515,000, and we think we can apply a modest growth of 5% across all the way to peak sales in 2035, which is what has been seen in terms of pricing dynamics for the Auto-CAR-T since their approval, so we come to a 2035 expected anchor list price of about $840,000. Now, we are going to bring this all together, looking at the target patient population, the expected price, and the expected therapeutic need, so if you look at the initial addressable patients, you come back to about 1,900 patients, which is the number that came from the previous slide, about 1,100 in the U.S. and 840 in EU4 plus UK. This is, of course, annual numbers. You apply the preference share of about 65% in this line. We still put a cut of 90% for market access of CAR-T therapies, which is standard for CAR-T therapies, which brings you to about 620 patients annually at year of peak sales for U.S. and 408 patients in EU4 plus U.K. Then finally, you apply gross pricing, which brings you to a 2035 expected potential peak gross sales of up to $700 million for the U.S., EU4, and U.K. And of course, this is excluding the rest of the world. We think this therapy will have also tremendous potential in other geographies, like the Asia-Pacific region, especially due to its off-the-shelf nature. But we've been conservative, and this up to $700 million is the figures for U.S., EU4, and U.K. Now, of course, the core indication that Adrian has mentioned for our initial label will be third-line plus. But we think if the results hold in this first trial, we will have the potential to extend UCART22 in other areas. We think that UCART22 has the potential to have a place in the second line. And we think that UCART22 has the potential to have a place in first-line MRD-positive consolidation, pretty much like Blincyto, especially as you're going in earlier lines of treatments where patients are more fit. So if you're factoring an additional opportunity for these label extensions in the future, we believe that peak sales could increase to up to $1.3 billion with this additional label extension. To put it all together, we think that UCART22, again, has a very strong commercial opportunity. It has the potential to be the first-in-class immunotherapy beyond CD19, and we think that what will especially drive adoption, as we have heard today, is the deep responses with high CR rates and the impressive MRD negativity that you've seen. We believe that there is a robust peak sales potential of up to $700 million in the first indication that we have, and again, very importantly, with the allogeneic approach, this is not just about peak sales, but this will be about EBITDA, and this is true pharmaceutical EBITDA, not autologous EBITDA, and we think that the industrialized off-the-shelf approach with the internalized manufacturing is going to be critical for launch and commercial success as we go into the third. Thank you very much for your attention, and I will hand it back to André for the next slide. Thank you very much, Arthur. And thank you very much for your attention. So I'm going to share the paper with my glasses. Because I would like to introduce our speaker, next speaker. So I probably told you you never had an opportunity to present in front of this type of audience that told him that you're a very friendly audience. So it's my great honor to introduce one of our distinguished speakers, Dr. Mark Cobbold. So Dr. Cobbold is a physician scientist and immunologist with a remarkable career at the interface of discovery and translation. From his first time at the University of Birmingham in Massachusets General Hospital, correct me if I'm wrong, where he made important advances in tumor immunology and immune control. His current role is Vice President, Early Oncology and Immunology Translational Medicine at AstraZeneca. He has dedicated his career to turning bold scientific ideas into therapies that change patient lives. You know how it works in this space, actually. We buy big companies. We're super impressed by a big pharma company because we're big, so plenty of money, et cetera. But we're usually super arrogant when we interact with them in terms of innovation, like crazy ideas, et cetera. We think we have it all. And the first time I've met with Mark and started discussing with him, seriously, that's where humility comes back to you. It's our privilege normally to be there. Maybe these guys, this guy, it's such a brain and so much disruptive with his ideas that I was really blown out. And since we started the collaboration I think two years ago, seriously, the level of sophistication and technology that we're bringing inside Cobbold's, I think this is going to be a big game changer. And the fact that AstraZeneca, the leadership of AstraZeneca, is so much putting emphasis on the fact of making these therapies functional, accessible to all patients, and also totally disruptive come from people such as Mark. It's going to make a presentation here. And I think that in the coming future, not so far, but a few months or so years that are coming, you will see a series of disruptive technology coming in the clinic and changing totally the game. Now, if you want to ask me what's going to happen, molecular medicine, and especially in vivo gene therapies that we're developing also with AstraZeneca are going to be a huge revolution in the field of medicine in general. A lot of people are going to have different types of treatment, single injection, and then they will go back home with a differentiation in their way of life, and really, something that will be very appreciated. With that, I would like to hand it to Mark. So Mark, you're very welcome. Thank you. I'm very proud. Thank you for the introduction. Yeah, it's a great pleasure to be here, actually. This is a great first presentation for that, so you guys are not the only people who are going to be there for them too, but I'll be there to go. I've been in South America for 25 years, actually, with my PhD, so I've worked with like 20,000. Yeah, it's just a real privilege to see where this technology is going and where it's going in the future. I believe we've just got started. This is a very exciting space. Yeah, let me tell you a little bit about what we're doing actually for the clinic. I guess most of you here will know this, but cell therapy is sort of transforming medicine. There's a lot of very, very significant personalized therapy. It's sort of one-and-done treatment for patients. It has very deep, durable responses. It's a new orthopod treatment that doesn't have any gross flexibility with chemo resistance, for instance. You can see on the right-hand side, there's been an enormous investment, I guess recognized by many others over the years in terms of this space. And that's brought us to where we are today, where we've got six approved CAR-T products. We've got one off-the-shelf therapy. And so we're living in an age of living medicine today. And these are genuinely transforming medicine for patient lives. But there's a lot more to go. And you can see why cell therapy is so exciting. On the left-hand side, you can see those six autologous CAR-T programs that are approved. And you can see the levels of overall response rate, particularly the lead response rates, are very, very high. And this is, perhaps the previous speakers have highlighted, with patients who are extremely multiply refractory. So you don't typically see this level of response. And on the right-hand side, you can see the other reason why everyone is excited is the tail. You look at the tail, and this is data from 2021, actually, from Kymriah, and you can see that there is a very, very significant durability. Now, there are very definitely some challenges ahead, particularly as we extend this autologous tumor to more refractory phase. But these therapies are delivering to patients with a quite transformative outcome, and so in terms of how we can drive more clinical benefit across patients and autologous, a number of challenges out there. We've seen that these are giving rise to deep and durable responses. There's a very great flow of money into this other space as it has a field. But there's a lot of challenges that remain, and I think that's where allogeneic CAR-Ts present an opportunity. We need to get adequate assistance for these CAR-Ts to live life for longer. In many clinical studies, the CAR-T don't stand well. They don't live for the system too long. I think anything currently at this should be a fairly expert site. I think that's what we need to resolve, so we've given more widely and scalability, but really isn't today enough manufacturing to actually deploy these therapies, especially to be there. In fact, as more indications get seed approvals, particularly as we're going to see approvals in the autoimmune space, it's very difficult to sort of see the current structure of the next scope for that, so it's important that we think about technology and the ability to scale as much as possible. So in terms of our journey as a company for cell therapy, it really started with when José Baselga came and joined from New York from Sloan Kettering. And Sloan Kettering did see the transformative potential of CAR-Ts that were on the borders of gene. So the one thing he did when he arrived at AstraZeneca was saying, "We've got to bring cell therapy into industrial engine." And that was a very significant challenge. Because back in 2016, certainly, there wasn't a great deal of belief that this was a viable proposition for pharmaceutical companies. And I'm very pleased that over five years, which we started the cell therapy at the end of 2019, beginning of 2020, I think now actually we're going to get very, very much cell therapy. It's an absolute critical part of medicines and patients with neuronal cancer problems in the autoimmune disease space. And you can see we've built very aggressively over those five years. We started our CAR-T program. We had no manufacturing. And so one of the things we did was adapt to the pandemic to deal with is how do we actually start. Right. So we partnered with the company called CBMG, which has now renamed itself into AbelZeta. And they've been the number one partners for us. And now they're starting our first CAR-T program, starting with a three cellular cross-member into an RNG space. That's what we've done. In 2022, we acquired a company called Neogene Therapeutics, which allowed us to get into intracellular oncology targets by acquiring Neogene based on AstraZeneca and cell manufacturing. And that company brought us two things. One is the TCR-T technology, which also actually gave us a significant manufacturing footprint. So now we have much upscaled ability for cell therapy for the clients. We announced a partnership in 2023 for Quell Therapeutics, exploring RNA breaks for a number of conservative therapeutics and immune diseases. And then one of the big ones was with Cellectis. We announced an acquisition. We had a partnership with Cellectis. Also, an investment in Cellectis. And we really felt that Cellectis had the depth of knowledge and more than 10 years' experience. Cell therapy would be an excellent partner. And really, it's been an absolute pleasure working with Cellectis team over the past few years. And we've introduced a really, I think, quite significant work together, actually. That's going to make a very much more difference. You can see since then, we've got even more enthusiasm about cell therapy. We were the first pharma company to acquire biotech company in China. We acquired Gracell Biotechnologies and therefore Behavior and that put together a three. And that's given us access to China normally, actually, since it's acquired that company. And it's also given us a different process that they've come up with the past two process, which actually is extremely important for how I think we've become clear with time. And then in terms of manufacturing, we acquired a manufacturing associate who was previously owned by autologous and cell therapeutics in Rockville, Maryland. We announced a key collaboration with the Roswell Park Cancer Center before. And then most recently, we've acquired a small proposal drive, so it's a biotech that has the first of the data on in vivo shots of cell space for cell therapy for our vector. And that, again, has been a very good collaboration with the scientists there. And it gives us the ability to scale in vivo therapy. So that's our journey. And in terms of what we're doing with our overall strategy, we're exploring multiple approaches in this space. So we're investing in TCRT, investing in CAR-T, we're investing in CAR-T rates, investing aggressively in off-the-shelf technologies, including in vivo therapy. And in terms of the portfolio on the right-hand side, you can see we've got quite a substantial share over the past few years. And actually, the portfolio you can't see is actually fairly large, which I'm very, very excited about. So there'll be many more things to hear about in the next coming years. But I'll just talk to the portfolio very, very, very quickly. We've got AZD0120, which is an anti-fast car, Gracell, which we've got actively in the ground for myeloma. And then also for autoimmune diseases, the GC012F to get the beta-armored CAR-T in China and also in the rest of the world. These are 703, you know, STEEP2 armored CAR-T, prostate cancer within 0.0754. And then we have a series of TCRT trials targeting driver mutations in cancer. And these are likely going off more genotypes. So there's a graphic of these as well. And then in terms of what our global footprint is going to be, including our tie-in with Cellectis, you can see going from west to east that we have now two manufacturing sites on the west coast, one in South America, one in nearby Teltani. We have in Maryland, this is Rockville. And then next is Cellectis, which they manufacture in North Carolina. We have a research base in Gaithersburg in Maryland. We also have, as I saw on the map, we also have two sites in Boston, one in Waltham and one in the Lexington Seaport, and we'll have a large RNA test for next year in Kendall Square, which is very significantly actually driving research and expectancies of cell therapy, sorry, brush, so that will include cell therapy, particularly cell therapy for autoimmunities, and then we've got a clinical site for RNA cyclical, which is the post-processed lipids, actually, which were in the same building, and Europe, we've got sites, again, starting with the next four sites in Paris that manufacture various components. We have our R&D site in Cambridge, and we have a significant number of cell therapy corporations. We have a site in Amsterdam. Yeah, is that clear? In Amsterdam, which is predominantly research. We have a facility now in Brussels, pretty surprising. And then as we head to China, we have a number of facilities in Suzhou, which are manufacturing facilities. And then we've got a number of sites in Shanghai for the research and development, as well as partnership with AbelZeta. We think this allows us to operate globally. It also allows us to get in and test trials very rapidly in our systems, which allows us to learn quickly. So that is something that's good. And then in terms of why Cellectis, why is this such a strategic big force to us? And really, I think there's a number of reasons. Going from left to right, we have the technologies, we have the capabilities, and we have the capacities. And so Cellectis brings with us more than nearly 20 years of molecular understanding of gene modification. And so enormous, a very deep understanding of how you can manipulate the genome of cells with our advanced capabilities. Cellectis are amazing process development. We've seen the shift with process monitoring tools, which is so important in terms of the cell therapy analytics for development, CMC, GMP capabilities, clinical regulatory gene editing expertise, the ability to really define exactly how to knock out on-target genes. Very exciting. I've been blown away by their technologies. And 10 years of experience. That's about the next-day delivery of cells. And that's really one of the toughest spaces in cell therapy. But the last few years have really shown that the field is really starting to make a significant amount of progress. And in terms of capacities, the Paris site's got fantastic manufacturing. I think the facilities to complement Raleigh where the cells are made in New York as the origin site. So again, partners for us. But I think as we sort of join forces, I think this is an area where it's a win-win for both. Almost French blend, and then in terms of where we're seeing, and this is the slide I'm most excited by, you can see where we're going. I'm not going to discuss too much as to what we're doing, but this will give you a bit of a hint of what we're doing. So you can see the autologous paradigm, which is really where cell therapy is showing that they're capable. It's a fantastic time for technology. They're not particularly stable. Then we have our classic allogeneic CAR-T that will allow you to scale to a much greater extent. This also resolves some of the issues related to the T cell fitness of donors. Where we want to go is we want to go beyond allogeneic and go into a cell which has much greater expansion capabilities. We're working very closely with sharing a lot of the research capabilities and building a cell, which I think has quite substantial capabilities in this particular space. It works. I think we'll now actually be very destructive in this particular space. We'll hear more about this paradigm next year. I think also, I think that one slide about what is happening in the autoimmune space. CAR-T cells have disrupted autophagy, but they actually are also showing even greater disruption in the autoimmune space. The ability to reset someone's immune response when the immune response has taken the wrong course is incredibly powerful. This work is led by Harold Chester. He's going to be introducing the concept of reset T cell development, immune development for patients with this deeply fixed autoimmune feature. Not all of these work here, but you can have very, very significant effects on those patients. We and other companies have actually shown similar data. We presented some data, and in this year, EULAR is showing the AZD0120, but actually, we have very similar data, so we believe in this. We believe this is a game changer for the autoimmune space and the ability to disrupt and reset the immune response of the patient where the immune response is just gone astray, and so autologous has clearly had a significant role. It's not particularly scalable. There's also a limited amount of people that take the types of approaches. Allogeneic approaches give you a much greater paintbox for which to create these kinds of regulations. I think in vivo is also very significant in this particular space, so we're very excited about this proposition and very enthusiastic about the cell therapy, and so in terms of where we're investing, we're investing in autologous. We're investing in our autoimmune platforms, particularly with Cellectis. We're investing in in vivo spaces, and I think there's room for these technologies to advance more. I think this is one of the most rapidly evolving spaces driven by the pace of technology and the pace of innovation, so I think what we are going to see, we're going to see some of these products that surpass others, but we'll also see many of them survive too, so this is the last slide, and this is kind of what our overall vision is. We see the first CAR-T approved back in 2017, and today we've got a large number of cell therapy principally being used in the context of delivering hematology. Where we're going to tomorrow is expanding this into solid tumors, and I think the solid tumor data that's emerging is also very exciting, and also immunities, and then longer term we're going to have much safer medicines and much scalable, I hope, and I think deployable at most hospitals without expert teams and a very safe profile, and this will include off-the-shelf, allogeneic and in vivo. Those autologous. Okay. With that, I thank you very much. Thank you very much for the presentation and my all your voices because we're definitely going to see things. We've got to a science fiction, but we're making it real. As we said, we might have updates soon, and it's going to be really interesting. So I'm going to make a quick conclusion on the presentation we did this morning. And then we're going to open Arthur, myself, and Adrian to questions for the Q&A session. So Adrian presented this slide. A few takeaways that I think are extremely important in this slide. We're deep believers in the fact that allogeneic CAR-T therapy fits definite needs in various spaces in oncology and potentially beyond oncology, as Mark has showed it, in autoimmune disease and maybe beyond. And it's interesting for the simple reason that you get a really standardized program. And this is all the difficulty is to make it super stable and standard and reproducible. And this is something Cellectis knows how to do. We've been doing this for more than 10 years. We've seen those difficulties. Remember the first patient we ever dealt with was 10 years ago with autologous CAR-T. We made CAR-T before 2018. It's now like alpha-1, not alpha-1a, but alpha-1. And this is something that we're extremely proud of. And since then, we've been working and working and working and improved the process to something that is extremely stabilized. And we believe we know how to make the pharmaceutical commercializable program. We'll give two chances to every patient. Give them chances to every patient. Remember, you have T cells. You have no T cells. It works. Why, for example, an ABC works differently than a CAR-T? So you know the hierarchy. It's like a monoclonal antibody will kill a cell if there is more than 100,000 tumor-associated antigen on the surface of the autologous cell. Or an ABC, it stands out. Below 10,000, it's not going to work. This is why, for example, some failures of ADC give the same chance for the CAR because it will be a few hundreds. We don't know exactly the number of tumor-associated antigen that needs to be expressed on the surface, can still take them, and this is what makes the difference between being able to bring a patient to MRD negativity versus not, and that's where CAR-T cells are a real game changer. They come in with something even if you don't have a consolidation and a few blood cells, it works, so we're excited about this, and also, we're excited about the strategy that has been developed and also endorsed by William Blair in terms of making this first program the best chances for patients both for the future. This is something that is totally innovative and a game changer. So the first patient will be recruited this year, by the end of the year. We'll have next year an interim analysis for the patient. And then it will continue up to general enrollment. And then we'll have the BLA in 2020. So a lot of things to do in the meantime, of course, like opening 75 sites, et cetera. But we have a clear road to success. Well, the strategic roadmap, something that we need to keep in mind for Cellectis, we're not all about TALEN stuff. We're super excited. We believe TALEN is a game changer. We believe it's a program that definitely fits the size of Cellectis. And we really just need to run a program like this with a very valuable program and something that has given fantastic market value creation for a company outsized and at the stage where we are really considered. The second thing that you have to keep in mind is after UCART22, you have Epicel. Talk a bit about Epicel. We'll see where it goes, but it's 20x22. It's still not the 19. Still a very high unmet need with a program that has double targeting, and you have a very nice strategy because you can grab even two targets instead of only one, CD20 and CD22, and you will have also a bit of information by the end of this year. So keep an eye on that, but that will be the end of phase I in refractory r/r B-cell ALL in 2026. And also some data on trials that we are doing that will be probably very exciting. I'm very excited about it, and we're definitely looking forward to presenting. And finally, a bit of the peak of the pre-clinical proof of concept 2026 of in vivo gene therapy. Gene therapy has been always very complex. You know, to take the cells out, it's complicated, et cetera. But if you take a pair of mRNA packages, it's something tha It's something that is going to go in vivo and is going to be a shock with something that can also have very powerful and decent cut and that will give probably also something that we know on the other side of the company and allow it to develop. So that's going to be a revolution in medicine, and we're here to bring revolution in medicine. This is our mission and our path. We will bring it. With that, I would like to thank you again for attendance. I'd like to open to questions for the viewers. Adrian and Arthur, please, so we'll start by Gina. I don't know. Yes, yes, yes. Okay, so first, I wanted to say congratulations. It's a great update. You really cover a lot of the questions that I've invested in. It's very impressive data, so I have tried to limit myself. I know a lot of the questions will be asked. I'll limit myself to two to three questions. One is the lasme-cel, the pivotal study, just want to confirm. The trial design is confirmed, agreed upon by the FDA and the EMA. Then the question is for the two doses, I assume one including dose level three, and the other doses are higher or lower dose. Then what is the definition of success given the kind of endpoints, CRs, CRis, CR? So that's one question. So I'll get to it. Then the other question is about the manufacturing and also to AstraZeneca. So the manufacturing will have to share the sq ft. But what is the capacity here? The current capacity and future peak capacity, I assume that will also be part of the topic of AstraZeneca and certain products. And then the question is, when will we see the pipeline of the collaboration on AstraZeneca? When will we see the data from Cellectis collaboration? So I will take the first question. There's probably going to be five questions and then Gina's going to answer. That's a great question. So yes, we're completely aligned with the regulatory authorities. The biggest issue is you're finding the right endpoint. I think we've got that. And get agreement that really this is a trial. So yes, there's a bit of clarification from my end. And sorry if I didn't make it clear. There's no dose optimization for AstraZeneca. It's dose level three. That's our recommended phase II dose. The dose optimization is actually for alemtuzumab, where they want us to try to make sure we've got a dose. And they want us to try a lower dose as well within the dose optimization. And that'll be that for the patients. We will not be testing any alternative doses of AstraZeneca. Those are my questions. What is the definition of success? Defining the development of Servier. Yes. So what is defining the success? Within the two hours, would that be frozen at two hours or would it be with the reflection when it reaches a certain severity? What is the defining of the success? So first thing in our trial, there's always the same wording for the regulators. It has to be compelling. So right now, there's an assumption in the background these patients have, I think, generously a CR/CRi rate maybe of 20%, although what we've seen with you, that that is probably a threshold many patients will meet. We have exceeded that quite significantly as our marker of success, and that's been generally agreed as it is, so we believe that threshold is probably the data we have here, if we hit this, we will certainly surpass our threshold. Yes, yes, so for the manufacturing question, yes, we share the square footage. That's, of course, something that is not relevant for the manufacturing capacity that we have. First of all, you're all invited to visit our site in Raleigh, but the nice picture of this building that you see is the entrance of our building in Raleigh. Some of you have visited. Friendly faces that have visited the site, but definitely, it's something that will show you how powerful and efficient and well-organized it is and if it's set for successful production. We have currently one suite that is active and allows us potentially to produce up to 4,000 doses a year, which covers way more than what is being built in terms of the 20%-87%. We're opening our collaboration with AstraZeneca. We decided to enable a second suite, and we'll have the same capacity. We have thoughts with two other suites, four in total, on one side of the building, but the second side of the building can be cloned on the other side. That would allow two other suites. We will have two suites that will be ready to go by the end of next year and for early 2027, but it's something they will be supposed to be by the end of next year. That's the completed capacity. Not only this, but the numbers that I'm giving you can be augmented pretty meaningfully because today, we don't have the need to have that many vials. But once we believe that we can supply the whole world in terms of the two products that we have and eventually also some of the products that we will be producing for AstraZeneca, there is no limit. So the Raleigh site can fill with multiple products. There is global need for even larger in the future. And then the last step. Yeah, so Mark said it, 2026, maybe the first piece on the things that we're doing, right? But you know, I think under the control of Astra, it's like 26, they say, "Oh, no, we don't want you to share this stuff. Let's do it," so then we'll not share because they are our partners and we'll do what our partners are willing to do. Thanks for taking my question. I'm Allen. I work with the Baird. I was wondering if I can ask questions to the doctors, if any of them would like to comment. I was wondering, in terms of using the AstraZeneca, would the doctors use it exclusively after for inotuzumab ozogamicin, or if there are scenarios where they can use it because this is to be followed by a transplant, right? I mean, essentially, it would be used as a result followed by a transplant and an alternative to either Blincyto or oncology. Perhaps Lisa can clarify that. Yeah, I think right now, as you know, Blincyto is a proven first-line setting. So practically, every patient in the U.S. is getting Blincyto or inotuzumab in the first-line B-ALL setting. So practically, all patients will have exposure to Blincyto and to the medicine. In terms of whether they need to be on CD19 refractory, in the trial, you saw 50% of the patients had a prior CD19 bispecific therapy. But as I said during the session, there are patients who cannot get a lot of those apheresis collection done because their counts are too low. There are no apheresis to collect. Or there are many situations where you want a quick CAR-T. There's no time for bridging, cell collection, root operations. All those things take too much time where you want to go quickly to a cell product where the allogeneic product is helpful. So I don't think it's a requirement per se that you must fail at CD19 CAR-T for this. But I think there will be some situations where some maybe kind of prefer just the logistics issue and how good you want to go with it. Thank you to the company. I think you talked about the greater quality agreed with the importance of the FDA. But in the label, so in the trial design, how is that reflected? Will the label, because CR/CRi, that's the FDA, right? Would that reflect in the DOR that will be officially recognized in the label or in the document? That's a great question. So yes, we agreed with them. They wanted to see efficacy first, which is CR/CRi. That's what they want to try to implement. However, within the design, we're including key secondary endpoints. We will be capturing CR efficacy for transplant-eligible. And that will allow us then to capture for the patients following up. We will not be mandating a transplant, but all patients entering the trial would be considered to benefit from transplant, and that is the goal of the treatment. So I think the design has allowed us to capture. But consider that at the more traditional endpoint, with, however, the aspirational endpoint of showing that getting these patients to transplant with the follow-up and improving the overall survival, that actually gives the label this. Great. Thank you. Thank you so much. Congrats on all the updates here. Very impressive data. I guess maybe the first one to the physicians, I'd love to get some more context around how many transplant-eligible patients have access to a transplant. Is the match rate very high in B-ALL? And how do you think about that when you're looking at clinical treatments that can be bridged to transplant? Probably worthwhile getting the U.S. and the European view on this. So maybe for Liz, what's that? Do you want that? Yeah, that's not different. It's not different. It's not different. So Dr. Riedell, my question, you're in the community setting. So perhaps as far as getting a donor for a transplant, the era where we match is going away. In fact, we're doing clinical trials right now where we're doing mismatch-friendly donor transplants and having similar success rates. So six out of eight to seven out of eight, or even a trial with a deceased bone marrow registry source that we can use for transplants. So pretty much in this era, almost every patient has a donor. It's very rare that we have to send someone. We don't do cord blood transplants in our center. Very few centers are doing it. If we do, in the rare occasion we have to do that, we send in the additional online committee at your site, and that pretty much covers everybody. I think you can pretty much guarantee 100% if you needed a transplant, there's nowhere else to. Great. That's great context and incredible to see the patient in that phase, and then maybe to Adrian, the design of the phase III study. I guess you mentioned that it incurs with 20%-25% complete response rate, but also I think earlier you talked about still looking at the literature. I'm not sure if that's pinned down that external control, and if there are any changes in the assumptions around that external control that dictate the size of the study as well. Was it an 80-patient study locked in, or could you go lower, or if you had a lower response rate based on the literature? So that's a great question. The size of our trial is not really driven by our assumed efficacy. It's actually driven by the size of the safety data patient on ELA. And if we were to power our trial based on efficacy, it would be much smaller. So that is the first point. So even if there's any change in numbers, we have so much room. We're very confident regardless of what we see in our control arm. We're very much overpowered to demonstrate the efficacy required. In terms of the synthetic control arm, and we've been talking to our investigators here about it. I don't want to dismiss this as being easy. It's not. This is a very specific group of patients that will require both an element of retrospective and prospective data collection. We have pretty much designed most of our propensity score matching and how we're going to capture them. There is really what is required for us now, and we have a little bit of time, is where are we going to get these patients from? Is it a mixture of databases versus academic institutions? It's going to have to be an element of capture both in Europe and in the U.S. It's complex, but I think we have a very good plan. I agree. And then maybe just one last one on the pivotal study design. You mentioned the Helms-Tewson ad dose that they're going to test in the pivotal is going to be a dose down. I'd just love to hear any context you provide around contribution to components and those discussions with the FDA and their reassurances of the ability to show that the current plan that you're playing out here? Yeah, we've had a lot, as you may expect. We've had a lot of conversation with the regulatory bodies in terms of how are we going to differentiate between two doses of Helms-Tewson ad in the context of patients who are incredibly unwell. From a disease perspective itself, they get a lot of toxicities. But we believe that the doses we've chosen are differentiated enough. But however, we will be monitoring. This is still open label. We want to make sure that patients are not underexposed to Helms-Tewson ad. What we've done over the last year is we've done a tremendous amount of modeling as to what is the right dose, what does underexposure and overexposure look like. Because what we've tried to get, and I think it's one of the learnings you can have having had so many patients treated with alemtuzumab in this context, we can start to see a picture of what is the right level. What dose levels are too low so you get very close T-cell reconstitution and you don't get your expansion. So we're coming into our phase II really better informed. So I think our two doses, we will be able to differentiate between the two. And as always, if we can get away with a lower dose of alemtuzumab, maintaining efficacy and minimizing toxicity, that is a good outcome for patients. Great. Thanks so much for taking the questions. Clara Dong, Jefferies. Congratulations on all the amazing progress and support for the patient from the CRC team and Mark in the panel discussion. So I just want to follow up on the question Jack asked about the external control arm. So what are the key design considerations for this external control arm, whether you're going to discuss with the FDA and EMA on the key design elements? And then maybe also want to ask the KOLs here that how do you think about the comfort level from community-based doctors to handle the addition of alemtuzumab, given the data you showed today, that the importance of the FCA regimen here and the company's vision of community-based delivery of the product in the future? Yeah, I'll take the first one. Dr. Ramakrishnan, question. Since you are a community-based practice, I think that's an accepted question for you. So in terms of one of the key considerations for the external control arm, which I think was your question, it is not easy to develop this control arm. We acknowledge that because there's not a lot of standard of care for these patients. These patients have had so heavily pretreated. There's not enough clarity on what the comparative arm looks like. So it will require a significant amount of efficacy score matching. Now, as we're looking at our databases, we decide, well, how many patients do we need in the database to qualify one patient in our external control arm? And that is actually far more reassuring than I thought it was going to be. I thought it was going to be a pretty big number. It's actually pretty small. So I think based on our initial analysis, we have enough patients in existing databases, both clinical trial databases, registries, and academic institutions that I believe will be able to fulfill the requirement. And Dr. Ramakrishnan, a question. So the question was efficacy and efficacy. More than that, I think cell therapy right now. Cell therapy right now, I mean, we're in the community, but we're a specialized center. I don't see anyone doing cell therapy in the community at this point. But if you think about access, most of the care is delivered in the community. I think we have to figure out ways how to expand that. As far as Helms-Tewson ad, I think that itself, I'm not too concerned about toxicity-wise. I've been around for a long time. People have used it. We have patients in the community with T-PLL who are getting Helms-Tewson ad. They're not getting it at academic centers, and community physicians are treating them. Our knowledge will. If they're educated on toxicity management, it touches both lines. Thank you. Well, the event has reached 10:33. You've been extremely generous with your time. I would like to thank you. This doesn't mean that we can't continue the discussion after with further meetings and etc. Like this, we'd be extremely happy to take more questions in the future. But I think that we're here on the need to fill the room. Again, thank you very much for your time. It's been my great pleasure and a great volunteer to like this because it's the first time I'm showing this kind of data, and keep up by the end of the year. Plenty of things are going to happen. In the meantime, there are a lot of data points that you will have to see. N26 will be extremely rich. We are going to present and continue to grow this information innovation for the next year. So thank you very much.

Speaker 2: You said also that the event will end up at 10:30, Charlie. With that, I would like to. So B-ALL is definitely on that medical. First of all, there's roughly 10,000 patients worldwide, not worldwide, in the U.S., EU, and the U.K. on a yearly basis. And most of the time, these patients are treated by chemotherapy as a first line. As we just said before, you have the heavy relapse rate for adults, essentially. ADCs have definitely an effect, but it's limited effect as there is a lot of relapse, especially using certain types of agents. And CD22. CD19-directed therapies have 50% relapse, so they can't do it. And all these therapies based on patient T cells, as I said before, where the T cells can be unfit or scarred, have no solution. You said also that the event will end up at 10:30, Charlie. you said also that the event will end up at 10:30 charlie With that, I would like to. with that i would like to So B-ALL is definitely on that medical. so b-all is definitely on that medical First of all, there's roughly 10,000 patients worldwide, not worldwide, in the U.S., EU, and the U.K. on a yearly basis. first of all there's roughly 10,000 patients worldwide not worldwide in the u.s eu and the u.k on a yearly basis And most of the time, these patients are treated by chemotherapy as a first line. and most of the time these patients are treated by chemotherapy as a first line As we just said before, you have the heavy relapse rate for adults, essentially. as we just said before you have the heavy relapse rate for adults essentially ADCs have definitely an effect, but it's limited effect as there is a lot of relapse, especially using certain types of agents. adcs have definitely an effect but it's limited effect as there is a lot of relapse especially using certain types of agents And CD22. and cd22 CD19-directed therapies have 50% relapse, so they can't do it. cd19-directed therapies have 50% relapse so they can't do it And all these therapies based on patient T cells, as I said before, where the T cells can be unfit or scarred, have no solution. and all these therapies based on patient t cells as i said before where the t cells can be unfit or scarred have no solution This is where it's important to come with healthy donor T cells to try to treat this patient. This is what we're going to share with you, so why allogeneic T cells? First of all, the quality of this T cell can be very, very stable on this side and healthier, less exhausted T cells coming from healthy donors, pre-selected patients, can give the same chance to every patient. If the patient doesn't have T cells, we're missing. The patient has plenty of T cells, we're also looking at them. The speed of the therapy is not the shelf therapy. They allow every day count. We're not talking about monthly sometimes. We're talking about weeks, sometimes days, so it's very important. It's also one thing that is really important in this field is to standardize the product. This is where it's important to come with healthy donor T cells to try to treat this patient. this is where it's important to come with healthy donor t cells to try to treat this patient This is what we're going to share with you, so why allogeneic T cells? this is what we're going to share with you so why allogeneic t cells First of all, the quality of this T cell can be very, very stable on this side and healthier, less exhausted T cells coming from healthy donors, pre-selected patients, can give the same chance to every patient. first of all the quality of this t cell can be very very stable on this side and healthier less exhausted t cells coming from healthy donors pre-selected patients can give the same chance to every patient If the patient doesn't have T cells, we're missing. if the patient doesn't have t cells we're missing The patient has plenty of T cells, we're also looking at them. the patient has plenty of t cells we're also looking at them The speed of the therapy is not the shelf therapy. the speed of the therapy is not the shelf therapy They allow every day count. they allow every day count We're not talking about monthly sometimes. we're not talking about monthly sometimes We're talking about weeks, sometimes days, so it's very important. we're talking about weeks sometimes days so it's very important It's also one thing that is really important in this field is to standardize the product. it's also one thing that is really important in this field is to standardize the product Repeatable quality of the product is one of the selected missions in the way we design these products. And finally, CD22 complements also preempt, for example, for CD19-negative or post-CD19 cells, or even engaging CD22, potentially less than CD19. You will see also that some people who are treated with product partly with CD22 potentially take them up with an allogeneic therapy. So one of the things we can try to select this is our manufacturing. People tend to forget about this. I've been talking about the importance of manufacturing for allogeneic T cells, usually autologous therapy. Most of the time in cell therapies, the product is the most important thing because this is the thing that is going to make the change in the patient. Repeatable quality of the product is one of the selected missions in the way we design these products. repeatable quality of the product is one of the selected missions in the way we design these products And finally, CD22 complements also preempt, for example, for CD19-negative or post-CD19 cells, or even engaging CD22, potentially less than CD19. and finally cd22 complements also preempt for example for cd19-negative or post-cd19 cells or even engaging cd22 potentially less than cd19 You will see also that some people who are treated with product partly with CD22 potentially take them up with an allogeneic therapy. you will see also that some people who are treated with product partly with cd22 potentially take them up with an allogeneic therapy So one of the things we can try to select this is our manufacturing. so one of the things we can try to select this is our manufacturing People tend to forget about this. people tend to forget about this I've been talking about the importance of manufacturing for allogeneic T cells, usually autologous therapy. i've been talking about the importance of manufacturing for allogeneic t cells usually autologous therapy Most of the time in cell therapies, the product is the most important thing because this is the thing that is going to make the change in the patient. most of the time in cell therapies the product is the most important thing because this is the thing that is going to make the change in the patient Also, at the time of the approval of the BLA, the quality of the production and the way to master the production is often what's most important. This is why we decided in 2018 to integrate inside Cellectis all manufacturing. I would say from A-Z because we do the buffers, we do the electroporation machines, we do the messenger RNA, the plasmid DNA, the antibody vectors, up to the final product. And also what we have is that our Raleigh manufacturing plant that makes the final product, where we have integrated all the supply chain and the logistics. So we have one in Europe and one in the United States. We're ready to go commercial today with the quality of the product we have. And we master all the details of the biochem. I think Adrian will walk you through P1 and P2. Also, at the time of the approval of the BLA, the quality of the production and the way to master the production is often what's most important. also at the time of the approval of the bla the quality of the production and the way to master the production is often what's most important This is why we decided in 2018 to integrate inside Cellectis all manufacturing. this is why we decided in 2018 to integrate inside cellectis all manufacturing I would say from A- Z because we do the buffers, we do the electroporation machines, we do the messenger RNA, the plasmid DNA, the antibody vectors, up to the final product. i would say from a- z because we do the buffers we do the electroporation machines we do the messenger rna the plasmid dna the antibody vectors up to the final product And also what we have is that our Raleigh manufacturing plant that makes the final product, where we have integrated all the supply chain and the logistics. and also what we have is that our raleigh manufacturing plant that makes the final product where we have integrated all the supply chain and the logistics So we have one in Europe and one in the United States. so we have one in europe and one in the united states We're ready to go commercial today with the quality of the product we have. we're ready to go commercial today with the quality of the product we have And we master all the details of the biochem. and we master all the details of the biochem I think Adrian will walk you through P1 and P2. i think adrian will walk you through p1 and p2 P1 is the process one that has been made at the CMO. It's helped us a lot this time. Since then, it's been required by Novartis and things changed. You cannot, if you're cell therapy competent, give your manufacturing to someone else because they're not going to treat it the same way you will treat the cell. And you will see the difference between P1 and P2 is essentially the fact that Cellectis just manufactured a process that we invented, and we make products that have no comparison. And at the end, you have an allogeneic T cell. It can be scalable. We do hundreds of doses per batch. This can also be scaled up more than this. And then finally, we have controlled costs. P1 is the process one that has been made at the CMO. p1 is the process one that has been made at the cmo It's helped us a lot this time. it's helped us a lot this time Since then, it's been required by Novartis and things changed. since then it's been required by novartis and things changed You cannot, if you're cell therapy competent, give your manufacturing to someone else because they're not going to treat it the same way you will treat the cell. you cannot if you're cell therapy competent give your manufacturing to someone else because they're not going to treat it the same way you will treat the cell And you will see the difference between P1 and P2 is essentially the fact that Cellectis just manufactured a process that we invented, and we make products that have no comparison. and you will see the difference between p1 and p2 is essentially the fact that cellectis just manufactured a process that we invented and we make products that have no comparison And at the end, you have an allogeneic T cell. and at the end you have an allogeneic t cell It can be scalable. it can be scalable We do hundreds of doses per batch. we do hundreds of doses per batch This can also be scaled up more than this. this can also be scaled up more than this And then finally, we have controlled costs. and then finally we have controlled costs This is in the presentation of Arthur, which is really important because if you want to have a product that is pharmaceutically valuable, product means not this negative gross margin, then you need to control the cost to make a very valuable product. We believe that we have this product. So like this cell, we're developing this first indication as a bridge transplant that we will be presenting. HSCT, so hematopoietic stem cell transplant, is currently the gold standard in acute lymphoblastic leukemia. This is what's going to give the best long-term chance to every patient. Long-curative disease and the patient will come back to the hospital with disorder. The patient is considered as cured. It secures, so like I said, we'll secure a window. We'll see how we secure this. It makes patients eligible for an HSCT. You need to be MRD negative, not only CR. This is in the presentation of Arthur, which is really important because if you want to have a product that is pharmaceutically valuable, product means not this negative gross margin, then you need to control the cost to make a very valuable product. this is in the presentation of arthur which is really important because if you want to have a product that is pharmaceutically valuable product means not this negative gross margin then you need to control the cost to make a very valuable product We believe that we have this product. we believe that we have this product So like this cell, we're developing this first indication as a bridge transplant that we will be presenting. so like this cell we're developing this first indication as a bridge transplant that we will be presenting HSCT, so hematopoietic stem cell transplant, is currently the gold standard in acute lymphoblastic leukemia. hsct so hematopoietic stem cell transplant is currently the gold standard in acute lymphoblastic leukemia This is what's going to give the best long-term chance to every patient. this is what's going to give the best long-term chance to every patient Long-curative disease and the patient will come back to the hospital with disorder. long-curative disease and the patient will come back to the hospital with disorder The patient is considered as cured. the patient is considered as cured It secures, so like I said, we'll secure a window. it secures so like i said we'll secure a window We'll see how we secure this. It makes patients eligible for an HSCT. we'll see how we secure this. it makes patients eligible for an hsct You need to be MRD negative, not only CR. you need to be mrd negative not only cr This gives a clear path forward with an HSCT and long-term remission. Also, I will show you that it's a very malleable safety profile. Much more. With that, I would like to hand the presentation to Adrian Kilcoyne and Professor Nitin Jain that will walk you through all the data of BALLI-01 and the way BALLI-01 works. Adrian? This gives a clear path forward with an HSCT and long-term remission. this gives a clear path forward with an hsct and long-term remission Also, I will show you that it's a very malleable safety profile. also i will show you that it's a very malleable safety profile Much more. much more With that, I would like to hand the presentation to Adrian Kilcoyne and Professor Nitin Jain that will walk you through all the data of BALLI-01 and the way BALLI-01 works. with that i would like to hand the presentation to adrian kilcoyne and professor nitin jain that will walk you through all the data of balli-01 and the way balli-01 works Adrian? adrian

Speaker 1: Thank you, André. Thank you all for being here today, and a special thank you to our three investigators who have supported this trial for being here to talk to us through the data, but also discuss it during our panel. Why I'm opening this session up is really to create an element of better. This is an incredibly important meeting for us. This is us transitioning to phase II, which is why we're focusing this day on UCART22, the National Center. Now, just so that people are aware, this shouldn't in any way be interpreted that we're not fully committed to our other program. We absolutely are, but given the importance of this event, we wanted to focus on that. But I will give you a little bit of a snippet of, sorry, wrong way, where we are with UCART22, which is now 87. Thank you, André. thank you andré Thank you all for being here today, and a special thank you to our three investigators who have supported this trial for being here to talk to us through the data, but also discuss it during our panel. thank you all for being here today and a special thank you to our three investigators who have supported this trial for being here to talk to us through the data but also discuss it during our panel Why I'm opening this session up is really to create an element of better. why i'm opening this session up is really to create an element of better This is an incredibly important meeting for us. this is an incredibly important meeting for us This is us transitioning to phase II, which is why we're focusing this day on UCART22, the National Center. this is us transitioning to phase ii which is why we're focusing this day on ucart22 the national center Now, just so that people are aware, this shouldn't in any way be interpreted that we're not fully committed to our other program. now just so that people are aware this shouldn't in any way be interpreted that we're not fully committed to our other program We absolutely are, but given the importance of this event, we wanted to focus on that. we absolutely are but given the importance of this event we wanted to focus on that But I will give you a little bit of a snippet of, sorry, wrong way, where we are with UCART22, which is now 87. but i will give you a little bit of a snippet of sorry wrong way where we are with ucart22 which is now 87 These are where we are at the current dose level. Now, there will be more data shared at ASTCT this coming year in terms of the update on the program. We can talk about it more then, but I just wanted to reassure those of you who are in the audience and online, we remain committed to this. Dr. Ramakrishnan is an investigator on the study. He is here today as well. But what we're seeing right now is response rates that are very encouraging at 57% complete response rate, partial response rate at 86% based on the seven patients at the current dose level. Now, I know you have lots of questions about this, but please, if we could hold that till we get ASH in our rearview mirror, that would be very good. These are where we are at the current dose level. these are where we are at the current dose level Now, there will be more data shared at ASTCT this coming year in terms of the update on the program. now there will be more data shared at astct this coming year in terms of the update on the program We can talk about it more then, but I just wanted to reassure those of you who are in the audience and online, we remain committed to this. we can talk about it more then but i just wanted to reassure those of you who are in the audience and online we remain committed to this Dr. Ramakrishnan is an investigator on the study. dr ramakrishnan is an investigator on the study He is here today as well. he is here today as well But what we're seeing right now is response rates that are very encouraging at 57% complete response rate, partial response rate at 86% based on the seven patients at the current dose level. but what we're seeing right now is response rates that are very encouraging at 57% complete response rate partial response rate at 86% based on the seven patients at the current dose level Now, I know you have lots of questions about this, but please, if we could hold that till we get ASH in our rearview mirror, that would be very good. now i know you have lots of questions about this but please if we could hold that till we get ash in our rearview mirror that would be very good But again, we just wanted to reassure you that we remain fully committed to this program. Right. I also want to contextualize the data you're about to see because what we have seen over the last few years, there's been advances in ALL, but what we've seen is increased access to targeted therapy. So if we look at frontline, second line, third line, fourth line, and beyond, what becomes very clear is some of these targeted therapies are moving earlier line. Blincyto, for instance, is up at frontline consolidation. Second line, there's a lot more response auto CAR-T. By the time we get to third line, things have changed because most of these patients have already been exposed to at least one targeted therapy. And as you go down multiple lines, many of them have been exposed to all of them. But again, we just wanted to reassure you that we remain fully committed to this program. but again we just wanted to reassure you that we remain fully committed to this program Right. right I also want to contextualize the data you're about to see because what we have seen over the last few years, there's been advances in ALL, but what we've seen is increased access to targeted therapy. i also want to contextualize the data you're about to see because what we have seen over the last few years there's been advances in all but what we've seen is increased access to targeted therapy So if we look at frontline, second line, third line, fourth line, and beyond, what becomes very clear is some of these targeted therapies are moving earlier line. so if we look at frontline second line third line fourth line and beyond what becomes very clear is some of these targeted therapies are moving earlier line Blincyto, for instance, is up at frontline consolidation. blincyto for instance is up at frontline consolidation Second line, there's a lot more response auto CAR-T. second line there's a lot more response auto car-t By the time we get to third line, things have changed because most of these patients have already been exposed to at least one targeted therapy. by the time we get to third line things have changed because most of these patients have already been exposed to at least one targeted therapy And as you go down multiple lines, many of them have been exposed to all of them. and as you go down multiple lines many of them have been exposed to all of them So all of these salvage therapies also have an impact on the response rates. And the mere exposure to many of these target therapies also changes the response rates to following target therapies. So let me look at our trial, and Professor Jain will go through this in a lot more detail. We know that the patients that we've recruited for this trial are very limited. And we know that many of them have been heavily exposed, not only to chemotherapy, but multiple. So for most of our patients, the real next line for them is yet again, salvage people. And the only real chance they have of getting a long-term admission based on what's currently available is to achieve the transplant. But what we can see from these data here is that getting to deep responses with MRD negative is very challenging for the most of them. So all of these salvage therapies also have an impact on the response rates. so all of these salvage therapies also have an impact on the response rates And the mere exposure to many of these target therapies also changes the response rates to following target therapies. and the mere exposure to many of these target therapies also changes the response rates to following target therapies So let me look at our trial, and Professor Jain will go through this in a lot more detail. so let me look at our trial and professor jain will go through this in a lot more detail We know that the patients that we've recruited for this trial are very limited. we know that the patients that we've recruited for this trial are very limited And we know that many of them have been heavily exposed, not only to chemotherapy, but multiple. and we know that many of them have been heavily exposed not only to chemotherapy but multiple So for most of our patients, the real next line for them is yet again, salvage people. so for most of our patients the real next line for them is yet again salvage people And the only real chance they have of getting a long-term admission based on what's currently available is to achieve the transplant. and the only real chance they have of getting a long-term admission based on what's currently available is to achieve the transplant But what we can see from these data here is that getting to deep responses with MRD negative is very challenging for the most of them. but what we can see from these data here is that getting to deep responses with mrd negative is very challenging for the most of them But we also acknowledge that our phase I program is very complex. And I wanted to make sure, just to give you a quick overview of how this program was run, so that you can understand it as you're seeing the data that will allow you to interpret it a little bit more accurately. So as André already said, we needed to answer a few questions. One, can we make better products from expertise? We needed to answer that question. What is very topical at the moment is an anti-CD52 antibody necessary to optimize response? We have looked at this. Of course, we want to know what the opportunity is, and Professor Jain will share that with you. And of course, touching on what André said, in the context of these very heavily pretreated patients, what is the best outcome measure? But we also acknowledge that our phase I program is very complex. but we also acknowledge that our phase i program is very complex And I wanted to make sure, just to give you a quick overview of how this program was run, so that you can understand it as you're seeing the data that will allow you to interpret it a little bit more accurately. and i wanted to make sure just to give you a quick overview of how this program was run so that you can understand it as you're seeing the data that will allow you to interpret it a little bit more accurately So as André already said, we needed to answer a few questions. so as andré already said we needed to answer a few questions One, can we make better products from expertise? one can we make better products from expertise We needed to answer that question. we needed to answer that question What is very topical at the moment is an anti-CD52 antibody necessary to optimize response? what is very topical at the moment is an anti-cd52 antibody necessary to optimize response We have looked at this. we have looked at this Of course, we want to know what the opportunity is, and Professor Jain will share that with you. of course we want to know what the opportunity is and professor jain will share that with you And of course, touching on what André said, in the context of these very heavily pretreated patients, what is the best outcome measure? and of course touching on what andré said in the context of these very heavily pretreated patients what is the best outcome measure What is the best viewpoint to reflect clinical value for patients? And we will share with you, after you see the data, all of the clinical trial design and timelines. So you'll be very clear about the pathologies. So this is the trial design. Now, there's a number of questions to be asked. Now, forgive the simplicity, but all the dose interchange is in the bottom top left-hand corner. Dose level three is the relevant dose here, 5 by 10 to the 5 millionths of kilo. But as you can see, we started off with dose test one. As André said, that is our external manufacturing. And we did do dose escalation by particularly three. But then we internalized our manufacturing for a number of reasons. And to André's point, nobody knows better how to make these living cells that we need. What is the best viewpoint to reflect clinical value for patients? what is the best viewpoint to reflect clinical value for patients And we will share with you, after you see the data, all of the clinical trial design and timelines. and we will share with you after you see the data all of the clinical trial design and timelines So you'll be very clear about the pathologies. so you'll be very clear about the pathologies So this is the trial design. so this is the trial design Now, there's a number of questions to be asked. now there's a number of questions to be asked Now, forgive the simplicity, but all the dose interchange is in the bottom top left-hand corner. now forgive the simplicity but all the dose interchange is in the bottom top left-hand corner Dose level three is the relevant dose here, 5 by 10 to the 5 millionths of kilo. dose level three is the relevant dose here 5 by 10 to the 5 millionths of kilo But as you can see, we started off with dose test one. but as you can see we started off with dose test one As André said, that is our external manufacturing. as andré said that is our external manufacturing And we did do dose escalation by particularly three. and we did do dose escalation by particularly three But then we internalized our manufacturing for a number of reasons. but then we internalized our manufacturing for a number of reasons And to André's point, nobody knows better how to make these living cells that we need. and to andré's point nobody knows better how to make these living cells that we need So we fundamentally believe that cell therapies, like allogeneic cell therapies, should be brought in house. But what you will notice as we transition from P1-P2, we don't escalate it. Why did we do that? Because it was very clear from our in vivo data that our product appeared to be more efficacious. So in the spare response, maintaining safety, we de-escalated and re-escalated back up to dose therapy. That's the first one. So throughout the data, you will see at the bottom P1 and at the 17th. Also, you'll see on the bottom, we have FC versus FCA. Now, this is very topical. FC is fludarabine standard conditioning and lymphodepletion. FCA is fludarabine plus alemtuzumab. And we will. So we fundamentally believe that cell therapies, like allogeneic cell therapies, should be brought in house. so we fundamentally believe that cell therapies like allogeneic cell therapies should be brought in house But what you will notice as we transition from P1- P2, we don't escalate it. but what you will notice as we transition from p1- p2 we don't escalate it Why did we do that? why did we do that Because it was very clear from our in vivo data that our product appeared to be more efficacious. because it was very clear from our in vivo data that our product appeared to be more efficacious So in the spare response, maintaining safety, we de-escalated and re-escalated back up to dose therapy. so in the spare response maintaining safety we de-escalated and re-escalated back up to dose therapy That's the first one. that's the first one So throughout the data, you will see at the bottom P1 and at the 17th. so throughout the data you will see at the bottom p1 and at the 17th Also, you'll see on the bottom, we have FC versus FCA. also you'll see on the bottom we have fc versus fca Now, this is very topical. now this is very topical FC is fludarabine standard conditioning and lymphodepletion. fc is fludarabine standard conditioning and lymphodepletion FCA is fludarabine plus alemtuzumab. fca is fludarabine plus alemtuzumab And we will. and we will Okay, sorry. I'm going to, I need to keep the microphone closer on that. So when we looked at FC versus FCA, we have looked at both to see what the responses were and what the depth of the responses were. And you will see that we very quickly transitioned away from FC alone. We understand that alemtuzumab is important, and we will share that data with you. And beyond that, all of the usual stuff, efficacy rates at the dose optimization, including what our target phase II population is. So hopefully you will find today informative, but this data is not for me to present. It's actually from Professor Jain, who's been a really key contributor to this trial, not only from delivering patients, but also the strategy behind it. Okay, sorry. okay sorry I'm going to, I need to keep the microphone closer on that. i'm going to i need to keep the microphone closer on that So when we looked at FC versus FCA, we have looked at both to see what the responses were and what the depth of the responses were. so when we looked at fc versus fca we have looked at both to see what the responses were and what the depth of the responses were And you will see that we very quickly transitioned away from FC alone. and you will see that we very quickly transitioned away from fc alone We understand that alemtuzumab is important, and we will share that data with you. we understand that alemtuzumab is important and we will share that data with you And beyond that, all of the usual stuff, efficacy rates at the dose optimization, including what our target phase II population is. and beyond that all of the usual stuff efficacy rates at the dose optimization including what our target phase ii population is So hopefully you will find today informative, but this data is not for me to present. so hopefully you will find today informative but this data is not for me to present It's actually from Professor Jain, who's been a really key contributor to this trial, not only from delivering patients, but also the strategy behind it. it's actually from professor jain who's been a really key contributor to this trial not only from delivering patients but also the strategy behind it I'll give you a sneak peek of the response rates between P1 and P2 with advance of what Professor Jain will show. Hopefully, it's very clear to you that there's a significant difference between P1 and P2, reinforcing the importance of us internalizing our manufacturing process. So without further ado, I'd like to welcome Professor Jain, who is the chief investigator on this study from MD Anderson. I'll give you a sneak peek of the response rates between P1 and P2 with advance of what Professor Jain will show. i'll give you a sneak peek of the response rates between p1 and p2 with advance of what professor jain will show Hopefully, it's very clear to you that there's a significant difference between P1 and P2, reinforcing the importance of us internalizing our manufacturing process. hopefully it's very clear to you that there's a significant difference between p1 and p2 reinforcing the importance of us internalizing our manufacturing process So without further ado, I'd like to welcome Professor Jain, who is the chief investigator on this study from MD Anderson. so without further ado i'd like to welcome professor jain who is the chief investigator on this study from md anderson

Speaker 12: Thank you. Thank you. thank you So everything you. So everything you. so everything you Right. Right. right Oh, sorry. Oh, sorry. oh sorry We're going to add this thing up. We're going to add this thing up. we're going to add this thing up Oh, just read. Oh, just read. oh just read

Speaker 1: Oh, hold on. Got it. All right. Good morning, everyone. As we just discussed with slides, as it's kind of shown here, we started the study with the FC process, then dose level one, dose level two, then we added alemtuzumab, went to dose level three, then the process changed to P2, then we just discussed, and then we had three dose levels, DL2, DL2i, and DL3. You can see the actual dose in cells ranging from 1 to 10 × 10^5. Right now, our DL3, which is our current dose, is 5 million cells per kilogram. That's what overall the study design has been for the course of last year. Oh, hold on. oh hold on Got it. got it All right. all right Good morning, everyone. good morning everyone As we just discussed with slides, as it's kind of shown here, we started the study with the FC process, then dose level one, dose level two, then we added alemtuzumab, went to dose level three, then the process changed to P2, then we just discussed, and then we had three dose levels, DL2, DL2i, and DL3. as we just discussed with slides as it's kind of shown here we started the study with the fc process then dose level one dose level two then we added alemtuzumab went to dose level three then the process changed to p2 then we just discussed and then we had three dose levels dl2 dl2i and dl3 You can see the actual dose in cells ranging from 1 to 10 × 10^5. you can see the actual dose in cells ranging from 1 to 10 × 10^5 Right now, our DL3, which is our current dose, is 5 million cells per kilogram. right now our dl3 which is our current dose is 5 million cells per kilogram That's what overall the study design has been for the course of last year. that's what overall the study design has been for the course of last year So in terms of the key inclusion criteria for this trial, patient age 15-70 years, so we have some pediatric population to say, between 18 years of age, good performance status, and obviously CD22 CAR, so CD22 expression more than 70%, at least more than two prior lines of therapy. And obviously, these patients were transplant ineligible, getting into the study because they had active disease with the eventual goal that any of these patients hopefully will go to transplant in completion. The key secondary key outcomes included obviously the safety of the product, investigator assessed the clinical response when phase II dose, and also the exposure of alemtuzumab. And then we had several exploratory objectives looking at the RT expansion, persistence, and also immune responsibility. So this shows the overall demographic of the patients. So if you look at the rightmost column, there were 40 patients. So in terms of the key inclusion criteria for this trial, patient age 15-70 years, so we have some pediatric population to say, between 18 years of age, good performance status, and obviously CD22 CAR, so CD22 expression more than 70%, at least more than two prior lines of therapy. so in terms of the key inclusion criteria for this trial patient age 15-70 years so we have some pediatric population to say between 18 years of age good performance status and obviously cd22 car so cd22 expression more than 70% at least more than two prior lines of therapy And obviously, these patients were transplant ineligible, getting into the study because they had active disease with the eventual goal that any of these patients hopefully will go to transplant in completion. and obviously these patients were transplant ineligible getting into the study because they had active disease with the eventual goal that any of these patients hopefully will go to transplant in completion The key secondary key outcomes included obviously the safety of the product, investigator assessed the clinical response when phase II dose, and also the exposure of alemtuzumab. the key secondary key outcomes included obviously the safety of the product investigator assessed the clinical response when phase ii dose and also the exposure of alemtuzumab And then we had several exploratory objectives looking at the RT expansion, persistence, and also immune responsibility. and then we had several exploratory objectives looking at the rt expansion persistence and also immune responsibility So this shows the overall demographic of the patients. so this shows the overall demographic of the patients So if you look at the rightmost column, there were 40 patients. so if you look at the rightmost column there were 40 patients So overall, the study, we have treated 40 patients over the course of the last several years. You can see the median age for all 40 patients was 27 years. But I would also like to highlight, if you look at the median number of prior therapies, it was four. So these are commonly treated patients. And again, if you look at the entire group of 40 patients, you can see 45% had prior allotransplant, 55% had prior alemtuzumab, 80% had prior blinatumomab, and actually half of the patients had failed a prior CD19 cell therapy, which they had failed. And then I also want to highlight the bone marrow blast count, which you can see is upwards of 60%, which is a high amount of disease these patients had. Now, what we have done is in the first two, we specifically were looking at DL3P2. So overall, the study, we have treated 40 patients over the course of the last several years. so overall the study we have treated 40 patients over the course of the last several years You can see the median age for all 40 patients was 27 years. you can see the median age for all 40 patients was 27 years But I would also like to highlight, if you look at the median number of prior therapies, it was four. but i would also like to highlight if you look at the median number of prior therapies it was four So these are commonly treated patients. so these are commonly treated patients And again, if you look at the entire group of 40 patients, you can see 45% had prior allotransplant, 55% had prior alemtuzumab, 80% had prior blinatumomab, and actually half of the patients had failed a prior CD19 cell therapy, which they had failed. and again if you look at the entire group of 40 patients you can see 45% had prior allotransplant 55% had prior alemtuzumab 80% had prior blinatumomab and actually half of the patients had failed a prior cd19 cell therapy which they had failed And then I also want to highlight the bone marrow blast count, which you can see is upwards of 60%, which is a high amount of disease these patients had. and then i also want to highlight the bone marrow blast count which you can see is upwards of 60% which is a high amount of disease these patients had Now, what we have done is in the first two, we specifically were looking at DL3P2. now what we have done is in the first two we specifically were looking at dl3p2 So this is the dose level three at process two, where we have treated 12 patients overall. And also, we want to specifically highlight the nine patients who were less than 50 years of age, which is kind of the focus of the trial. And we'll talk about that in a few slides down the line. So in that group of patients, you can also see still a high amount of five parallels of therapy for this group of patients. And again, you can see the bone marrow blast count of our server was 60%. I think that point remains that these are very heavily treated patients who have failed most of these standard therapies, which are available, and then we have to start next step of therapy. The same thing is kind of exemplified here in this kind of figure here. So this is the dose level three at process two, where we have treated 12 patients overall. so this is the dose level three at process two where we have treated 12 patients overall And also, we want to specifically highlight the nine patients who were less than 50 years of age, which is kind of the focus of the trial. and also we want to specifically highlight the nine patients who were less than 50 years of age which is kind of the focus of the trial And we'll talk about that in a few slides down the line. and we'll talk about that in a few slides down the line So in that group of patients, you can also see still a high amount of five parallels of therapy for this group of patients. so in that group of patients you can also see still a high amount of five parallels of therapy for this group of patients And again, you can see the bone marrow blast count of our server was 60%. and again you can see the bone marrow blast count of our server was 60% I think that point remains that these are very heavily treated patients who have failed most of these standard therapies, which are available, and then we have to start next step of therapy. i think that point remains that these are very heavily treated patients who have failed most of these standard therapies which are available and then we have to start next step of therapy The same thing is kind of exemplified here in this kind of figure here. the same thing is kind of exemplified here in this kind of figure here Again, heavily treated patient population, 4-5 lines of therapy, 80% had prior Blincyto, 55% had prior inotuzumab ozogamicin, and then half of the patients had CD19 CAR cell therapy either T-cell or CAR cell. So what were the responses seen? So this kind of, again, goes through, and you saw a snapshot briefly. So P1 is listed first, then the entire P2, so this takes the RP2D patient cohort, the total patients we treated. And as Adrian had shown you, I think we're already, you can see that the P2 process appears better. And then we also separated the response rates for the 12 patients in DL3, and then the 9 patients who are less than 50 years of age, which is the target population for the phase II study. The response rate here is the strength overall response rate, which includes CR/CRi, as well as what is called MLFS. Again, heavily treated patient population, 4-5 lines of therapy, 80% had prior Blincyto, 55% had prior inotuzumab ozogamicin, and then half of the patients had CD19 CAR cell therapy either T-cell or CAR cell. again heavily treated patient population 4-5 lines of therapy 80% had prior blincyto 55% had prior inotuzumab ozogamicin and then half of the patients had cd19 car cell therapy either t-cell or car cell So what were the responses seen? so what were the responses seen So this kind of, again, goes through, and you saw a snapshot briefly. so this kind of again goes through and you saw a snapshot briefly So P1 is listed first, then the entire P2, so this takes the RP2D patient cohort, the total patients we treated. so p1 is listed first then the entire p2 so this takes the rp2d patient cohort the total patients we treated And as Adrian had shown you, I think we're already, you can see that the P2 process appears better. and as adrian had shown you i think we're already you can see that the p2 process appears better And then we also separated the response rates for the 12 patients in DL3, and then the 9 patients who are less than 50 years of age, which is the target population for the phase II study. and then we also separated the response rates for the 12 patients in dl3 and then the 9 patients who are less than 50 years of age which is the target population for the phase ii study The response rate here is the strength overall response rate, which includes CR/CRi, as well as what is called MLFS. the response rate here is the strength overall response rate which includes cr/cri as well as what is called mlfs The bullet point you see there, the recommended phase II dose for this product is dose level 3, which is the 5 million cells per kilogram. And the target phase II patient population is at dose level 3, less than 50 years of age. Now, the patients who achieve CR/CRi, so this is among those group of patients who've achieved their remission, especially the CR/CRi, we are looking at the MRD negativity within that group of patients. So the dark part of the curve here is within the CR/CRi population, how many patients are MRD negative versus MRD positive. As you can see, the majority of the patients who achieved their remission were also MRD negative. Again, this kind of shows the kind of the same data, kind of in a similar way. The bullet point you see there, the recommended phase II dose for this product is dose level 3, which is the 5 million cells per kilogram. the bullet point you see there the recommended phase ii dose for this product is dose level 3 which is the 5 million cells per kilogram And the target phase II patient population is at dose level 3, less than 50 years of age. and the target phase ii patient population is at dose level 3 less than 50 years of age Now, the patients who achieve CR/CRi, so this is among those group of patients who've achieved their remission, especially the CR/CRi, we are looking at the MRD negativity within that group of patients. now the patients who achieve cr/cri so this is among those group of patients who've achieved their remission especially the cr/cri we are looking at the mrd negativity within that group of patients So the dark part of the curve here is within the CR/CRi population, how many patients are MRD negative versus MRD positive. so the dark part of the curve here is within the cr/cri population how many patients are mrd negative versus mrd positive As you can see, the majority of the patients who achieved their remission were also MRD negative. as you can see the majority of the patients who achieved their remission were also mrd negative Again, this kind of shows the kind of the same data, kind of in a similar way. again this kind of shows the kind of the same data kind of in a similar way Again, we have split by phase I-II, specifically targeting those 12 patients, and then the nine patients who are at the target phase II kind of patient population, and again, among the CR/CRi or overall cohort, high rates of MRD-negative remission in these patients, so next, we wanted to really specifically look at the nine patients. We talked about the nine patients who were at the target phase II population, so again, to remind everyone, these are phase II, dose level three, less than 50 years of age, so we happen to have nine patients in the study who we have treated with this, and this shows the kind of the similar plot going through these patients in more kind of detail. What you see here is the red triangle is the patients who achieved an MRD-negative response. Again, we have split by phase I-II , specifically targeting those 12 patients, and then the nine patients who are at the target phase II kind of patient population, and again, among the CR/CRi or overall cohort, high rates of MRD-negative remission in these patients, so next, we wanted to really specifically look at the nine patients. again we have split by phase i-ii specifically targeting those 12 patients and then the nine patients who are at the target phase ii kind of patient population and again among the cr/cri or overall cohort high rates of mrd-negative remission in these patients so next we wanted to really specifically look at the nine patients We talked about the nine patients who were at the target phase II population, so again, to remind everyone, these are phase II, dose level three, less than 50 years of age, so we happen to have nine patients in the study who we have treated with this, and this shows the kind of the similar plot going through these patients in more kind of detail. we talked about the nine patients who were at the target phase ii population so again to remind everyone these are phase ii dose level three less than 50 years of age so we happen to have nine patients in the study who we have treated with this and this shows the kind of the similar plot going through these patients in more kind of detail What you see here is the red triangle is the patients who achieved an MRD-negative response. what you see here is the red triangle is the patients who achieved an mrd-negative response Anyone which is censored is a patient who had a transplant, and then the arrows, which are for the three patients who are still alive and they are censored at that time, so as you can see, I mean, in this cohort, all actually nine patients had a response. Again, response means either CR/CRi or MLFS, and many of these patients, as you can see, have gone to transplant, and then there are a couple of patients who are still in the process of being evaluated for that, so this kind of shows you kind of the spectrum of the patients here then. The patient number one, or top patient who has an office follow-up, had a transplant and then doing well now, close to 14 months in the transplant, so now this shows the overall survival. This is not censored post-transplant. Anyone which is censored is a patient who had a transplant, and then the arrows, which are for the three patients who are still alive and they are censored at that time, so as you can see, I mean, in this cohort, all actually nine patients had a response. anyone which is censored is a patient who had a transplant and then the arrows which are for the three patients who are still alive and they are censored at that time so as you can see i mean in this cohort all actually nine patients had a response Again, response means either CR/CRi or MLFS, and many of these patients, as you can see, have gone to transplant, and then there are a couple of patients who are still in the process of being evaluated for that, so this kind of shows you kind of the spectrum of the patients here then. again response means either cr/cri or mlfs and many of these patients as you can see have gone to transplant and then there are a couple of patients who are still in the process of being evaluated for that so this kind of shows you kind of the spectrum of the patients here then The patient number one, or top patient who has an office follow-up, had a transplant and then doing well now, close to 14 months in the transplant, so now this shows the overall survival. the patient number one or top patient who has an office follow-up had a transplant and then doing well now close to 14 months in the transplant so now this shows the overall survival This is not censored post-transplant. this is not censored post-transplant So we look at the first patient with transplant. And you can see the summary at the bottom here, that the median survival for patients who achieved the MRD-negative remission was 14.8 months. And again, you can specifically at the kind of graph on the right side there, overall for P2, the median survival was 1.4 months. But if you look again at the dose level three patients or the less than 50-year age group patients, the median survival, again, this is a group of patients who had four or five parallels of therapy, the median survival was about 40%. Now, one of the important aspects here was to get the patient to transplant. So we look at the first patient with transplant. so we look at the first patient with transplant And you can see the summary at the bottom here, that the median survival for patients who achieved the MRD-negative remission was 14.8 months. and you can see the summary at the bottom here that the median survival for patients who achieved the mrd-negative remission was 14.8 months And again, you can specifically at the kind of graph on the right side there, overall for P2, the median survival was 1.4 months. and again you can specifically at the kind of graph on the right side there overall for p2 the median survival was 1.4 months But if you look again at the dose level three patients or the less than 50-year age group patients, the median survival, again, this is a group of patients who had four or five parallels of therapy, the median survival was about 40%. but if you look again at the dose level three patients or the less than 50-year age group patients the median survival again this is a group of patients who had four or five parallels of therapy the median survival was about 40% Now, one of the important aspects here was to get the patient to transplant. now one of the important aspects here was to get the patient to transplant So, this is because we know that for these patients who are multifactorial, at the end point for them is to get to a transplant and hopefully they can achieve a long-term remission post-transplant. And to get to a transplant, we really need to be in remission for patients with DLF. So the goal here and what we are going to mention here is that at the phase II target population, which is those nine patients we talked about, all of them either have received or are eligible to get a central transplant for this patient population. And then again, it's kind of shown here in a graphic that if you look at the last bar here, which is the nine patients, 80% had proceeded with the transplant, and the remaining 40% are the kind of what's the more recent data for these patients. So, this is because we know that for these patients who are multifactorial, at the end point for them is to get to a transplant and hopefully they can achieve a long-term remission post-transplant. so this is because we know that for these patients who are multifactorial at the end point for them is to get to a transplant and hopefully they can achieve a long-term remission post-transplant And to get to a transplant, we really need to be in remission for patients with DLF. and to get to a transplant we really need to be in remission for patients with dlf So the goal here and what we are going to mention here is that at the phase II target population, which is those nine patients we talked about, all of them either have received or are eligible to get a central transplant for this patient population. so the goal here and what we are going to mention here is that at the phase ii target population which is those nine patients we talked about all of them either have received or are eligible to get a central transplant for this patient population And then again, it's kind of shown here in a graphic that if you look at the last bar here, which is the nine patients, 80% had proceeded with the transplant, and the remaining 40% are the kind of what's the more recent data for these patients. and then again it's kind of shown here in a graphic that if you look at the last bar here which is the nine patients 80% had proceeded with the transplant and the remaining 40% are the kind of what's the more recent data for these patients So I think the majority of the patients are able to get transplant kind of the cohort. And the transplant does seem to improve the outcome. Certainly, patients who are able to get transplant, they are doing better than versus patients who are not. Kind of makes sense because then they derive long-term benefit from the transplant. So you can see the curve. The top curve here is patients who agreed with the patients who received the dose level three, process two. So these were the 12 patients, and then patients who were able to go to transplant versus one. Now, as we're thinking about designing kind of a phase II part, one of the things we also wanted to look at is the number of parallels of therapy. So I think the majority of the patients are able to get transplant kind of the cohort. so i think the majority of the patients are able to get transplant kind of the cohort And the transplant does seem to improve the outcome. and the transplant does seem to improve the outcome Certainly, patients who are able to get transplant, they are doing better than versus patients who are not. certainly patients who are able to get transplant they are doing better than versus patients who are not Kind of makes sense because then they derive long-term benefit from the transplant. kind of makes sense because then they derive long-term benefit from the transplant So you can see the curve. so you can see the curve The top curve here is patients who agreed with the patients who received the dose level three, process two. the top curve here is patients who agreed with the patients who received the dose level three process two So these were the 12 patients, and then patients who were able to go to transplant versus one. so these were the 12 patients and then patients who were able to go to transplant versus one Now, as we're thinking about designing kind of a phase II part, one of the things we also wanted to look at is the number of parallels of therapy. now as we're thinking about designing kind of a phase ii part one of the things we also wanted to look at is the number of parallels of therapy Certainly, when we split the number of patients by four or less lines of therapy, there doesn't seem to be a big bit of a difference in terms of the survival seems to be the same with less than four versus four or more lines of therapy in this patient population. Now, as was mentioned before, right, in these days, everyone, at least moving forward, getting Blincyto in the first-line setting because of approval of Blincyto in the first-line setting. Obviously, inotuzumab ozogamicin is approved in the later-line setting. So most patients who come to the trial have certainly received Blincyto, have received inotuzumab ozogamicin, and many times they may have received CD19 CAR-T cell therapy as well. Because inotuzumab ozogamicin is also CD22-targeting drug, and we published CD22 because of target CD22, we wanted to specifically look at the outcomes of patients who had prior inotuzumab ozogamicin. Certainly, when we split the number of patients by four or less lines of therapy, there doesn't seem to be a big bit of a difference in terms of the survival seems to be the same with less than four versus four or more lines of therapy in this patient population. certainly when we split the number of patients by four or less lines of therapy there doesn't seem to be a big bit of a difference in terms of the survival seems to be the same with less than four versus four or more lines of therapy in this patient population Now, as was mentioned before, right, in these days, everyone, at least moving forward, getting Blincyto in the first-line setting because of approval of Blincyto in the first-line setting. now as was mentioned before right in these days everyone at least moving forward getting blincyto in the first-line setting because of approval of blincyto in the first-line setting Obviously, inotuzumab ozogamicin is approved in the later-line setting. obviously, inotuzumab ozogamicin is approved in the later-line setting So most patients who come to the trial have certainly received Blincyto, have received inotuzumab ozogamicin, and many times they may have received CD19 CAR-T cell therapy as well. so most patients who come to the trial have certainly received blincyto have received inotuzumab ozogamicin and many times they may have received cd19 car-t cell therapy as well Because inotuzumab ozogamicin is also CD22-targeting drug, and we published CD22 because of target CD22, we wanted to specifically look at the outcomes of patients who had prior inotuzumab ozogamicin. because inotuzumab ozogamicin is also cd22-targeting drug and we published cd22 because of target cd22 we wanted to specifically look at the outcomes of patients who had prior inotuzumab ozogamicin And again, as you can see, it appears to work in patients who had prior inotuzumab ozogamicin as well. Obviously, for these patients, before study N3, what is the correct therapy set in person? CD19 CAR cell therapy. This again shows the CR/CRi for the same. So this is the CR/CRi rate. And among the CR/CRi, how many were MRD negative? And again, as you can see, high rate among the patients who had prior inotuzumab ozogamicin. Now, we also wanted to look at the group of patients who really had all target therapies. So obviously, these patients have chemotherapy. We look at everyone who gets ALL these days, patients who had inotuzumab ozogamicin, patients who had blinatumomab, and also patients who had a prior CD19 CAR cell therapy. So the number of patients becomes relatively small here. And again, as you can see, it appears to work in patients who had prior inotuzumab ozogamicin as well. and again as you can see it appears to work in patients who had prior inotuzumab ozogamicin as well Obviously, for these patients, before study N3, what is the correct therapy set in person? CD19 CAR cell therapy. obviously for these patients before study n3 what is the correct therapy set in person? cd19 car cell therapy This again shows the CR/CRi for the same. this again shows the cr/cri for the same So this is the CR/CRi rate. so this is the cr/cri rate And among the CR/CRi, how many were MRD negative? and among the cr/cri how many were mrd negative And again, as you can see, high rate among the patients who had prior inotuzumab ozogamicin. and again as you can see high rate among the patients who had prior inotuzumab ozogamicin Now, we also wanted to look at the group of patients who really had all target therapies. now we also wanted to look at the group of patients who really had all target therapies So obviously, these patients have chemotherapy. so obviously these patients have chemotherapy We look at everyone who gets ALL these days, patients who had inotuzumab ozogamicin, patients who had blinatumomab, and also patients who had a prior CD19 CAR cell therapy. we look at everyone who gets all these days patients who had inotuzumab ozogamicin patients who had blinatumomab and also patients who had a prior cd19 car cell therapy So the number of patients becomes relatively small here. so the number of patients becomes relatively small here But if you just focus on the P2 dose level three, five, and then at the target population four patients, again, these are the patients who had received all three approved target agents in the context of R/R ALL. They had appeared to be responding to this therapy. And it shows here the same kind of a patient population. Again, the numbers are small, but these are all patients who have received inotuzumab and CD19 CAR-T cell therapy. And again, just to show the CR/CRi rate, these patients are responding, and they're MRD negative. So for example, four patients at the target dose three or four responded with CR/CRi, and they were MRD negative. Obviously, we talked about the efficacy part. The next part is the toxicity part. I'll just show how this cytotrophic is doing. But if you just focus on the P2 dose level three, five, and then at the target population four patients, again, these are the patients who had received all three approved target agents in the context of R/R ALL. but if you just focus on the p2 dose level three five and then at the target population four patients again these are the patients who had received all three approved target agents in the context of r/r all They had appeared to be responding to this therapy. they had appeared to be responding to this therapy And it shows here the same kind of a patient population. and it shows here the same kind of a patient population Again, the numbers are small, but these are all patients who have received inotuzumab and CD19 CAR-T cell therapy. again the numbers are small but these are all patients who have received inotuzumab and cd19 car-t cell therapy And again, just to show the CR/CRi rate, these patients are responding, and they're MRD negative. and again just to show the cr/cri rate these patients are responding and they're mrd negative So for example, four patients at the target dose three or four responded with CR/CRi, and they were MRD negative. so for example four patients at the target dose three or four responded with cr/cri and they were mrd negative Obviously, we talked about the efficacy part. obviously we talked about the efficacy part The next part is the toxicity part. the next part is the toxicity part I'll just show how this cytotrophic is doing. i'll just show how this cytotrophic is doing And this shows the CRS and ICANS, first for the overall population or in 40 patients who have been treated. And that's specifically for the 18 patients at dose level three, which have been treated. So as you can see, in general, I mean, most of the CRS events were grade one and grade two. Similarly, same thing for the ICANS, grade one and grade two. You can see that grade three, 2.5% of the overall population for CRS, and then 5% for ICANS in the overall population for grade three. And then the right part shows specifically for the 18 patients at the L3. And overall, low rates of grade three or higher toxicity. Now, one of the other things which have been talked about is the IEC-HS, which has been associated with some kind of seen for different targeting agents. And this shows the CRS and ICANS, first for the overall population or in 40 patients who have been treated. and this shows the crs and icans first for the overall population or in 40 patients who have been treated And that's specifically for the 18 patients at dose level three, which have been treated. and that's specifically for the 18 patients at dose level three which have been treated So as you can see, in general, I mean, most of the CRS events were grade one and grade two. so as you can see in general i mean most of the crs events were grade one and grade two Similarly, same thing for the ICANS, grade one and grade two. similarly same thing for the icans grade one and grade two You can see that grade three, 2.5% of the overall population for CRS, and then 5% for ICANS in the overall population for grade three. you can see that grade three 2.5% of the overall population for crs and then 5% for icans in the overall population for grade three And then the right part shows specifically for the 18 patients at the L3. and then the right part shows specifically for the 18 patients at the l3 And overall, low rates of grade three or higher toxicity. and overall low rates of grade three or higher toxicity Now, one of the other things which have been talked about is the IEC-HS, which has been associated with some kind of seen for different targeting agents. now one of the other things which have been talked about is the iec-hs which has been associated with some kind of seen for different targeting agents But in this, we had one patient who had IEC-HS, which was called the NF-11, so-called. And so we haven't seen a higher incidence except just one patient who had the IEC-HS. This shows these are specifically the related cytokine adverse events which were reported for CRS and ICANS and others which are kind of listed here. Again, overall, if you look at the 40 patients, these are again only the serious adverse events we talked about, the overall CRS and ICANS, single incidence. Only two patients were reported as serious SAEs for CRS as well as for ICANS. In terms of other adverse events of special interest, you can see here. One thing to highlight is graft-versus-host disease. There's only just one patient, which was at the dose level one, who had a grade two graft-versus-host disease of the skin. But in this, we had one patient who had IEC-HS, which was called the NF-11, so-called. but in this we had one patient who had iec-hs which was called the nf-11 so-called And so we haven't seen a higher incidence except just one patient who had the IEC-HS. and so we haven't seen a higher incidence except just one patient who had the iec-hs This shows these are specifically the related cytokine adverse events which were reported for CRS and ICANS and others which are kind of listed here. this shows these are specifically the related cytokine adverse events which were reported for crs and icans and others which are kind of listed here Again, overall, if you look at the 40 patients, these are again only the serious adverse events we talked about, the overall CRS and ICANS, single incidence. again overall if you look at the 40 patients these are again only the serious adverse events we talked about the overall crs and icans single incidence Only two patients were reported as serious SAEs for CRS as well as for ICANS. only two patients were reported as serious saes for crs as well as for icans In terms of other adverse events of special interest, you can see here. in terms of other adverse events of special interest you can see here One thing to highlight is graft-versus-host disease. one thing to highlight is graft-versus-host disease There's only just one patient, which was at the dose level one, who had a grade two graft-versus-host disease of the skin. there's only just one patient which was at the dose level one who had a grade two graft-versus-host disease of the skin But we haven't seen that with GvHD process one. Now, obviously, the product uses a CD52 antibody, which can be at the risk of infections. And this shows all grade three or higher infections which were related to CD52 exposure. So this kind of shows the process one or the dose level they were noted. And in the next slide, we'll talk more about the CMV reactivation, which is something common we see with the CD52 exposure. This shows specifically the CMV reactivation, which is, let's see, there were six patients who had CMV reactivation, again, at the dose level and the process that they had. And the investigator assessed the relation to alemtuzumab, cyclophosphamide, or fludarabine. Now, as we mentioned in how the study started very early on, initially, we were only using FC without the blinatumomab. This is when the trial started with process one. But we haven't seen that with GvHD process one. but we haven't seen that with gvhd process one Now, obviously, the product uses a CD52 antibody, which can be at the risk of infections. now obviously the product uses a cd52 antibody which can be at the risk of infections And this shows all grade three or higher infections which were related to CD52 exposure. and this shows all grade three or higher infections which were related to cd52 exposure So this kind of shows the process one or the dose level they were noted. so this kind of shows the process one or the dose level they were noted And in the next slide, we'll talk more about the CMV reactivation, which is something common we see with the CD52 exposure. and in the next slide we'll talk more about the cmv reactivation which is something common we see with the cd52 exposure This shows specifically the CMV reactivation, which is, let's see, there were six patients who had CMV reactivation, again, at the dose level and the process that they had. this shows specifically the cmv reactivation which is let's see there were six patients who had cmv reactivation again at the dose level and the process that they had And the investigator assessed the relation to alemtuzumab, cyclophosphamide, or fludarabine. and the investigator assessed the relation to alemtuzumab cyclophosphamide or fludarabine Now, as we mentioned in how the study started very early on, initially, we were only using FC without the blinatumomab. now as we mentioned in how the study started very early on initially we were only using fc without the blinatumomab This is when the trial started with process one. this is when the trial started with process one Then we moved process one with FCA, and then process two with FCA. Five patients were treated. The first five patients in the study were with FC alone. And at that time, we really didn't see any response in these five patients, making a point that. I think that is my part of the study. So I'm now going to talk you through the next steps as we're transitioning to our clinical phase II program. I'll give you an overview of what we've done thus far. So for those of you who have been following us, you'll be aware that we have already completed or in the phase I and scientific advice meetings with both the EMA and the FDA. And these were very encouraging meetings. They both agreed that this was an area of specific front-end need. Then we moved process one with FCA, and then process two with FCA. then we moved process one with fca and then process two with fca Five patients were treated. five patients were treated The first five patients in the study were with FC alone. the first five patients in the study were with fc alone And at that time, we really didn't see any response in these five patients, making a point that. I think that is my part of the study. and at that time we really didn't see any response in these five patients making a point that i think that is my part of the study So I'm now going to talk you through the next steps as we're transitioning to our clinical phase II program. so i'm now going to talk you through the next steps as we're transitioning to our clinical phase ii program I'll give you an overview of what we've done thus far. i'll give you an overview of what we've done thus far So for those of you who have been following us, you'll be aware that we have already completed or in the phase I and scientific advice meetings with both the EMA and the FDA. so for those of you who have been following us you'll be aware that we have already completed or in the phase i and scientific advice meetings with both the ema and the fda And these were very encouraging meetings. and these were very encouraging meetings They both agreed that this was an area of specific front-end need. they both agreed that this was an area of specific front-end need And they also agreed that transplant represents a very positive clinical outcome for these patients. And this is an important step for us based on the data you've seen where all patients were able to get to transplant at our chosen dose. This is, again, gives patients the opportunity of some durable remission and, in some cases, hopefully cure. Equally importantly, we got agreement on our end points of our trial. And I will take you through the design of the program so that you're aware of what that is. And given that there is very little other option for these patients, the regulatory authorities have also agreed that this will be a single-arm trial. And that's important for us in terms of patient numbers. But we will have an external control arm supporting it, which we are designing. And they also agreed that transplant represents a very positive clinical outcome for these patients. and they also agreed that transplant represents a very positive clinical outcome for these patients And this is an important step for us based on the data you've seen where all patients were able to get to transplant at our chosen dose. and this is an important step for us based on the data you've seen where all patients were able to get to transplant at our chosen dose This is, again, gives patients the opportunity of some durable remission and, in some cases, hopefully cure. this is again gives patients the opportunity of some durable remission and in some cases hopefully cure Equally importantly, we got agreement on our end points of our trial. equally importantly we got agreement on our end points of our trial And I will take you through the design of the program so that you're aware of what that is. and i will take you through the design of the program so that you're aware of what that is And given that there is very little other option for these patients, the regulatory authorities have also agreed that this will be a single-arm trial. and given that there is very little other option for these patients the regulatory authorities have also agreed that this will be a single-arm trial And that's important for us in terms of patient numbers. and that's important for us in terms of patient numbers But we will have an external control arm supporting it, which we are designing. but we will have an external control arm supporting it which we are designing But nonetheless, what is clear from all our regulatory interactions is we have a registration path for this program, understanding the importance of achieving a transplant for this particularly difficult-to-treat patient population. So let me talk you through the single-arm study design. Now, for those of you who are used to interacting with the regulatory authorities, they will always want us to have a traditional endpoint. And indeed, we have a traditional endpoint, which is CR/CRi rates in the three months between day 28 and day 84. You will notice from Professor Jain's presentation that our phase I program covered patients 15-70. Based on our observed responses, we lowered the upper age limit. So our move forward phase II pivotal program will be looking at patients age 12-50. And this does two things. But nonetheless, what is clear from all our regulatory interactions is we have a registration path for this program, understanding the importance of achieving a transplant for this particularly difficult-to-treat patient population. but nonetheless what is clear from all our regulatory interactions is we have a registration path for this program understanding the importance of achieving a transplant for this particularly difficult-to-treat patient population So let me talk you through the single-arm study design. so let me talk you through the single-arm study design Now, for those of you who are used to interacting with the regulatory authorities, they will always want us to have a traditional endpoint. now for those of you who are used to interacting with the regulatory authorities they will always want us to have a traditional endpoint And indeed, we have a traditional endpoint, which is CR/CRi rates in the three months between day 28 and day 84. and indeed we have a traditional endpoint which is cr/cri rates in the three months between day 28 and day 84 You will notice from Professor Jain's presentation that our phase I program covered patients 15-70. you will notice from professor jain's presentation that our phase i program covered patients 15-70 Based on our observed responses, we lowered the upper age limit. based on our observed responses we lowered the upper age limit So our move forward phase II pivotal program will be looking at patients age 12-50. so our move forward phase ii pivotal program will be looking at patients age 12-50 And this does two things. and this does two things One, it gets us a registrational data, but it also satisfies a significant portion of our pediatric investigation path, which we're also working on right now, and we'll talk about that in a couple of slides. Now, this is a CD22 targeted therapy, and within our phase I, we had a cutoff of 70% of CD22 expression. Now, we think that's important, but given the way mode of action of a CAR-T, do we need higher levels of expression like we've seen in the NCI trial, etc., where there seems to be a cutoff of 70% below which efficacy starts to reduce? But nonetheless, we think it's important to answer this question, so there will be another cohort. Yes, the pivotal cohort will be with CD22 greater than 70%, which is the overwhelming majority of the patients, probably 85% and above. If you're CD22 positive, you're very highly positive. One, it gets us a registrational data, but it also satisfies a significant portion of our pediatric investigation path, which we're also working on right now, and we'll talk about that in a couple of slides. one it gets us a registrational data but it also satisfies a significant portion of our pediatric investigation path which we're also working on right now and we'll talk about that in a couple of slides Now, this is a CD22 targeted therapy, and within our phase I, we had a cutoff of 70% of CD22 expression. now this is a cd22 targeted therapy and within our phase i we had a cutoff of 70% of cd22 expression Now, we think that's important, but given the way mode of action of a CAR-T, do we need higher levels of expression like we've seen in the NCI trial, etc., where there seems to be a cutoff of 70% below which efficacy starts to reduce? now we think that's important but given the way mode of action of a car-t do we need higher levels of expression like we've seen in the nci trial etc where there seems to be a cutoff of 70% below which efficacy starts to reduce But nonetheless, we think it's important to answer this question, so there will be another cohort. but nonetheless we think it's important to answer this question so there will be another cohort Yes, the pivotal cohort will be with CD22 greater than 70%, which is the overwhelming majority of the patients, probably 85% and above. yes the pivotal cohort will be with cd22 greater than 70% which is the overwhelming majority of the patients probably 85% and above If you're CD22 positive, you're very highly positive. if you're cd22 positive you're very highly positive In the NCI trial, for instance, I think the median CD22 positivity was in the region of 98%, so we know that there will be some patient attrition from this, but we will still capture them in Cohort B, where we're going to specifically look at patients with lower level of expression, so we will be capturing all comers within this trial. An important part of this program is also the first part, which is the dose optimization of alemtuzumab. This is a requirement, and we will be looking at two doses: the dose we already have investigated and one other dose, and it will be randomized in terms of the exposure to alemtuzumab, and at the end of 40 patients in each arm, 40 patients overall, we will do our first interim analysis. In the NCI trial, for instance, I think the median CD22 positivity was in the region of 98%, so we know that there will be some patient attrition from this, but we will still capture them in Cohort B, where we're going to specifically look at patients with lower level of expression, so we will be capturing all comers within this trial. in the nci trial for instance i think the median cd22 positivity was in the region of 98% so we know that there will be some patient attrition from this but we will still capture them in cohort b where we're going to specifically look at patients with lower level of expression so we will be capturing all comers within this trial An important part of this program is also the first part, which is the dose optimization of alemtuzumab. an important part of this program is also the first part which is the dose optimization of alemtuzumab This is a requirement, and we will be looking at two doses: the dose we already have investigated and one other dose, and it will be randomized in terms of the exposure to alemtuzumab, and at the end of 40 patients in each arm, 40 patients overall, we will do our first interim analysis. this is a requirement and we will be looking at two doses the dose we already have investigated and one other dose and it will be randomized in terms of the exposure to alemtuzumab and at the end of 40 patients in each arm 40 patients overall we will do our first interim analysis And that will allow us to decide what is the optimal dose of alemtuzumab to take forward into the remainder of the trial. Now, just to be clear, this is an essentially seamless design. So the patients in the dose optimization of the chosen dose will also form part of the pivotal patient population. So it reduces the burden of recruitment on us for the remainder of the study. With that, we will have another interim analysis at 50% of the pivotal cohort recruitment. And for the primary analysis for BLA, we'll be based on CR/CRi at three months following full recruitment. You will note that we have a follow-up analysis for overall survival, which will be up to two years. And that will allow us to decide what is the optimal dose of alemtuzumab to take forward into the remainder of the trial. and that will allow us to decide what is the optimal dose of alemtuzumab to take forward into the remainder of the trial Now, just to be clear, this is an essentially seamless design. now just to be clear this is an essentially seamless design So the patients in the dose optimization of the chosen dose will also form part of the pivotal patient population. so the patients in the dose optimization of the chosen dose will also form part of the pivotal patient population So it reduces the burden of recruitment on us for the remainder of the study. so it reduces the burden of recruitment on us for the remainder of the study With that, we will have another interim analysis at 50% of the pivotal cohort recruitment. with that we will have another interim analysis at 50% of the pivotal cohort recruitment And for the primary analysis for BLA, we'll be based on CR/CRi at three months following full recruitment. and for the primary analysis for bla we'll be based on cr/cri at three months following full recruitment You will note that we have a follow-up analysis for overall survival, which will be up to two years. you will note that we have a follow-up analysis for overall survival which will be up to two years Because as you've seen from Professor Jain's presentation, we believe that one of the challenges we've had in recruiting our phase I program, it's not recruiting it, but actually analyzing it, is interpreting response in the context of durability of response. What we found is once patients got to MRD negativity with a deep response, they were immediately going to transplant, and therefore by three months, most patients had already had a transplant, and because we were censoring for transplant, it's very difficult to show durability of response. Moving forward, because we won't be censoring for transplant, we will be able to show much more clarity around duration of response for these patients, so based on our phase II plan, as I already said, we are currently working on a pediatric investigation plan. Because as you've seen from Professor Jain's presentation, we believe that one of the challenges we've had in recruiting our phase I program, it's not recruiting it, but actually analyzing it, is interpreting response in the context of durability of response. because as you've seen from professor jain's presentation we believe that one of the challenges we've had in recruiting our phase i program it's not recruiting it but actually analyzing it is interpreting response in the context of durability of response What we found is once patients got to MRD negativity with a deep response, they were immediately going to transplant, and therefore by three months, most patients had already had a transplant, and because we were censoring for transplant, it's very difficult to show durability of response. what we found is once patients got to mrd negativity with a deep response they were immediately going to transplant and therefore by three months most patients had already had a transplant and because we were censoring for transplant it's very difficult to show durability of response Moving forward, because we won't be censoring for transplant, we will be able to show much more clarity around duration of response for these patients, so based on our phase II plan, as I already said, we are currently working on a pediatric investigation plan. moving forward because we won't be censoring for transplant we will be able to show much more clarity around duration of response for these patients so based on our phase ii plan as i already said we are currently working on a pediatric investigation plan The current phase II program will capture patients from 12-50, but we will also have almost parallel pediatric plan looking at patients from 0-12, so we are capturing the majority of patients from 0-50 years of age. That's not to say we're abandoning the patients above 50. We will look at those, but not just yet. We believe our first indication will be in patients up to 50 years of age, and again, once we have an update on how we're going to address the remainder of the patients, we will share that with you. We now have. Our protocol has been submitted to the regulatory authorities. We are now opening. We are now setting up our study, and because we want to accelerate this, we have increased the number of sites we're using when we're opening. The current phase II program will capture patients from 12- 50, but we will also have almost parallel pediatric plan looking at patients from 0- 12, so we are capturing the majority of patients from 0- 50 years of age. the current phase ii program will capture patients from 12- 50 but we will also have almost parallel pediatric plan looking at patients from 0- 12 so we are capturing the majority of patients from 0- 50 years of age That's not to say we're abandoning the patients above 50. that's not to say we're abandoning the patients above 50 We will look at those, but not just yet. we will look at those but not just yet We believe our first indication will be in patients up to 50 years of age, and again, once we have an update on how we're going to address the remainder of the patients, we will share that with you. we believe our first indication will be in patients up to 50 years of age and again once we have an update on how we're going to address the remainder of the patients we will share that with you We now have. we now have Our protocol has been submitted to the regulatory authorities. our protocol has been submitted to the regulatory authorities We are now opening. we are now opening we are now We are now setting up our study, and because we want to accelerate this, we have increased the number of sites we're using when we're opening. we are now setting up our study and because we want to accelerate this we have increased the number of sites we're using when we're opening So we're going to globally open sites, 75 centers across North America and Europe. The numbers for each of those countries are there. Apologies to the Italians. I forgot to shade in that one, but we will be going to Italy as well. But 75 centers will give us what we consider reasonably brisk recruitment to give us these timelines. These are the timelines we are working toward. We are, of course, hoping that we can beat those timelines, but we anticipate toward the end of this year, we will have our first patient recruited. Based on our recruitment projections, we will have our first interim analysis at Q4 2026. Now, because we will continue to recruit, we will not be pausing recruitment at any point in time. And at that time, we will have all centers active and recruiting. So we're going to globally open sites, 75 centers across North America and Europe. so we're going to globally open sites 75 centers across north america and europe The numbers for each of those countries are there. the numbers for each of those countries are there Apologies to the Italians. apologies to the italians I forgot to shade in that one, but we will be going to Italy as well. i forgot to shade in that one but we will be going to italy as well But 75 centers will give us what we consider reasonably brisk recruitment to give us these timelines. but 75 centers will give us what we consider reasonably brisk recruitment to give us these timelines These are the timelines we are working toward. these are the timelines we are working toward We are, of course, hoping that we can beat those timelines, but we anticipate toward the end of this year, we will have our first patient recruited. we are of course hoping that we can beat those timelines but we anticipate toward the end of this year we will have our first patient recruited Based on our recruitment projections, we will have our first interim analysis at Q4 2026. based on our recruitment projections we will have our first interim analysis at q4 2026 Now, because we will continue to recruit, we will not be pausing recruitment at any point in time. now because we will continue to recruit we will not be pausing recruitment at any point in time And at that time, we will have all centers active and recruiting. and at that time we will have all centers active and recruiting The second interim analysis comes fairly quickly after, in the second quarter of 2027, and that will be at 50% of the pivotal cohort. By Q3 2027, we anticipate we will have completed enrollment, and then we know that we have our three-month follow-up for CR/CRi. We should have our primary analysis complete, allowing for that in the first quarter of 2028. Now, assuming all of that, we should be submitting for the second half of 2028 our BLA. Now, I just want to reiterate one thing that I haven't probably made clear enough. When we're submitting this BLA, we're actually submitting two BLAs, because throughout this, we have two investigational products. We have the UCART22, but we also have alemtuzumab, so by the second half of 2028, we will be submitting not one, but two BLAs. Now, that's all I'm going to cover. The second interim analysis comes fairly quickly after, in the second quarter of 2027, and that will be at 50% of the pivotal cohort. the second interim analysis comes fairly quickly after in the second quarter of 2027 and that will be at 50% of the pivotal cohort By Q3 2027, we anticipate we will have completed enrollment, and then we know that we have our three-month follow-up for CR/CRi. by q3 2027 we anticipate we will have completed enrollment and then we know that we have our three-month follow-up for cr/cri We should have our primary analysis complete, allowing for that in the first quarter of 2028. we should have our primary analysis complete allowing for that in the first quarter of 2028 Now, assuming all of that, we should be submitting for the second half of 2028 our BLA. now assuming all of that we should be submitting for the second half of 2028 our bla Now, I just want to reiterate one thing that I haven't probably made clear enough. now i just want to reiterate one thing that i haven't probably made clear enough When we're submitting this BLA, we're actually submitting two BLAs, because throughout this, we have two investigational products. when we're submitting this bla we're actually submitting two blas because throughout this we have two investigational products We have the UCART22, but we also have alemtuzumab, so by the second half of 2028, we will be submitting not one, but two BLAs. we have the ucart22 but we also have alemtuzumab so by the second half of 2028 we will be submitting not one but two blas Now, that's all I'm going to cover. now that's all i'm going to cover Hopefully, the timelines and our plans are clear. But I'd like now to invite our three investigators. I'm delighted to have them here. We've been introduced to Professor Jain already, who's the chief investigator of our studies and a huge supporter. I would also like to invite Professor Boissel to join us from the Hôpital Saint-Louis in Paris. And again, he's the head of young adults and adolescents. And your insight is going to be really important. And very important also is Dr. Ramakrishnan from San Antonio. Sarah Kim. Oh, sorry. Excuse me. Sorry. But he's particularly important today because he is the only investigator who's running both our studies. So he is doing 22 and 20x22. So his insights are really helpful to us. So what we want to really do now is just, you've seen the data. Hopefully, the timelines and our plans are clear. hopefully the timelines and our plans are clear But I'd like now to invite our three investigators. but i'd like now to invite our three investigators I'm delighted to have them here. i'm delighted to have them here We've been introduced to Professor Jain already, who's the chief investigator of our studies and a huge supporter. we've been introduced to professor jain already who's the chief investigator of our studies and a huge supporter I would also like to invite Professor Boissel to join us from the Hôpital Saint-Louis in Paris. i would also like to invite professor boissel to join us from the hôpital saint-louis in paris And again, he's the head of young adults and adolescents. and again he's the head of young adults and adolescents And your insight is going to be really important. and your insight is going to be really important And very important also is Dr. Ramakrishnan from San Antonio. and very important also is dr ramakrishnan from san antonio Sarah Kim. sarah kim Oh, sorry. oh sorry Excuse me. excuse me Sorry. sorry but But he's particularly important today because he is the only investigator who's running both our studies. but he's particularly important today because he is the only investigator who's running both our studies So he is doing 22 and 20x22. so he is doing 22 and 20x22 So his insights are really helpful to us. so his insights are really helpful to us So what we want to really do now is just, you've seen the data. so what we want to really do now is just you've seen the data And it would be great if we could really start thinking about the, as we look at the data, just for the audience and for those online, what is the level of unmet needs that we're addressing? Maybe we can start with you to get a European perspective, Professor Boissel, to talk about the unmet need of these particular patients. And it would be great if we could really start thinking about the, as we look at the data, just for the audience and for those online, what is the level of unmet needs that we're addressing? and it would be great if we could really start thinking about the as we look at the data just for the audience and for those online what is the level of unmet needs that we're addressing Maybe we can start with you to get a European perspective, Professor Boissel, to talk about the unmet need of these particular patients. maybe we can start with you to get a european perspective professor boissel to talk about the unmet need of these particular patients

Speaker 2: Start with your point of view. So we're not so far from what we're hearing in the U.S. doing for the patients in children and adults. We are, of course, now exposing our patients to Blincyto frontline. So all the patients, including in first or several relapse, who have been exposed to Blincyto, we can treat with targeted inotuzumab ozogamicin. So CAR T cells. So it may be surprising to speak about first-line ALL because it's not something that has been usual in prior study, but that's the reality now. Start with your point of view. start with your point of view So we're not so far from what we're hearing in the U.S. doing for the patients in children and adults. so we're not so far from what we're hearing in the u.s doing for the patients in children and adults We are, of course, now exposing our patients to Blincyto frontline. we are of course now exposing our patients to blincyto frontline So all the patients, including in first or several relapse, who have been exposed to Blincyto, we can treat with targeted inotuzumab ozogamicin. so all the patients including in first or several relapse who have been exposed to blincyto we can treat with targeted inotuzumab ozogamicin So CAR T cells. so car t cells So it may be surprising to speak about first-line ALL because it's not something that has been usual in prior study, but that's the reality now. so it may be surprising to speak about first-line all because it's not something that has been usual in prior study but that's the reality now So a lot of drugs we propose to our patients, and mostly CD19-targeted. What is probably also changing now in Europe is, because of the use of Blincyto frontline, we will postpone allogeneic stem cell transplant to several months, so we were traditionally more consulting patient frontline than how it's here in the U.S., but we will come closer to the standard practice because of the use of targeted alemtuzumab therapy frontline, and so obviously, the patient will have built in terms of relapse or refractory status will be exposed to CD19-targeted therapy with two different profiles who will lose the target, so it will be CD19-negative, and those who are not completely identified so far are those who have an immune system that is unfit to either respond to Blincyto or to provide it to CAR-T. That is something that is still unclear. So a lot of drugs we propose to our patients, and mostly CD19-targeted. so a lot of drugs we propose to our patients and mostly cd19-targeted What is probably also changing now in Europe is, because of the use of Blincyto frontline, we will postpone allogeneic stem cell transplant to several months, so we were traditionally more consulting patient frontline than how it's here in the U.S., but we will come closer to the standard practice because of the use of targeted alemtuzumab therapy frontline, and so obviously, the patient will have built in terms of relapse or refractory status will be exposed to CD19-targeted therapy with two different profiles who will lose the target, so it will be CD19-negative, and those who are not completely identified so far are those who have an immune system that is unfit to either respond to Blincyto or to provide it to CAR-T. what is probably also changing now in europe is because of the use of blincyto frontline we will postpone allogeneic stem cell transplant to several months so we were traditionally more consulting patient frontline than how it's here in the u.s but we will come closer to the standard practice because of the use of targeted alemtuzumab therapy frontline and so obviously the patient will have built in terms of relapse or refractory status will be exposed to cd19-targeted therapy with two different profiles who will lose the target so it will be cd19-negative and those who are not completely identified so far are those who have an immune system that is unfit to either respond to blincyto or to provide it to car-t That is something that is still unclear. that is something that is still unclear So I think there's always a question about the likelihood of the T cell patients for frontline or advanced patients. I think that, yeah, the first surprise about this, the results of the patients were exposed at a high rate of prior exposure to immunotherapy. I think none of the studies or pivotal study were done for ALL in relapse or refractory disease for this kind of profile or prior target. It's clear that frontline and 80% of Blincyto, the number is up to 55% or 60% binding to Blincyto in high rate of transplants, something that medicine wants, and so clearly, these patients will require to have an innovative strategy as presented. Reports. So I think there's always a question about the likelihood of the T cell patients for frontline or advanced patients. so i think there's always a question about the likelihood of the t cell patients for frontline or advanced patients I think that, yeah, the first surprise about this, the results of the patients were exposed at a high rate of prior exposure to immunotherapy. i think that yeah the first surprise about this the results of the patients were exposed at a high rate of prior exposure to immunotherapy I think none of the studies or pivotal study were done for ALL in relapse or refractory disease for this kind of profile or prior target. i think none of the studies or pivotal study were done for all in relapse or refractory disease for this kind of profile or prior target It's clear that frontline and 80% of Blincyto, the number is up to 55% or 60% binding to Blincyto in high rate of transplants, something that medicine wants, and so clearly, these patients will require to have an innovative strategy as presented. it's clear that frontline and 80% of blincyto the number is up to 55% or 60% binding to blincyto in high rate of transplants something that medicine wants and so clearly these patients will require to have an innovative strategy as presented Reports. reports So of course, I think that the agency is required to move to relapsed or refractory disease, but when you are addressing the question of unmet needs at different stages, including frontline patients, we are trying, we are now identifying patients that are also refractory to CD19 targeted therapy, so it's still not well described. It's the E1910 study that led to the approval of blinatumomab frontline was for MRD negative patients, so they were MRD negative, good responders, and then received blinatumomab, so there are good responders. But we know also from limited studies, and if you consider the overall population of patients, we will identify very rapidly patients that are refractory to primary positive blinatumomab, and that do not convert to MRD negative, especially with the high sensitive MRD tool that we are using now. So of course, I think that the agency is required to move to relapsed or refractory disease, but when you are addressing the question of unmet needs at different stages, including frontline patients, we are trying, we are now identifying patients that are also refractory to CD19 targeted therapy, so it's still not well described. so of course i think that the agency is required to move to relapsed or refractory disease but when you are addressing the question of unmet needs at different stages including frontline patients we are trying we are now identifying patients that are also refractory to cd19 targeted therapy so it's still not well described It's the E1910 study that led to the approval of blinatumomab frontline was for MRD negative patients, so they were MRD negative, good responders, and then received blinatumomab, so there are good responders. it's the e1910 study that led to the approval of blinatumomab frontline was for mrd negative patients so they were mrd negative good responders and then received blinatumomab so there are good responders But we know also from limited studies, and if you consider the overall population of patients, we will identify very rapidly patients that are refractory to primary positive blinatumomab, and that do not convert to MRD negative, especially with the high sensitive MRD tool that we are using now. but we know also from limited studies and if you consider the overall population of patients we will identify very rapidly patients that are refractory to primary positive blinatumomab and that do not convert to mrd negative especially with the high sensitive mrd tool that we are using now In this patient, we know that they have quite a high risk of progression. And that in this situation, it's not the option to treat them with allogeneic stem cell transplant with this MRD-positive cell. So it is clear that also this kind of appropriation for early phase. In this patient, we know that they have quite a high risk of progression. in this patient we know that they have quite a high risk of progression And that in this situation, it's not the option to treat them with allogeneic stem cell transplant with this MRD-positive cell. and that in this situation it's not the option to treat them with allogeneic stem cell transplant with this mrd-positive cell So it is clear that also this kind of appropriation for early phase. so it is clear that also this kind of appropriation for early phase So any tool that helps me convert my patient standpoint within curative intent, especially if we can stage the advancement regimens, we have very good outcomes in getting them into MRD negative stage. Regarding that, patients we're seeing now are also exposed to all these targeted therapies. So it's much harder to get them to that point. I mean, I think when I see the data and look at numbers this high for MRD negativity, actually activity is very, very encouraging. I think the other thing, I've worked with allogeneic CAR T therapies for some years now. And I want to highlight what André said, that the manufacturing is very critical of this team. And I'm looking at, do we get reproducible CAR T expansion and response? And I think that's also been very reassuring with this product. And I think that distinguisher. So any tool that helps me convert my patient standpoint within curative intent, especially if we can stage the advancement regimens, we have very good outcomes in getting them into MRD negative stage. so any tool that helps me convert my patient standpoint within curative intent especially if we can stage the advancement regimens we have very good outcomes in getting them into mrd negative stage Regarding that, patients we're seeing now are also exposed to all these targeted therapies. regarding that patients we're seeing now are also exposed to all these targeted therapies So it's much harder to get them to that point. so it's much harder to get them to that point I mean, I think when I see the data and look at numbers this high for MRD negativity, actually activity is very, very encouraging. i mean i think when i see the data and look at numbers this high for mrd negativity actually activity is very very encouraging I think the other thing, I've worked with allogeneic CAR T therapies for some years now. i think the other thing i've worked with allogeneic car t therapies for some years now And I want to highlight what André said, that the manufacturing is very critical of this team. and i want to highlight what andré said that the manufacturing is very critical of this team And I'm looking at, do we get reproducible CAR T expansion and response? and i'm looking at do we get reproducible car t expansion and response And I think that's also been very reassuring with this product. and i think that's also been very reassuring with this product And I think that distinguisher. and i think that distinguisher So I mean, the critical thing we often see is patients coming in, they have refractory disease. With the standard CAR T, how are you going to collect T cells on someone while maintaining their disease at a state, controlling them, getting them to transplant? This product provides a lot of advantages. Ready to go. We know it works very well. We have a very good target. And we have high rates of MRD negativity. So we're typically planning a transplant while they're probably. So it's been very encouraging. I think I will just say on the same point. I think one of the things which I, so I treat ALL, but so I think one of the challenges with the outlook of CAR T cell therapy which has been great that we run into issues with these patients who are cytopenic from the disease. So I mean, the critical thing we often see is patients coming in, they have refractory disease. so i mean the critical thing we often see is patients coming in they have refractory disease With the standard CAR T, how are you going to collect T cells on someone while maintaining their disease at a state, controlling them, getting them to transplant? with the standard car t how are you going to collect t cells on someone while maintaining their disease at a state controlling them getting them to transplant This product provides a lot of advantages. this product provides a lot of advantages Ready to go. ready to go We know it works very well. we know it works very well We have a very good target. we have a very good target And we have high rates of MRD negativity. and we have high rates of mrd negativity So we're typically planning a transplant while they're probably. so we're typically planning a transplant while they're probably So it's been very encouraging. so it's been very encouraging I think I will just say on the same point. i think i will just say on the same point I think one of the things which I, so I treat ALL, but so I think one of the challenges with the outlook of CAR T cell therapy which has been great that we run into issues with these patients who are cytopenic from the disease. i think one of the things which i so i treat all but so i think one of the challenges with the outlook of car t cell therapy which has been great that we run into issues with these patients who are cytopenic from the disease So their white count is like 0.5, 0.3, and there is no T. You cannot collect. There is nothing to collect. There's no T cell getting T cells. So I think that's a challenge especially for B-ALL. Maybe not so much for NHL. I mean, maybe, but because B-ALL is a disease. So I think that's also a point that I think for specifically for B-ALL, allogeneic CAR T cell therapy will have a point because you don't need to worry about blood counts. Your results are pre-made. So I think that's another important point we used to be really running into issues in our department trying to say, "Oh, let's do a CAR T cell therapy," but, "Oh, the white count is 0.2." They talk about all those CAR T cell therapy and, "Oh, we're going to do that." The results are below. So their white count is like 0.5, 0.3, and there is no T. so their white count is like 0.5 0.3 and there is no t You cannot collect. you cannot collect There is nothing to collect. there is nothing to collect There's no T cell getting T cells. there's no t cell getting t cells So I think that's a challenge especially for B-ALL. so i think that's a challenge especially for b-all Maybe not so much for NHL. maybe not so much for nhl I mean, maybe, but because B-ALL is a disease. i mean maybe but because b-all is a disease So I think that's also a point that I think for specifically for B-ALL, allogeneic CAR T cell therapy will have a point because you don't need to worry about blood counts. so i think that's also a point that i think for specifically for b-all allogeneic car t cell therapy will have a point because you don't need to worry about blood counts Your results are pre-made. your results are pre-made So I think that's another important point we used to be really running into issues in our department trying to say, "Oh, let's do a CAR T cell therapy," but, "Oh, the white count is 0.2." They talk about all those CAR T cell therapy and, "Oh, we're going to do that." The results are below. so i think that's another important point we used to be really running into issues in our department trying to say "oh let's do a car t cell therapy," but "oh the white count is 0.2." they talk about all those car t cell therapy and "oh we're going to do that." the results are below So I think that is a potential challenge for a B-ALL. What was really interesting, I met with you a few weeks ago. All three of you asked me the same question, which was, "Tell us what's happening with prior CD22 exposure." And it would be great to get your view on the data you've seen because I was a little surprised when I saw the response, to be honest. So maybe we'll start back with you, Professor Boissel. So I think that is a potential challenge for a B-ALL. so i think that is a potential challenge for a b-all What was really interesting, I met with you a few weeks ago. what was really interesting i met with you a few weeks ago All three of you asked me the same question, which was, "Tell us what's happening with prior CD22 exposure." And it would be great to get your view on the data you've seen because I was a little surprised when I saw the response, to be honest. all three of you asked me the same question which was "tell us what's happening with prior cd22 exposure." and it would be great to get your view on the data you've seen because i was a little surprised when i saw the response to be honest So maybe we'll start back with you, Professor Boissel. so maybe we'll start back with you professor boissel

Speaker 7: Yes. So the question was, I think, obvious because of the disappearance of the CD19 and repeated CD19 targeted therapy, so blinatumomab, like you said. And we now know that this will emerge from real-world experience here in the U.S. where we know that prior blinatumomab exposure may have an impact on early response, but also on the risk of progression of their response to CD19 targeted CAR T. Yes. yes So the question was, I think, obvious because of the disappearance of the CD19 and repeated CD19 targeted therapy, so blinatumomab, like you said. so the question was i think obvious because of the disappearance of the cd19 and repeated cd19 targeted therapy so blinatumomab like you said And we now know that this will emerge from real-world experience here in the U.S. where we know that prior blinatumomab exposure may have an impact on early response, but also on the risk of progression of their response to CD19 targeted CAR T. and we now know that this will emerge from real-world experience here in the u.s where we know that prior blinatumomab exposure may have an impact on early response but also on the risk of progression of their response to cd19 targeted car t So the mechanisms are a little bit different in terms of CD22 expression modulation between CD19 and CD22. But we know that, and also from daily experience, that exposure to CD22 with inotuzumab ozogamicin may modulate sometimes transiently the expression of CD22. So we start to have some data, but I think it was very important to have the analysis done. And so yes, I was a bit surprised by the results you showed me yesterday. It was certainly a surprise. Remember, I write small, but yes, people hear that, but there is no clear evidence that prior exposure to inotuzumab ozogamicin will modulate the response to the cells. So it's something a bit encouraging. So the mechanisms are a little bit different in terms of CD22 expression modulation between CD19 and CD22. so the mechanisms are a little bit different in terms of cd22 expression modulation between cd19 and cd22 But we know that, and also from daily experience, that exposure to CD22 with inotuzumab ozogamicin may modulate sometimes transiently the expression of CD22. but we know that and also from daily experience that exposure to cd22 with inotuzumab ozogamicin may modulate sometimes transiently the expression of cd22 So we start to have some data, but I think it was very important to have the analysis done. so we start to have some data but i think it was very important to have the analysis done And so yes, I was a bit surprised by the results you showed me yesterday. and so yes i was a bit surprised by the results you showed me yesterday It was certainly a surprise. it was certainly a surprise Remember, I write small, but yes, people hear that, but there is no clear evidence that prior exposure to inotuzumab ozogamicin will modulate the response to the cells. remember i write small but yes people hear that but there is no clear evidence that prior exposure to inotuzumab ozogamicin will modulate the response to the cells So it's something a bit encouraging. so it's something a bit encouraging

Speaker 1: Dr. Ramakrishnan. Yeah. Dr. Ramakrishnan. dr ramakrishnan Yeah. yeah

Speaker 3: So I would concur, I think, with a lot of Blincyto usage where you see a downregulation of CD19 and those patients are no longer eligible for CD19 CAR T if we can't affect the target. So I was a little surprised with prior inotuzumab ozogamicin. A majority of patients are getting it. Perhaps the mechanism of resistance is a little bit different. The target is still, I mean, it is a different type of approach. It's an ADC versus a T cell redirect agent. But it's very encouraging that I know that I had patients with heavy ino exposure that went into an MRD-negative position. They're very encouraging. So I would concur, I think, with a lot of Blincyto usage where you see a downregulation of CD19 and those patients are no longer eligible for CD19 CAR T if we can't affect the target. so i would concur i think with a lot of blincyto usage where you see a downregulation of cd19 and those patients are no longer eligible for cd19 car t if we can't affect the target So I was a little surprised with prior inotuzumab ozogamicin. so i was a little surprised with prior inotuzumab ozogamicin A majority of patients are getting it. a majority of patients are getting it Perhaps the mechanism of resistance is a little bit different. perhaps the mechanism of resistance is a little bit different The target is still, I mean, it is a different type of approach. the target is still i mean it is a different type of approach It's an ADC versus a T cell redirect agent. it's an adc versus a t cell redirect agent But it's very encouraging that I know that I had patients with heavy ino exposure that went into an MRD-negative position. but it's very encouraging that i know that i had patients with heavy ino exposure that went into an mrd-negative position They're very encouraging. they're very encouraging

Speaker 1: Yeah. And they're doing the same thoughts. I think, as was mentioned, I think for CD19, it's more of an issue because it was not of the Blincyto and obviously after CD19 targeted therapy. Yeah. yeah And they're doing the same thoughts. and they're doing the same thoughts I think, as was mentioned, I think for CD19, it's more of an issue because it was not of the Blincyto and obviously after CD19 targeted therapy. i think as was mentioned i think for cd19 it's more of an issue because it was not of the blincyto and obviously after cd19 targeted therapy I think for CD22 with inotuzumab ozogamicin, yes, there could be some loss, but it's not as frequent as the CD19. So I think in that sense, I think it's very good because you're preserving your target immunoprophylactically for inotuzumab ozogamicin. But also the fact that, which is encouraging, is that, yes, you had prior inotuzumab ozogamicin, but all these patients are still sensitive to never see that Blincyto targeted patient. And I think moving forward, I think it's quite likely that, I think, at least in the U.S., certainly a lot of patients will have prior Blincyto for sure. And I think a lot of these patients that we saw in the study will have prior inotuzumab ozogamicin before they go into the targeted therapy. So I think we also have to address the inotuzumab ozogamicin issue. And we have seen that inotuzumab ozogamicin appears to be very important in achieving results. I think for CD22 with inotuzumab ozogamicin, yes, there could be some loss, but it's not as frequent as the CD19. i think for cd22 with inotuzumab ozogamicin yes there could be some loss but it's not as frequent as the cd19 So I think in that sense, I think it's very good because you're preserving your target immunoprophylactically for inotuzumab ozogamicin. so i think in that sense i think it's very good because you're preserving your target immunoprophylactically for inotuzumab ozogamicin But also the fact that, which is encouraging, is that, yes, you had prior inotuzumab ozogamicin, but all these patients are still sensitive to never see that Blincyto targeted patient. but also the fact that which is encouraging is that yes you had prior inotuzumab ozogamicin but all these patients are still sensitive to never see that blincyto targeted patient And I think moving forward, I think it's quite likely that, I think, at least in the U.S., certainly a lot of patients will have prior Blincyto for sure. and i think moving forward i think it's quite likely that i think at least in the u.s certainly a lot of patients will have prior blincyto for sure And I think a lot of these patients that we saw in the study will have prior inotuzumab ozogamicin before they go into the targeted therapy. and i think a lot of these patients that we saw in the study will have prior inotuzumab ozogamicin before they go into the targeted therapy So I think we also have to address the inotuzumab ozogamicin issue. so i think we also have to address the inotuzumab ozogamicin issue And we have seen that inotuzumab ozogamicin appears to be very important in achieving results. and we have seen that inotuzumab ozogamicin appears to be very important in achieving results So it would be great to get your insights on the management of your patients with alemtuzumab. We've seen the toxicity profile, which I think is reasonably reassuring. But just get your view on using it. Maybe we can mix it up with. So when I first took on this study and alemtuzumab, I heard that I was like, "Really?" But that being said, now we're actually using it. I think the advances in infectious prophylaxis have made it more safe, particularly with CMV. We've had a big advance with alemtuzumab here for prophylaxis. And that's pretty much not been that issue for the most part. We also have other drugs. So I think the key aspect there is having those anti-infectious prophylaxis and being on top of that so that you manage that with your patient with antithromboprophylaxis that comes on other drugs. So it would be great to get your insights on the management of your patients with alemtuzumab. so it would be great to get your insights on the management of your patients with alemtuzumab We've seen the toxicity profile, which I think is reasonably reassuring. we've seen the toxicity profile which i think is reasonably reassuring But just get your view on using it. but just get your view on using it Maybe we can mix it up with. maybe we can mix it up with So when I first took on this study and alemtuzumab, I heard that I was like, "Really?" But that being said, now we're actually using it. so when i first took on this study and alemtuzumab i heard that i was like "really?" but that being said now we're actually using it I think the advances in infectious prophylaxis have made it more safe, particularly with CMV. i think the advances in infectious prophylaxis have made it more safe particularly with cmv We've had a big advance with alemtuzumab here for prophylaxis. we've had a big advance with alemtuzumab here for prophylaxis And that's pretty much not been that issue for the most part. and that's pretty much not been that issue for the most part We also have other drugs. we also have other drugs So I think the key aspect there is having those anti-infectious prophylaxis and being on top of that so that you manage that with your patient with antithromboprophylaxis that comes on other drugs. so i think the key aspect there is having those anti-infectious prophylaxis and being on top of that so that you manage that with your patient with antithromboprophylaxis that comes on other drugs And I think it can be safely delivered. And clearly, it seems to be very important in the expansion of the T cells and activity of the path. Yeah. So I think my previous we use alemtuzumab for infectious disease T cells B-ALL at a much higher dose for much longer. And they are certainly. You're not going to see immediate activation and all these things. It's an issue, it's a challenge. But here, as we've kind of discussed, we're using much shorter duration overall, much lower than what we use for B-ALL. And again, with the infectious prophylaxis, monitoring the patients closely. I think, thankfully, the infectious issues. That's not been a major issue with alemtuzumab. And it appears, as we just discussed, at least for this product, that the use of alemtuzumab is quite important. And I think it can be safely delivered. and i think it can be safely delivered And clearly, it seems to be very important in the expansion of the T cells and activity of the path. and clearly it seems to be very important in the expansion of the t cells and activity of the path Yeah. yeah So I think my previous we use alemtuzumab for infectious disease T cells B-ALL at a much higher dose for much longer. so i think my previous we use alemtuzumab for infectious disease t cells b-all at a much higher dose for much longer And they are certainly. and they are certainly You're not going to see immediate activation and all these things. you're not going to see immediate activation and all these things It's an issue, it's a challenge. it's an issue it's a challenge But here, as we've kind of discussed, we're using much shorter duration overall, much lower than what we use for B-ALL. but here as we've kind of discussed we're using much shorter duration overall much lower than what we use for b-all And again, with the infectious prophylaxis, monitoring the patients closely. and again with the infectious prophylaxis monitoring the patients closely I think, thankfully, the infectious issues. i think thankfully the infectious issues That's not been a major issue with alemtuzumab. that's not been a major issue with alemtuzumab And it appears, as we just discussed, at least for this product, that the use of alemtuzumab is quite important. and it appears as we just discussed at least for this product that the use of alemtuzumab is quite important Choosing to have the OBR, also using alemtuzumab for some transplants that can be used to manage this infectious disease that are not that aggressive in terms of viral levels in the infectious patients here. Of course, the organization of this is really important to explore this to those levels, and I think it was described by the agency that it seems wise, and I'm happy to go forward with this kind of questions. I suppose I have maybe one more question. I'm mindful of time. When we look, and I know the numbers are really small, we have to contextualize. We have to interpret the case on the small numbers. We have those really heavily pre-exposed childhood therapies getting those level of MRD negative responses, which I think are very encouraging. Choosing to have the OBR, also using alemtuzumab for some transplants that can be used to manage this infectious disease that are not that aggressive in terms of viral levels in the infectious patients here. choosing to have the obr also using alemtuzumab for some transplants that can be used to manage this infectious disease that are not that aggressive in terms of viral levels in the infectious patients here Of course, the organization of this is really important to explore this to those levels, and I think it was described by the agency that it seems wise, and I'm happy to go forward with this kind of questions. of course the organization of this is really important to explore this to those levels and i think it was described by the agency that it seems wise and i'm happy to go forward with this kind of questions I suppose I have maybe one more question. i suppose i have maybe one more question I'm mindful of time. i'm mindful of time When we look, and I know the numbers are really small, we have to contextualize. when we look and i know the numbers are really small we have to contextualize We have to interpret the case on the small numbers. we have to interpret the case on the small numbers We have those really heavily pre-exposed childhood therapies getting those level of MRD negative responses, which I think are very encouraging. we have those really heavily pre-exposed childhood therapies getting those level of mrd negative responses which i think are very encouraging But it would be great to get your insight into, based on your practice, what really would be the likely response rates for those patients with what's available to them beyond the next available salvage therapy, if at all? So maybe we'll start with you, Dr. Ramakrishnan. But it would be great to get your insight into, based on your practice, what really would be the likely response rates for those patients with what's available to them beyond the next available salvage therapy, if at all? but it would be great to get your insight into based on your practice what really would be the likely response rates for those patients with what's available to them beyond the next available salvage therapy if at all So maybe we'll start with you, Dr. Ramakrishnan. so maybe we'll start with you dr ramakrishnan

Speaker 3: So I think we're talking about patients who are still on trial lines of therapy and who have failed, obviously, chemotherapy, BlinCyto, and maybe a CD19 targeted therapy. I think that we are really, there is no proven available agents. I mean, chemotherapy at that time will have a less than 40% chance of response, additional chemotherapy, I mean, to say. And really, I think we're relying on some kind of a clinical trial, new drugs. And I think we're talking about, again, response rate. So hopefully, 20%-30% response rate where we hope, then we'll get MRD negative, and then they'll be transferred. So I think we're talking about patients who are still on trial lines of therapy and who have failed, obviously, chemotherapy, BlinCyto, and maybe a CD19 targeted therapy. so i think we're talking about patients who are still on trial lines of therapy and who have failed obviously chemotherapy blincyto and maybe a cd19 targeted therapy I think that we are really, there is no proven available agents. i think that we are really there is no proven available agents I mean, chemotherapy at that time will have a less than 40% chance of response, additional chemotherapy, I mean, to say. i mean chemotherapy at that time will have a less than 40% chance of response additional chemotherapy i mean to say And really, I think we're relying on some kind of a clinical trial, new drugs. and really i think we're relying on some kind of a clinical trial new drugs And I think we're talking about, again, response rate. and i think we're talking about again response rate So hopefully, 20%-30% response rate where we hope, then we'll get MRD negative, and then they'll be transferred. so hopefully 20%-30% response rate where we hope then we'll get mrd negative and then they'll be transferred So I think if we go, I think, and that's an important point. I think also I think the ALL, I think if you go four or five prior lines of therapy, these are really. I don't think there's anything standard here. And we're talking about really very reasonable outcomes for the project. So I think if we go, I think, and that's an important point. so i think if we go, i think and that's an important point I think also I think the ALL, I think if you go four or five prior lines of therapy, these are really. i think also i think the all i think if you go four or five prior lines of therapy these are really I don't think there's anything standard here. i don't think there's anything standard here And we're talking about really very reasonable outcomes for the project. and we're talking about really very reasonable outcomes for the project

Speaker 1: I would concur, I think. I typically, when I see these patients, do not recommend chemotherapy because the rates of response are going to be so low. We're always looking for a clinical trial for these patients. Usually, we don't have anything that's called NIPTN. And then the patient then try to get them on some sort of clinical trial. And that's. I can't emphasize how refractory this population is. And often, they're very young individuals also. So it's heartbreaking stories. For example, a 23-year-old girl with a 22-year-old. I would concur, I think. i would concur i think I typically, when I see these patients, do not recommend chemotherapy because the rates of response are going to be so low. i typically when i see these patients do not recommend chemotherapy because the rates of response are going to be so low We're always looking for a clinical trial for these patients. we're always looking for a clinical trial for these patients Usually, we don't have anything that's called NIPTN. usually we don't have anything that's called niptn And then the patient then try to get them on some sort of clinical trial. and then the patient then try to get them on some sort of clinical trial And that's. and that's I can't emphasize how refractory this population is. i can't emphasize how refractory this population is And often, they're very young individuals also. and often they're very young individuals also So it's heartbreaking stories. so it's heartbreaking stories For example, a 23-year-old girl with a 22-year-old. for example a 23-year-old girl with a 22-year-old And just imagine sitting in front of that person and telling them, "Yeah, we got nothing else." And to be able to take that type of individual and give them a product that gets them to MRD negative, gets them to transplant, it changes their life. She's now going to be able to raise her child. That's sort of, I think, why we all here do what we do. It's to make sure we make sure we have people. And just imagine sitting in front of that person and telling them, "Yeah, we got nothing else." And to be able to take that type of individual and give them a product that gets them to MRD negative, gets them to transplant, it changes their life. and just imagine sitting in front of that person and telling them "yeah we got nothing else." and to be able to take that type of individual and give them a product that gets them to mrd negative gets them to transplant it changes their life She's now going to be able to raise her child. she's now going to be able to raise her child That's sort of, I think, why we all here do what we do. that's sort of i think why we all here do what we do It's to make sure we make sure we have people. it's to make sure we make sure we have people

Speaker 3: Yeah. It's a good question. But I'm not surprised because other studies have shown that when you read the median of four lines and you compare less than four lines and more than four lines, you don't see any difference. So it's important for this group, of course, to move forward. Yeah. yeah It's a good question. it's a good question But I'm not surprised because other studies have shown that when you read the median of four lines and you compare less than four lines and more than four lines, you don't see any difference. but i'm not surprised because other studies have shown that when you read the median of four lines and you compare less than four lines and more than four lines you don't see any difference So it's important for this group, of course, to move forward. so it's important for this group of course to move forward And particularly, I come back to the MRD positive population of patients first, or also with several lines, because we have also this kind of patients in several lines. And we'd be very happy to see the results of this kind of study. I think they're built also for this kind of patient that, of course, we also use in a third of all of our patients right now. Well, thank you all for your insights. I'm going to ask one cheeky question of you, Dr. Ramakrishnan, because I know we didn't want to focus at all on 2022. But maybe for the audience, at least, just give your own view of how your patients are doing with it. What's your experience of it thus far. Again, the experience has been very positive so far. I think we are seeing more targeted therapies in lymphoma as well. And particularly, I come back to the MRD positive population of patients first, or also with several lines, because we have also this kind of patients in several lines. and particularly i come back to the mrd positive population of patients first or also with several lines because we have also this kind of patients in several lines And we'd be very happy to see the results of this kind of study. and we'd be very happy to see the results of this kind of study I think they're built also for this kind of patient that, of course, we also use in a third of all of our patients right now. i think they're built also for this kind of patient that of course we also use in a third of all of our patients right now Well, thank you all for your insights. well thank you all for your insights I'm going to ask one cheeky question of you, Dr. Ramakrishnan, because I know we didn't want to focus at all on 2022. i'm going to ask one cheeky question of you dr ramakrishnan because i know we didn't want to focus at all on 2022 But maybe for the audience, at least, just give your own view of how your patients are doing with it. but maybe for the audience at least just give your own view of how your patients are doing with it What's your experience of it thus far. what's your experience of it thus far Again, the experience has been very positive so far. again the experience has been very positive so far I think we are seeing more targeted therapies in lymphoma as well. i think we are seeing more targeted therapies in lymphoma as well We're seeing that clinical trials coming earlier in the line of treatments. But there is an unmet need there for patients who relapse. And again, I think one of the things about T-cell fitness, you kind of wonder in those patients whether how good were the T cells that we started off with for the CD19 CAR. And lymphoma is also, I think, a little bit different than ALL, where maybe we don't use the same duration of T-cell persistence maybe a couple of months. And we get a good response. We get rid of the lymphoma and get durable remission. So again, I think the product so far, we've been very happy with cell expansion and responses. Everyone I've treated has responded, which is very encouraging. Again, durability is, I guess, what we see in its early days, but also encouraging. We're seeing that clinical trials coming earlier in the line of treatments. we're seeing that clinical trials coming earlier in the line of treatments But there is an unmet need there for patients who relapse. but there is an unmet need there for patients who relapse And again, I think one of the things about T-cell fitness, you kind of wonder in those patients whether how good were the T cells that we started off with for the CD19 CAR. and again i think one of the things about t-cell fitness you kind of wonder in those patients whether how good were the t cells that we started off with for the cd19 car And lymphoma is also, I think, a little bit different than ALL, where maybe we don't use the same duration of T-cell persistence maybe a couple of months. and lymphoma is also i think a little bit different than all where maybe we don't use the same duration of t-cell persistence maybe a couple of months And we get a good response. and we get a good response We get rid of the lymphoma and get durable remission. we get rid of the lymphoma and get durable remission So again, I think the product so far, we've been very happy with cell expansion and responses. so again i think the product so far we've been very happy with cell expansion and responses Everyone I've treated has responded, which is very encouraging. everyone i've treated has responded which is very encouraging Again, durability is, I guess, what we see in its early days, but also encouraging. again durability is i guess what we see in its early days but also encouraging

Speaker 1: All right. All right. all right Thank you so much. It's a very short time. I would say thank you to our three investigators. Thank you for your. I'd like to hand over to Arthur Stril, Chief Financial Officer and Chief Business Officer. Thank you so much. thank you so much It's a very short time. it's a very short time I would say thank you to our three investigators. i would say thank you to our three investigators Thank you for your. thank you for your I'd like to hand over to Arthur Stril, Chief Financial Officer and Chief Business Officer. i'd like to hand over to arthur stril chief financial officer and chief business officer

Speaker 4: Thank you, Adrian. Good morning, everyone. Thank you so much for being here. None of what you've seen today and will see in the coming months would be possible without your support. Thank you so much for being here. I think as we have our BLA in line of sight, as Adrian has explained, it was a good time to discuss the commercial opportunity for UCART22. What are we talking about in terms of sales and commercial opportunity? Thank you, Adrian. thank you adrian Good morning, everyone. good morning everyone Thank you so much for being here. thank you so much for being here None of what you've seen today and will see in the coming months would be possible without your support. none of what you've seen today and will see in the coming months would be possible without your support Thank you so much for being here. thank you so much for being here I think as we have our BLA in line of sight, as Adrian has explained, it was a good time to discuss the commercial opportunity for UCART22. i think as we have our bla in line of sight as adrian has explained it was a good time to discuss the commercial opportunity for ucart22 What are we talking about in terms of sales and commercial opportunity? what are we talking about in terms of sales and commercial opportunity Now, if you have to take two takeaways from my presentation, the first one would be that this is a meaningful opportunity from a peak sales perspective, as you will see. But the second thing is that not all peak sales are created equal. There are peak sales from autologous therapies with razor-thin margins and individualized complicated therapies to scale. And there are peak sales coming from allogeneic therapies, which are true pharmaceutical off-the-shelf products that benefit from all the economies of scale that you've been used to in the antibody or small molecule world. And it is this kind of peak sales that Cellectis is bringing forward today. So you've heard a lot about this molecule. I'm not going to repeat too much. Now, if you have to take two takeaways from my presentation, the first one would be that this is a meaningful opportunity from a peak sales perspective, as you will see. now if you have to take two takeaways from my presentation the first one would be that this is a meaningful opportunity from a peak sales perspective as you will see But the second thing is that not all peak sales are created equal. but the second thing is that not all peak sales are created equal There are peak sales from autologous therapies with razor-thin margins and individualized complicated therapies to scale. there are peak sales from autologous therapies with razor-thin margins and individualized complicated therapies to scale And there are peak sales coming from allogeneic therapies, which are true pharmaceutical off-the-shelf products that benefit from all the economies of scale that you've been used to in the antibody or small molecule world. and there are peak sales coming from allogeneic therapies which are true pharmaceutical off-the-shelf products that benefit from all the economies of scale that you've been used to in the antibody or small molecule world And it is this kind of peak sales that Cellectis is bringing forward today. and it is this kind of peak sales that cellectis is bringing forward today So you've heard a lot about this molecule . so you've heard a lot about this molecule I'm not going to repeat too much. i'm not going to repeat too much But the differentiation of the CD22 approach, the fact that this is an allogeneic off-the-shelf therapy, the fact that we have truly internalized manufacturing, which will be highly beneficial for a fast uptake upon potential BLA approval, and of course, the highly attractive margins linked to the off-the-shelf allogeneic approach are key differentiators of this product. Now, we've talked a lot about the competitive landscape. Today, as you know, if you accept chemotherapies, the vast majority of therapies are targeting CD19, and there is a desperate need, we've heard it many times from our panelists, for another target. The only other product targeting CD22 is Besponsa, an ADC, so it doesn't truly benefit from the T-cell mechanism of action that you can see with CAR-T and T-cell engagers. But the differentiation of the CD22 approach, the fact that this is an allogeneic off-the-shelf therapy, the fact that we have truly internalized manufacturing, which will be highly beneficial for a fast uptake upon potential BLA approval, and of course, the highly attractive margins linked to the off-the-shelf allogeneic approach are key differentiators of this product. but the differentiation of the cd22 approach the fact that this is an allogeneic off-the-shelf therapy the fact that we have truly internalized manufacturing which will be highly beneficial for a fast uptake upon potential bla approval and of course the highly attractive margins linked to the off-the-shelf allogeneic approach are key differentiators of this product Now, we've talked a lot about the competitive landscape. now we've talked a lot about the competitive landscape Today, as you know, if you accept chemotherapies, the vast majority of therapies are targeting CD19, and there is a desperate need, we've heard it many times from our panelists, for another target. today as you know if you accept chemotherapies the vast majority of therapies are targeting cd19 and there is a desperate need we've heard it many times from our panelists for another target The only other product targeting CD22 is Besponsa, an ADC, so it doesn't truly benefit from the T-cell mechanism of action that you can see with CAR-T and T-cell engagers. the only other product targeting cd22 is besponsa an adc so it doesn't truly benefit from the t-cell mechanism of action that you can see with car-t and t-cell engagers And of course, the other therapies are leveraging the patient's own T cells, which can be really problematic, whereas UCART22 would be the only product to leverage off-the-shelf donor-derived T cells. So thinking a little bit when we start building the peak sales opportunity about the landscape, again, we heard it today from our panelists. Today, the majority of frontline patients are treated with chemotherapies. There's, of course, the arrival of Blincyto. We heard about its importance in the frontline consolidation, especially following the 2024 label expansion. In the second line, there's often multiple classes. We've heard about Blincyto. We've heard about, again, rounds of chemo. We've heard about Besponsa and auto-CD19. And physicians would generally alternate between these therapies. Starting from the third line, it starts breaking down, and efficacy is going lower and lower. And of course, the other therapies are leveraging the patient's own T cells, which can be really problematic, whereas UCART22 would be the only product to leverage off-the-shelf donor-derived T cells. and of course the other therapies are leveraging the patient's own t cells which can be really problematic whereas ucart22 would be the only product to leverage off-the-shelf donor-derived t cells So thinking a little bit when we start building the peak sales opportunity about the landscape, again, we heard it today from our panelists. so thinking a little bit when we start building the peak sales opportunity about the landscape again we heard it today from our panelists Today, the majority of frontline patients are treated with chemotherapies. today the majority of frontline patients are treated with chemotherapies There's, of course, the arrival of Blincyto. there's of course the arrival of blincyto We heard about its importance in the frontline consolidation, especially following the 2024 label expansion. we heard about its importance in the frontline consolidation especially following the 2024 label expansion In the second line, there's often multiple classes. in the second line there's often multiple classes We've heard about Blincyto. we've heard about blincyto We've heard about, again, rounds of chemo. we've heard about again rounds of chemo We've heard about Besponsa and auto-CD19. we've heard about besponsa and auto-cd19 And physicians would generally alternate between these therapies. and physicians would generally alternate between these therapies Starting from the third line, it starts breaking down, and efficacy is going lower and lower. starting from the third line it starts breaking down and efficacy is going lower and lower And of course, if you're going fourth line and beyond, as we've heard, especially from Professor Ramakrishnan, everything is becoming clinical trial. So really, the focus today, when you think about the first opportunity for this molecule, is going to be this third line and fourth line and below patient population. Now, how many patients are we talking about? So here, we're looking only about U.S., EU4, and U.K. And so we start with the incidence first line treated population. And this is projected to 2035, which is our year of expected peak sales. So we have about 9,200 patients, of which 5,100 in the U.S. and 4,100 in the EU4 plus U.K. Now, from these patients, we estimate that about 45% will go into the second line, mostly adolescents and adults, given the good outcome of treatments in children in the first line. And of course, if you're going fourth line and beyond, as we've heard, especially from Professor Ramakrishnan, everything is becoming clinical trial. and of course if you're going fourth line and beyond as we've heard especially from professor ramakrishnan everything is becoming clinical trial So really, the focus today, when you think about the first opportunity for this molecule , is going to be this third line and fourth line and below patient population. so really the focus today when you think about the first opportunity for this molecule is going to be this third line and fourth line and below patient population Now, how many patients are we talking about? now how many patients are we talking about So here, we're looking only about U.S., EU4, and U.K. so here we're looking only about u.s eu4 and u.k And so we start with the incidence first line treated population. and so we start with the incidence first line treated population And this is projected to 2035, which is our year of expected peak sales. and this is projected to 2035 which is our year of expected peak sales So we have about 9,200 patients, of which 5,100 in the U.S. and 4,100 in the EU4 plus U.K. so we have about 9,200 patients of which 5,100 in the u.s and 4,100 in the eu4 plus u.k Now, from these patients, we estimate that about 45% will go into the second line, mostly adolescents and adults, given the good outcome of treatments in children in the first line. now from these patients we estimate that about 45% will go into the second line mostly adolescents and adults given the good outcome of treatments in children in the first line So that brings it to about 3,900 patients treated in the second line setting. Moving from that second line setting, we expect that about two-thirds of patients will require further therapeutic intervention, which will bring you to about 2,700 patients in the third line setting. This is, of course, annual. And then finally, we apply a last cut-off for CAR-T eligibility, which would be about 70% based on the outcome we've seen with Auto-CAR-T. And this is mostly to take into account the patient fitness and comorbidities to account for eligibility for CAR-T. So our core target population in the U.S., EU4, and U.K. for the year of peak sales would be about 1,900 patients. Now, of course, this is the addressable market. And to get into peak sales, you have to have an estimate of what is going to be the preference for this molecule. So that brings it to about 3,900 patients treated in the second line setting. so that brings it to about 3,900 patients treated in the second line setting Moving from that second line setting, we expect that about two-thirds of patients will require further therapeutic intervention, which will bring you to about 2,700 patients in the third line setting. moving from that second line setting we expect that about two-thirds of patients will require further therapeutic intervention which will bring you to about 2,700 patients in the third line setting This is, of course, annual. this is of course annual And then finally, we apply a last cut-off for CAR-T eligibility, which would be about 70% based on the outcome we've seen with Auto-CAR-T. and then finally we apply a last cut-off for car-t eligibility which would be about 70% based on the outcome we've seen with auto-car-t And this is mostly to take into account the patient fitness and comorbidities to account for eligibility for CAR-T. and this is mostly to take into account the patient fitness and comorbidities to account for eligibility for car-t So our core target population in the U.S., EU4, and U.K. for the year of peak sales would be about 1,900 patients. so our core target population in the u.s eu4 and u.k for the year of peak sales would be about 1,900 patients Now, of course, this is the addressable market. now of course this is the addressable market And to get into peak sales, you have to have an estimate of what is going to be the preference for this molecule . and to get into peak sales you have to have an estimate of what is going to be the preference for this molecule So as you have heard during the panel from Adrian and our physician experts, we think that UCART22 will be a very promising opportunity for the third-line and above market. UCART22 is an alternative target to CD19. It benefits from the convenience of the one-off dosing. It's obviously an off-the-shelf availability, so no need for apheresis, no need to bring them to manufacturing, no need to have patients to go through bridging chemotherapy. It can be immediately available from the hospital pharmacy. And of course, as you have heard, we benefit from the deep MRD-negative responses in this therapy. So we estimate, based on oncology precedents, but also interviews from physicians, preferred market share of about 65% for this line of treatment. So as you have heard during the panel from Adrian and our physician experts, we think that UCART22 will be a very promising opportunity for the third-line and above market. so as you have heard during the panel from adrian and our physician experts we think that ucart22 will be a very promising opportunity for the third-line and above market UCART22 is an alternative target to CD19. ucart22 is an alternative target to cd19 It benefits from the convenience of the one-off dosing. it benefits from the convenience of the one-off dosing It's obviously an off-the-shelf availability, so no need for apheresis, no need to bring them to manufacturing, no need to have patients to go through bridging chemotherapy. it's obviously an off-the-shelf availability so no need for apheresis no need to bring them to manufacturing no need to have patients to go through bridging chemotherapy It can be immediately available from the hospital pharmacy. it can be immediately available from the hospital pharmacy And of course, as you have heard, we benefit from the deep MRD-negative responses in this therapy. and of course as you have heard we benefit from the deep mrd-negative responses in this therapy So we estimate, based on oncology precedents, but also interviews from physicians, preferred market share of about 65% for this line of treatment. so we estimate based on oncology precedents but also interviews from physicians preferred market share of about 65% for this line of treatment We think that the other therapies, be it because they target CD19, they're leveraging the patient's own T cells, or they have very limited efficacy and a high toxicity profile, the case for chemotherapy, as you have just heard, would not be the prominent therapies once UCART22 is approved. Second, we think that UCART22 has high pricing potential due to the unmet medical need it is going to solve. In Europe, we're being a bit conservative. So we're using the anchor price in 2025 of the average price of the approved therapies that's CAR-T and Kymriah. And we project a flat pricing until year of peak sales to 2035. So we have an anchor 2035 expected list price of about $365,000 for the EU. We think that the other therapies, be it because they target CD19, they're leveraging the patient's own T cells, or they have very limited efficacy and a high toxicity profile, the case for chemotherapy, as you have just heard, would not be the prominent therapies once UCART22 is approved. we think that the other therapies be it because they target cd19 they're leveraging the patient's own t cells or they have very limited efficacy and a high toxicity profile the case for chemotherapy as you have just heard would not be the prominent therapies once ucart22 is approved Second, we think that UCART22 has high pricing potential due to the unmet medical need it is going to solve. second we think that ucart22 has high pricing potential due to the unmet medical need it is going to solve In Europe, we're being a bit conservative. in europe we're being a bit conservative So we're using the anchor price in 2025 of the average price of the approved therapies that's CAR-T and Kymriah. so we're using the anchor price in 2025 of the average price of the approved therapies that's car-t and kymriah And we project a flat pricing until year of peak sales to 2035. and we project a flat pricing until year of peak sales to 2035 So we have an anchor 2035 expected list price of about $365,000 for the EU. so we have an anchor 2035 expected list price of about $365,000 for the eu In the U.S., we have looked at what has happened with the price of Kymriah, Yescarta, and the CAR-T, the three autologous CAR-Ts that were approved. The current anchor price for 2025 has been about $515,000, and we think we can apply a modest growth of 5% across all the way to peak sales in 2035, which is what has been seen in terms of pricing dynamics for the Auto-CAR-T since their approval, so we come to a 2035 expected anchor list price of about $840,000. Now, we are going to bring this all together, looking at the target patient population, the expected price, and the expected therapeutic need, so if you look at the initial addressable patients, you come back to about 1,900 patients, which is the number that came from the previous slide, about 1,100 in the U.S. and 840 in EU4 plus UK. In the U.S., we have looked at what has happened with the price of Kymriah, Yescarta, and the CAR-T, the three autologous CAR-Ts that were approved. in the u.s we have looked at what has happened with the price of kymriah yescarta and the car-t the three autologous car-ts that were approved The current anchor price for 2025 has been about $515,000, and we think we can apply a modest growth of 5% across all the way to peak sales in 2035, which is what has been seen in terms of pricing dynamics for the Auto-CAR-T since their approval, so we come to a 2035 expected anchor list price of about $840,000. the current anchor price for 2025 has been about $515,000 and we think we can apply a modest growth of 5% across all the way to peak sales in 2035 which is what has been seen in terms of pricing dynamics for the auto-car-t since their approval so we come to a 2035 expected anchor list price of about $840,000 Now, we are going to bring this all together, looking at the target patient population, the expected price, and the expected therapeutic need, so if you look at the initial addressable patients, you come back to about 1,900 patients, which is the number that came from the previous slide, about 1,100 in the U.S. and 840 in EU4 plus UK. now we are going to bring this all together looking at the target patient population the expected price and the expected therapeutic need so if you look at the initial addressable patients you come back to about 1,900 patients which is the number that came from the previous slide about 1,100 in the u.s and 840 in eu4 plus uk This is, of course, annual numbers. You apply the preference share of about 65% in this line. We still put a cut of 90% for market access of CAR-T therapies, which is standard for CAR-T therapies, which brings you to about 620 patients annually at year of peak sales for U.S. and 408 patients in EU4 plus U.K. Then finally, you apply gross pricing, which brings you to a 2035 expected potential peak gross sales of up to $700 million for the U.S., EU4, and U.K. And of course, this is excluding the rest of the world. We think this therapy will have also tremendous potential in other geographies, like the Asia-Pacific region, especially due to its off-the-shelf nature. But we've been conservative, and this up to $700 million is the figures for U.S., EU4, and U.K. This is, of course, annual numbers. this is of course annual numbers You apply the preference share of about 65% in this line. you apply the preference share of about 65% in this line We still put a cut of 90% for market access of CAR-T therapies, which is standard for CAR-T therapies, which brings you to about 620 patients annually at year of peak sales for U.S. and 408 patients in EU4 plus U.K. we still put a cut of 90% for market access of car-t therapies which is standard for car-t therapies which brings you to about 620 patients annually at year of peak sales for u.s and 408 patients in eu4 plus u.k Then finally, you apply gross pricing, which brings you to a 2035 expected potential peak gross sales of up to $700 million for the U.S., EU4, and U.K. then finally you apply gross pricing which brings you to a 2035 expected potential peak gross sales of up to $700 million for the u.s eu4 and u.k And of course, this is excluding the rest of the world. and of course this is excluding the rest of the world We think this therapy will have also tremendous potential in other geographies, like the Asia-Pacific region, especially due to its off-the-shelf nature. we think this therapy will have also tremendous potential in other geographies like the asia-pacific region especially due to its off-the-shelf nature But we've been conservative, and this up to $700 million is the figures for U.S., EU4, and U.K. but we've been conservative and this up to $700 million is the figures for u.s eu4 and u.k Now, of course, the core indication that Adrian has mentioned for our initial label will be third-line plus. But we think if the results hold in this first trial, we will have the potential to extend UCART22 in other areas. We think that UCART22 has the potential to have a place in the second line. And we think that UCART22 has the potential to have a place in first-line MRD-positive consolidation, pretty much like Blincyto, especially as you're going in earlier lines of treatments where patients are more fit. So if you're factoring an additional opportunity for these label extensions in the future, we believe that peak sales could increase to up to $1.3 billion with this additional label extension. To put it all together, we think that UCART22, again, has a very strong commercial opportunity. Now, of course, the core indication that Adrian has mentioned for our initial label will be third-line plus. now of course the core indication that adrian has mentioned for our initial label will be third-line plus But we think if the results hold in this first trial, we will have the potential to extend UCART22 in other areas. but we think if the results hold in this first trial we will have the potential to extend ucart22 in other areas We think that UCART22 has the potential to have a place in the second line. we think that ucart22 has the potential to have a place in the second line And we think that UCART22 has the potential to have a place in first-line MRD-positive consolidation, pretty much like Blincyto, especially as you're going in earlier lines of treatments where patients are more fit. and we think that ucart22 has the potential to have a place in first-line mrd-positive consolidation pretty much like blincyto especially as you're going in earlier lines of treatments where patients are more fit So if you're factoring an additional opportunity for these label extensions in the future, we believe that peak sales could increase to up to $1.3 billion with this additional label extension. so if you're factoring an additional opportunity for these label extensions in the future we believe that peak sales could increase to up to $1.3 billion with this additional label extension To put it all together, we think that UCART22, again, has a very strong commercial opportunity. to put it all together we think that ucart22 again has a very strong commercial opportunity It has the potential to be the first-in-class immunotherapy beyond CD19, and we think that what will especially drive adoption, as we have heard today, is the deep responses with high CR rates and the impressive MRD negativity that you've seen. We believe that there is a robust peak sales potential of up to $700 million in the first indication that we have, and again, very importantly, with the allogeneic approach, this is not just about peak sales, but this will be about EBITDA, and this is true pharmaceutical EBITDA, not autologous EBITDA, and we think that the industrialized off-the-shelf approach with the internalized manufacturing is going to be critical for launch and commercial success as we go into the third. Thank you very much for your attention, and I will hand it back to André for the next slide. It has the potential to be the first-in-class immunotherapy beyond CD19, and we think that what will especially drive adoption, as we have heard today, is the deep responses with high CR rates and the impressive MRD negativity that you've seen. it has the potential to be the first-in-class immunotherapy beyond cd19 and we think that what will especially drive adoption as we have heard today is the deep responses with high cr rates and the impressive mrd negativity that you've seen We believe that there is a robust peak sales potential of up to $700 million in the first indication that we have, and again, very importantly, with the allogeneic approach, this is not just about peak sales, but this will be about EBITDA, and this is true pharmaceutical EBITDA , not autologous EBITDA , and we think that the industrialized off-the-shelf approach with the internalized manufacturing is going to be critical for launch and commercial success as we go into the third. we believe that there is a robust peak sales potential of up to $700 million in the first indication that we have and again very importantly with the allogeneic approach this is not just about peak sales but this will be about ebitda and this is true pharmaceutical ebitda not autologous ebitda and we think that the industrialized off-the-shelf approach with the internalized manufacturing is going to be critical for launch and commercial success as we go into the third Thank you very much for your attention, and I will hand it back to André for the next slide. thank you very much for your attention and i will hand it back to andré for the next slide

Speaker 2: Thank you very much, Arthur. Thank you very much, Arthur. thank you very much arthur And thank you very much for your attention. So I'm going to share the paper with my glasses. Because I would like to introduce our speaker, next speaker. So I probably told you you never had an opportunity to present in front of this type of audience that told him that you're a very friendly audience. So it's my great honor to introduce one of our distinguished speakers, Dr. Mark Cobbold. So Dr. Cobbold is a physician scientist and immunologist with a remarkable career at the interface of discovery and translation. From his first time at the University of Birmingham in Massachusets General Hospital, correct me if I'm wrong, where he made important advances in tumor immunology and immune control. His current role is Vice President, Early Oncology and Immunology Translational Medicine at AstraZeneca. And thank you very much for your attention. and thank you very much for your attention So I'm going to share the paper with my glasses. so i'm going to share the paper with my glasses Because I would like to introduce our speaker, next speaker. because i would like to introduce our speaker next speaker So I probably told you you never had an opportunity to present in front of this type of audience that told him that you're a very friendly audience. so i probably told you you never had an opportunity to present in front of this type of audience that told him that you're a very friendly audience So it's my great honor to introduce one of our distinguished speakers, Dr. Mark Cobbold. so it's my great honor to introduce one of our distinguished speakers dr mark cobbold So Dr. Cobbold is a physician scientist and immunologist with a remarkable career at the interface of discovery and translation. so dr cobbold is a physician scientist and immunologist with a remarkable career at the interface of discovery and translation From his first time at the University of Birmingham in Massachusets General Hospital, correct me if I'm wrong, where he made important advances in tumor immunology and immune control. from his first time at the university of birmingham in massachusets general hospital correct me if i'm wrong where he made important advances in tumor immunology and immune control His current role is Vice President, Early Oncology and Immunology Translational Medicine at AstraZeneca. his current role is vice president early oncology and immunology translational medicine at astrazeneca He has dedicated his career to turning bold scientific ideas into therapies that change patient lives. You know how it works in this space, actually. We buy big companies. We're super impressed by a big pharma company because we're big, so plenty of money, et cetera. But we're usually super arrogant when we interact with them in terms of innovation, like crazy ideas, et cetera. We think we have it all. And the first time I've met with Mark and started discussing with him, seriously, that's where humility comes back to you. It's our privilege normally to be there. Maybe these guys, this guy, it's such a brain and so much disruptive with his ideas that I was really blown out. He has dedicated his career to turning bold scientific ideas into therapies that change patient lives. he has dedicated his career to turning bold scientific ideas into therapies that change patient lives You know how it works in this space, actually. you know how it works in this space actually We buy big companies. we buy big companies We're super impressed by a big pharma company because we're big, so plenty of money, et cetera. we're super impressed by a big pharma company because we're big so plenty of money et cetera But we're usually super arrogant when we interact with them in terms of innovation, like crazy ideas, et cetera. but we're usually super arrogant when we interact with them in terms of innovation like crazy ideas et cetera We think we have it all. we think we have it all And the first time I've met with Mark and started discussing with him, seriously, that's where humility comes back to you. and the first time i've met with mark and started discussing with him seriously that's where humility comes back to you It's our privilege normally to be there. it's our privilege normally to be there Maybe these guys, this guy, it's such a brain and so much disruptive with his ideas that I was really blown out. maybe these guys this guy it's such a brain and so much disruptive with his ideas that i was really blown out And since we started the collaboration I think two years ago, seriously, the level of sophistication and technology that we're bringing inside Cobbold's, I think this is going to be a big game changer. And the fact that AstraZeneca, the leadership of AstraZeneca, is so much putting emphasis on the fact of making these therapies functional, accessible to all patients, and also totally disruptive come from people such as Mark. It's going to make a presentation here. And I think that in the coming future, not so far, but a few months or so years that are coming, you will see a series of disruptive technology coming in the clinic and changing totally the game. And since we started the collaboration I think two years ago, seriously, the level of sophistication and technology that we're bringing inside Cobbold's, I think this is going to be a big game changer. and since we started the collaboration i think two years ago seriously the level of sophistication and technology that we're bringing inside cobbold's i think this is going to be a big game changer And the fact that AstraZeneca, the leadership of AstraZeneca, is so much putting emphasis on the fact of making these therapies functional, accessible to all patients, and also totally disruptive come from people such as Mark. and the fact that astrazeneca the leadership of astrazeneca is so much putting emphasis on the fact of making these therapies functional accessible to all patients and also totally disruptive come from people such as mark It's going to make a presentation here. it's going to make a presentation here And I think that in the coming future, not so far, but a few months or so years that are coming, you will see a series of disruptive technology coming in the clinic and changing totally the game. and i think that in the coming future not so far but a few months or so years that are coming you will see a series of disruptive technology coming in the clinic and changing totally the game Now, if you want to ask me what's going to happen, molecular medicine, and especially in vivo gene therapies that we're developing also with AstraZeneca are going to be a huge revolution in the field of medicine in general. A lot of people are going to have different types of treatment, single injection, and then they will go back home with a differentiation in their way of life, and really, something that will be very appreciated. With that, I would like to hand it to Mark. So Mark, you're very welcome. Now, if you want to ask me what's going to happen, molecular medicine, and especially in vivo gene therapies that we're developing also with AstraZeneca are going to be a huge revolution in the field of medicine in general. now if you want to ask me what's going to happen molecular medicine and especially in vivo gene therapies that we're developing also with astrazeneca are going to be a huge revolution in the field of medicine in general A lot of people are going to have different types of treatment, single injection, and then they will go back home with a differentiation in their way of life, and really, something that will be very appreciated. a lot of people are going to have different types of treatment single injection and then they will go back home with a differentiation in their way of life and really something that will be very appreciated With that, I would like to hand it to Mark. with that i would like to hand it to mark So Mark, you're very welcome. so mark you're very welcome

Speaker 6: Thank you. I'm very proud. Thank you for the introduction. Yeah, it's a great pleasure to be here, actually. This is a great first presentation for that, so you guys are not the only people who are going to be there for them too, but I'll be there to go. Thank you. thank you I'm very proud. i'm very proud Thank you for the introduction. thank you for the introduction Yeah, it's a great pleasure to be here, actually. yeah it's a great pleasure to be here actually This is a great first presentation for that, so you guys are not the only people who are going to be there for them too, but I'll be there to go. this is a great first presentation for that so you guys are not the only people who are going to be there for them too but i'll be there to go I've been in South America for 25 years, actually, with my PhD, so I've worked with like 20,000. Yeah, it's just a real privilege to see where this technology is going and where it's going in the future. I believe we've just got started. This is a very exciting space. Yeah, let me tell you a little bit about what we're doing actually for the clinic. I guess most of you here will know this, but cell therapy is sort of transforming medicine. There's a lot of very, very significant personalized therapy. It's sort of one-and-done treatment for patients. It has very deep, durable responses. It's a new orthopod treatment that doesn't have any gross flexibility with chemo resistance, for instance. I've been in South America for 25 years, actually, with my PhD, so I've worked with like 20,000. i've been in south america for 25 years actually with my phd so i've worked with like 20,000 Yeah, it's just a real privilege to see where this technology is going and where it's going in the future. yeah it's just a real privilege to see where this technology is going and where it's going in the future I believe we've just got started. i believe we've just got started This is a very exciting space. this is a very exciting space Yeah, let me tell you a little bit about what we're doing actually for the clinic. yeah let me tell you a little bit about what we're doing actually for the clinic I guess most of you here will know this, but cell therapy is sort of transforming medicine. i guess most of you here will know this but cell therapy is sort of transforming medicine There's a lot of very, very significant personalized therapy. there's a lot of very very significant personalized therapy It's sort of one-and-done treatment for patients. it's sort of one-and-done treatment for patients It has very deep, durable responses. it has very deep durable responses It's a new orthopod treatment that doesn't have any gross flexibility with chemo resistance, for instance. it's a new orthopod treatment that doesn't have any gross flexibility with chemo resistance for instance You can see on the right-hand side, there's been an enormous investment, I guess recognized by many others over the years in terms of this space. And that's brought us to where we are today, where we've got six approved CAR-T products. We've got one off-the-shelf therapy. And so we're living in an age of living medicine today. And these are genuinely transforming medicine for patient lives. But there's a lot more to go. And you can see why cell therapy is so exciting. On the left-hand side, you can see those six autologous CAR-T programs that are approved. And you can see the levels of overall response rate, particularly the lead response rates, are very, very high. And this is, perhaps the previous speakers have highlighted, with patients who are extremely multiply refractory. So you don't typically see this level of response. You can see on the right-hand side, there's been an enormous investment, I guess recognized by many others over the years in terms of this space. you can see on the right-hand side there's been an enormous investment i guess recognized by many others over the years in terms of this space And that's brought us to where we are today, where we've got six approved CAR-T products. and that's brought us to where we are today where we've got six approved car-t products We've got one off-the-shelf therapy. we've got one off-the-shelf therapy And so we're living in an age of living medicine today. and so we're living in an age of living medicine today And these are genuinely transforming medicine for patient lives. and these are genuinely transforming medicine for patient lives But there's a lot more to go. but there's a lot more to go And you can see why cell therapy is so exciting. and you can see why cell therapy is so exciting On the left-hand side, you can see those six autologous CAR-T programs that are approved. on the left-hand side you can see those six autologous car-t programs that are approved And you can see the levels of overall response rate, particularly the lead response rates, are very, very high. and you can see the levels of overall response rate particularly the lead response rates are very very high And this is, perhaps the previous speakers have highlighted, with patients who are extremely multiply refractory. and this is perhaps the previous speakers have highlighted with patients who are extremely multiply refractory So you don't typically see this level of response. so you don't typically see this level of response And on the right-hand side, you can see the other reason why everyone is excited is the tail. You look at the tail, and this is data from 2021, actually, from Kymriah, and you can see that there is a very, very significant durability. Now, there are very definitely some challenges ahead, particularly as we extend this autologous tumor to more refractory phase. But these therapies are delivering to patients with a quite transformative outcome, and so in terms of how we can drive more clinical benefit across patients and autologous, a number of challenges out there. We've seen that these are giving rise to deep and durable responses. There's a very great flow of money into this other space as it has a field. But there's a lot of challenges that remain, and I think that's where allogeneic CAR-Ts present an opportunity. And on the right-hand side, you can see the other reason why everyone is excited is the tail. and on the right-hand side you can see the other reason why everyone is excited is the tail You look at the tail, and this is data from 2021, actually, from Kymriah, and you can see that there is a very, very significant durability. you look at the tail and this is data from 2021 actually from kymriah and you can see that there is a very very significant durability Now, there are very definitely some challenges ahead, particularly as we extend this autologous tumor to more refractory phase. now there are very definitely some challenges ahead particularly as we extend this autologous tumor to more refractory phase But these therapies are delivering to patients with a quite transformative outcome, and so in terms of how we can drive more clinical benefit across patients and autologous, a number of challenges out there. but these therapies are delivering to patients with a quite transformative outcome and so in terms of how we can drive more clinical benefit across patients and autologous a number of challenges out there We've seen that these are giving rise to deep and durable responses. we've seen that these are giving rise to deep and durable responses There's a very great flow of money into this other space as it has a field. there's a very great flow of money into this other space as it has a field But there's a lot of challenges that remain, and I think that's where allogeneic CAR-Ts present an opportunity. but there's a lot of challenges that remain and i think that's where allogeneic car-ts present an opportunity We need to get adequate assistance for these CAR-Ts to live life for longer. In many clinical studies, the CAR-T don't stand well. They don't live for the system too long. I think anything currently at this should be a fairly expert site. I think that's what we need to resolve, so we've given more widely and scalability, but really isn't today enough manufacturing to actually deploy these therapies, especially to be there. In fact, as more indications get seed approvals, particularly as we're going to see approvals in the autoimmune space, it's very difficult to sort of see the current structure of the next scope for that, so it's important that we think about technology and the ability to scale as much as possible. We need to get adequate assistance for these CAR-Ts to live life for longer. we need to get adequate assistance for these car-ts to live life for longer In many clinical studies, the CAR-T don't stand well. in many clinical studies the car-t don't stand well They don't live for the system too long. they don't live for the system too long I think anything currently at this should be a fairly expert site. i think anything currently at this should be a fairly expert site I think that's what we need to resolve, so we've given more widely and scalability, but really isn't today enough manufacturing to actually deploy these therapies, especially to be there. i think that's what we need to resolve so we've given more widely and scalability but really isn't today enough manufacturing to actually deploy these therapies especially to be there In fact, as more indications get seed approvals, particularly as we're going to see approvals in the autoimmune space, it's very difficult to sort of see the current structure of the next scope for that, so it's important that we think about technology and the ability to scale as much as possible. in fact as more indications get seed approvals particularly as we're going to see approvals in the autoimmune space it's very difficult to sort of see the current structure of the next scope for that so it's important that we think about technology and the ability to scale as much as possible So in terms of our journey as a company for cell therapy, it really started with when José Baselga came and joined from New York from Sloan Kettering. And Sloan Kettering did see the transformative potential of CAR-Ts that were on the borders of gene. So the one thing he did when he arrived at AstraZeneca was saying, "We've got to bring cell therapy into industrial engine." And that was a very significant challenge. Because back in 2016, certainly, there wasn't a great deal of belief that this was a viable proposition for pharmaceutical companies. And I'm very pleased that over five years, which we started the cell therapy at the end of 2019, beginning of 2020, I think now actually we're going to get very, very much cell therapy. It's an absolute critical part of medicines and patients with neuronal cancer problems in the autoimmune disease space. So in terms of our journey as a company for cell therapy, it really started with when José Baselga came and joined from New York from Sloan Kettering. so in terms of our journey as a company for cell therapy it really started with when josé baselga came and joined from new york from sloan kettering And Sloan Kettering did see the transformative potential of CAR-Ts that were on the borders of gene. and sloan kettering did see the transformative potential of car-ts that were on the borders of gene So the one thing he did when he arrived at AstraZeneca was saying, "We've got to bring cell therapy into industrial engine." And that was a very significant challenge. so the one thing he did when he arrived at astrazeneca was saying "we've got to bring cell therapy into industrial engine." and that was a very significant challenge Because back in 2016, certainly, there wasn't a great deal of belief that this was a viable proposition for pharmaceutical companies. because back in 2016 certainly there wasn't a great deal of belief that this was a viable proposition for pharmaceutical companies And I'm very pleased that over five years, which we started the cell therapy at the end of 2019, beginning of 2020, I think now actually we're going to get very, very much cell therapy. and i'm very pleased that over five years which we started the cell therapy at the end of 2019 beginning of 2020 i think now actually we're going to get very very much cell therapy It's an absolute critical part of medicines and patients with neuronal cancer problems in the autoimmune disease space. it's an absolute critical part of medicines and patients with neuronal cancer problems in the autoimmune disease space And you can see we've built very aggressively over those five years. We started our CAR-T program. We had no manufacturing. And so one of the things we did was adapt to the pandemic to deal with is how do we actually start. Right. So we partnered with the company called CBMG, which has now renamed itself into AbelZeta. And they've been the number one partners for us. And now they're starting our first CAR-T program, starting with a three cellular cross-member into an RNG space. That's what we've done. In 2022, we acquired a company called Neogene Therapeutics, which allowed us to get into intracellular oncology targets by acquiring Neogene based on AstraZeneca and cell manufacturing. And that company brought us two things. One is the TCR-T technology, which also actually gave us a significant manufacturing footprint. And you can see we've built very aggressively over those five years. and you can see we've built very aggressively over those five years We started our CAR-T program. we started our car-t program We had no manufacturing. we had no manufacturing And so one of the things we did was adapt to the pandemic to deal with is how do we actually start. and so one of the things we did was adapt to the pandemic to deal with is how do we actually start Right. right So we partnered with the company called CBMG, which has now renamed itself into AbelZeta. so we partnered with the company called cbmg which has now renamed itself into abelzeta And they've been the number one partners for us. and they've been the number one partners for us And now they're starting our first CAR-T program, starting with a three cellular cross-member into an RNG space. and now they're starting our first car-t program starting with a three cellular cross-member into an rng space That's what we've done. that's what we've done In 2022, we acquired a company called Neogene Therapeutics, which allowed us to get into intracellular oncology targets by acquiring Neogene based on AstraZeneca and cell manufacturing. in 2022 we acquired a company called neogene therapeutics which allowed us to get into intracellular oncology targets by acquiring neogene based on astrazeneca and cell manufacturing And that company brought us two things. and that company brought us two things One is the TCR-T technology, which also actually gave us a significant manufacturing footprint. one is the tcr-t technology which also actually gave us a significant manufacturing footprint So now we have much upscaled ability for cell therapy for the clients. We announced a partnership in 2023 for Quell Therapeutics, exploring RNA breaks for a number of conservative therapeutics and immune diseases. And then one of the big ones was with Cellectis. We announced an acquisition. We had a partnership with Cellectis. Also, an investment in Cellectis. And we really felt that Cellectis had the depth of knowledge and more than 10 years' experience. Cell therapy would be an excellent partner. And really, it's been an absolute pleasure working with Cellectis team over the past few years. And we've introduced a really, I think, quite significant work together, actually. That's going to make a very much more difference. You can see since then, we've got even more enthusiasm about cell therapy. We were the first pharma company to acquire biotech company in China. So now we have much upscaled ability for cell therapy for the clients. so now we have much upscaled ability for cell therapy for the clients We announced a partnership in 2023 for Quell Therapeutics, exploring RNA breaks for a number of conservative therapeutics and immune diseases. we announced a partnership in 2023 for quell therapeutics exploring rna breaks for a number of conservative therapeutics and immune diseases And then one of the big ones was with Cellectis. and then one of the big ones was with cellectis We announced an acquisition. we announced an acquisition We had a partnership with Cellectis. we had a partnership with cellectis Also, an investment in Cellectis. also an investment in cellectis And we really felt that Cellectis had the depth of knowledge and more than 10 years' experience. and we really felt that cellectis had the depth of knowledge and more than 10 years' experience Cell therapy would be an excellent partner. cell therapy would be an excellent partner And really, it's been an absolute pleasure working with Cellectis team over the past few years. and really it's been an absolute pleasure working with cellectis team over the past few years And we've introduced a really, I think, quite significant work together, actually. and we've introduced a really i think quite significant work together actually That's going to make a very much more difference. that's going to make a very much more difference You can see since then, we've got even more enthusiasm about cell therapy. you can see since then we've got even more enthusiasm about cell therapy We were the first pharma company to acquire biotech company in China. we were the first pharma company to acquire biotech company in china We acquired Gracell Biotechnologies and therefore Behavior and that put together a three. And that's given us access to China normally, actually, since it's acquired that company. And it's also given us a different process that they've come up with the past two process, which actually is extremely important for how I think we've become clear with time. And then in terms of manufacturing, we acquired a manufacturing associate who was previously owned by autologous and cell therapeutics in Rockville, Maryland. We announced a key collaboration with the Roswell Park Cancer Center before. And then most recently, we've acquired a small proposal drive, so it's a biotech that has the first of the data on in vivo shots of cell space for cell therapy for our vector. And that, again, has been a very good collaboration with the scientists there. We acquired Gracell Biotechnologies and therefore Behavior and that put together a three. we acquired gracell biotechnologies and therefore behavior and that put together a three And that's given us access to China normally, actually, since it's acquired that company. and that's given us access to china normally actually since it's acquired that company And it's also given us a different process that they've come up with the past two process, which actually is extremely important for how I think we've become clear with time. and it's also given us a different process that they've come up with the past two process which actually is extremely important for how i think we've become clear with time And then in terms of manufacturing, we acquired a manufacturing associate who was previously owned by autologous and cell therapeutics in Rockville, Maryland. and then in terms of manufacturing we acquired a manufacturing associate who was previously owned by autologous and cell therapeutics in rockville maryland We announced a key collaboration with the Roswell Park Cancer Center before. we announced a key collaboration with the roswell park cancer center before And then most recently, we've acquired a small proposal drive, so it's a biotech that has the first of the data on in vivo shots of cell space for cell therapy for our vector. and then most recently we've acquired a small proposal drive so it's a biotech that has the first of the data on in vivo shots of cell space for cell therapy for our vector And that, again, has been a very good collaboration with the scientists there. and that again has been a very good collaboration with the scientists there And it gives us the ability to scale in vivo therapy. So that's our journey. And in terms of what we're doing with our overall strategy, we're exploring multiple approaches in this space. So we're investing in TCRT, investing in CAR-T, we're investing in CAR-T rates, investing aggressively in off-the-shelf technologies, including in vivo therapy. And in terms of the portfolio on the right-hand side, you can see we've got quite a substantial share over the past few years. And actually, the portfolio you can't see is actually fairly large, which I'm very, very excited about. So there'll be many more things to hear about in the next coming years. But I'll just talk to the portfolio very, very, very quickly. We've got AZD0120, which is an anti-fast car, Gracell, which we've got actively in the ground for myeloma. And it gives us the ability to scale in vivo therapy. and it gives us the ability to scale in vivo therapy So that's our journey. so that's our journey And in terms of what we're doing with our overall strategy, we're exploring multiple approaches in this space. and in terms of what we're doing with our overall strategy we're exploring multiple approaches in this space So we're investing in TCRT, investing in CAR-T, we're investing in CAR-T rates, investing aggressively in off-the-shelf technologies, including in vivo therapy. so we're investing in tcrt investing in car-t we're investing in car-t rates investing aggressively in off-the-shelf technologies including in vivo therapy And in terms of the portfolio on the right-hand side, you can see we've got quite a substantial share over the past few years. and in terms of the portfolio on the right-hand side you can see we've got quite a substantial share over the past few years And actually, the portfolio you can't see is actually fairly large, which I'm very, very excited about. and actually the portfolio you can't see is actually fairly large which i'm very very excited about So there'll be many more things to hear about in the next coming years. so there'll be many more things to hear about in the next coming years But I'll just talk to the portfolio very, very, very quickly. but i'll just talk to the portfolio very very very quickly We've got AZD0120, which is an anti-fast car, Gracell, which we've got actively in the ground for myeloma. we've got azd0120 which is an anti-fast car gracell which we've got actively in the ground for myeloma And then also for autoimmune diseases, the GC012F to get the beta-armored CAR-T in China and also in the rest of the world. These are 703, you know, STEEP2 armored CAR-T, prostate cancer within 0.0754. And then we have a series of TCRT trials targeting driver mutations in cancer. And these are likely going off more genotypes. So there's a graphic of these as well. And then in terms of what our global footprint is going to be, including our tie-in with Cellectis, you can see going from west to east that we have now two manufacturing sites on the west coast, one in South America, one in nearby Teltani. We have in Maryland, this is Rockville. And then next is Cellectis, which they manufacture in North Carolina. We have a research base in Gaithersburg in Maryland. And then also for autoimmune diseases, the GC012F to get the beta-armored CAR-T in China and also in the rest of the world. and then also for autoimmune diseases the gc012f to get the beta-armored car-t in china and also in the rest of the world These are 703, you know, STEEP2 armored CAR-T, prostate cancer within 0.0754. these are 703 you know steep2 armored car-t prostate cancer within 0.0754 And then we have a series of TCRT trials targeting driver mutations in cancer. and then we have a series of tcrt trials targeting driver mutations in cancer And these are likely going off more genotypes. and these are likely going off more genotypes So there's a graphic of these as well. so there's a graphic of these as well And then in terms of what our global footprint is going to be, including our tie-in with Cellectis, you can see going from west to east that we have now two manufacturing sites on the west coast, one in South America, one in nearby Teltani. and then in terms of what our global footprint is going to be including our tie-in with cellectis you can see going from west to east that we have now two manufacturing sites on the west coast one in south america one in nearby teltani We have in Maryland, this is Rockville. we have in maryland this is rockville And then next is Cellectis, which they manufacture in North Carolina. and then next is cellectis which they manufacture in north carolina We have a research base in Gaithersburg in Maryland. we have a research base in gaithersburg in maryland We also have, as I saw on the map, we also have two sites in Boston, one in Waltham and one in the Lexington Seaport, and we'll have a large RNA test for next year in Kendall Square, which is very significantly actually driving research and expectancies of cell therapy, sorry, brush, so that will include cell therapy, particularly cell therapy for autoimmunities, and then we've got a clinical site for RNA cyclical, which is the post-processed lipids, actually, which were in the same building, and Europe, we've got sites, again, starting with the next four sites in Paris that manufacture various components. We have our R&D site in Cambridge, and we have a significant number of cell therapy corporations. We have a site in Amsterdam. Yeah, is that clear? In Amsterdam, which is predominantly research. We have a facility now in Brussels, pretty surprising. We also have, as I saw on the map, we also have two sites in Boston, one in Waltham and one in the Lexington Seaport, and we'll have a large RNA test for next year in Kendall Square, which is very significantly actually driving research and expectancies of cell therapy, sorry, brush, so that will include cell therapy, particularly cell therapy for autoimmunities, and then we've got a clinical site for RNA cyclical, which is the post-processed lipids, actually, which were in the same building, and Europe, we've got sites, again, starting with the next four sites in Paris that manufacture various components. we also have as i saw on the map we also have two sites in boston one in waltham and one in the lexington seaport and we'll have a large rna test for next year in kendall square which is very significantly actually driving research and expectancies of cell therapy sorry brush so that will include cell therapy particularly cell therapy for autoimmunities and then we've got a clinical site for rna cyclical which is the post-processed lipids actually which were in the same building and europe we've got sites again starting with the next four sites in paris that manufacture various components We have our R&D site in Cambridge, and we have a significant number of cell therapy corporations. we have our r&d site in cambridge and we have a significant number of cell therapy corporations We have a site in Amsterdam. we have a site in amsterdam Yeah, is that clear? yeah is that clear In Amsterdam, which is predominantly research. in amsterdam which is predominantly research We have a facility now in Brussels, pretty surprising. we have a facility now in brussels pretty surprising And then as we head to China, we have a number of facilities in Suzhou, which are manufacturing facilities. And then we've got a number of sites in Shanghai for the research and development, as well as partnership with AbelZeta. We think this allows us to operate globally. It also allows us to get in and test trials very rapidly in our systems, which allows us to learn quickly. So that is something that's good. And then in terms of why Cellectis, why is this such a strategic big force to us? And really, I think there's a number of reasons. Going from left to right, we have the technologies, we have the capabilities, and we have the capacities. And so Cellectis brings with us more than nearly 20 years of molecular understanding of gene modification. And then as we head to China, we have a number of facilities in Suzhou, which are manufacturing facilities. and then as we head to china we have a number of facilities in suzhou which are manufacturing facilities And then we've got a number of sites in Shanghai for the research and development, as well as partnership with AbelZeta. and then we've got a number of sites in shanghai for the research and development as well as partnership with abelzeta We think this allows us to operate globally. we think this allows us to operate globally It also allows us to get in and test trials very rapidly in our systems, which allows us to learn quickly. it also allows us to get in and test trials very rapidly in our systems which allows us to learn quickly So that is something that's good. so that is something that's good And then in terms of why Cellectis, why is this such a strategic big force to us? and then in terms of why cellectis why is this such a strategic big force to us And really, I think there's a number of reasons. and really i think there's a number of reasons Going from left to right, we have the technologies, we have the capabilities, and we have the capacities. going from left to right we have the technologies we have the capabilities and we have the capacities And so Cellectis brings with us more than nearly 20 years of molecular understanding of gene modification. and so cellectis brings with us more than nearly 20 years of molecular understanding of gene modification And so enormous, a very deep understanding of how you can manipulate the genome of cells with our advanced capabilities. Cellectis are amazing process development. We've seen the shift with process monitoring tools, which is so important in terms of the cell therapy analytics for development, CMC, GMP capabilities, clinical regulatory gene editing expertise, the ability to really define exactly how to knock out on-target genes. Very exciting. I've been blown away by their technologies. And 10 years of experience. That's about the next-day delivery of cells. And that's really one of the toughest spaces in cell therapy. But the last few years have really shown that the field is really starting to make a significant amount of progress. And in terms of capacities, the Paris site's got fantastic manufacturing. And so enormous, a very deep understanding of how you can manipulate the genome of cells with our advanced capabilities. and so enormous a very deep understanding of how you can manipulate the genome of cells with our advanced capabilities Cellectis are amazing process development. cellectis are amazing process development We've seen the shift with process monitoring tools, which is so important in terms of the cell therapy analytics for development, CMC, GMP capabilities, clinical regulatory gene editing expertise, the ability to really define exactly how to knock out on-target genes. we've seen the shift with process monitoring tools which is so important in terms of the cell therapy analytics for development cmc gmp capabilities clinical regulatory gene editing expertise the ability to really define exactly how to knock out on-target genes Very exciting. very exciting I've been blown away by their technologies. i've been blown away by their technologies And 10 years of experience. and 10 years of experience That's about the next-day delivery of cells. that's about the next-day delivery of cells And that's really one of the toughest spaces in cell therapy. and that's really one of the toughest spaces in cell therapy But the last few years have really shown that the field is really starting to make a significant amount of progress. but the last few years have really shown that the field is really starting to make a significant amount of progress And in terms of capacities, the Paris site's got fantastic manufacturing. and in terms of capacities the paris site's got fantastic manufacturing I think the facilities to complement Raleigh where the cells are made in New York as the origin site. So again, partners for us. But I think as we sort of join forces, I think this is an area where it's a win-win for both. Almost French blend, and then in terms of where we're seeing, and this is the slide I'm most excited by, you can see where we're going. I'm not going to discuss too much as to what we're doing, but this will give you a bit of a hint of what we're doing. So you can see the autologous paradigm, which is really where cell therapy is showing that they're capable. It's a fantastic time for technology. They're not particularly stable. Then we have our classic allogeneic CAR-T that will allow you to scale to a much greater extent. I think the facilities to complement Raleigh where the cells are made in New York as the origin site. i think the facilities to complement raleigh where the cells are made in new york as the origin site So again, partners for us. so again partners for us But I think as we sort of join forces, I think this is an area where it's a win-win for both. but i think as we sort of join forces i think this is an area where it's a win-win for both Almost French blend, and then in terms of where we're seeing, and this is the slide I'm most excited by, you can see where we're going. almost french blend and then in terms of where we're seeing and this is the slide i'm most excited by you can see where we're going I'm not going to discuss too much as to what we're doing, but this will give you a bit of a hint of what we're doing. i'm not going to discuss too much as to what we're doing but this will give you a bit of a hint of what we're doing So you can see the autologous paradigm, which is really where cell therapy is showing that they're capable. so you can see the autologous paradigm which is really where cell therapy is showing that they're capable It's a fantastic time for technology. it's a fantastic time for technology They're not particularly stable. they're not particularly stable Then we have our classic allogeneic CAR-T that will allow you to scale to a much greater extent. then we have our classic allogeneic car-t that will allow you to scale to a much greater extent This also resolves some of the issues related to the T cell fitness of donors. Where we want to go is we want to go beyond allogeneic and go into a cell which has much greater expansion capabilities. We're working very closely with sharing a lot of the research capabilities and building a cell, which I think has quite substantial capabilities in this particular space. It works. I think we'll now actually be very destructive in this particular space. We'll hear more about this paradigm next year. I think also, I think that one slide about what is happening in the autoimmune space. CAR-T cells have disrupted autophagy, but they actually are also showing even greater disruption in the autoimmune space. The ability to reset someone's immune response when the immune response has taken the wrong course is incredibly powerful. This also resolves some of the issues related to the T cell fitness of donors. this also resolves some of the issues related to the t cell fitness of donors Where we want to go is we want to go beyond allogeneic and go into a cell which has much greater expansion capabilities. where we want to go is we want to go beyond allogeneic and go into a cell which has much greater expansion capabilities We're working very closely with sharing a lot of the research capabilities and building a cell, which I think has quite substantial capabilities in this particular space. we're working very closely with sharing a lot of the research capabilities and building a cell which i think has quite substantial capabilities in this particular space It works. it works I think we'll now actually be very destructive in this particular space. i think we'll now actually be very destructive in this particular space We'll hear more about this paradigm next year. we'll hear more about this paradigm next year I think also, I think that one slide about what is happening in the autoimmune space. i think also i think that one slide about what is happening in the autoimmune space CAR-T cells have disrupted autophagy, but they actually are also showing even greater disruption in the autoimmune space. car-t cells have disrupted autophagy but they actually are also showing even greater disruption in the autoimmune space The ability to reset someone's immune response when the immune response has taken the wrong course is incredibly powerful. the ability to reset someone's immune response when the immune response has taken the wrong course is incredibly powerful This work is led by Harold Chester. He's going to be introducing the concept of reset T cell development, immune development for patients with this deeply fixed autoimmune feature. Not all of these work here, but you can have very, very significant effects on those patients. We and other companies have actually shown similar data. We presented some data, and in this year, EULAR is showing the AZD0120, but actually, we have very similar data, so we believe in this. We believe this is a game changer for the autoimmune space and the ability to disrupt and reset the immune response of the patient where the immune response is just gone astray, and so autologous has clearly had a significant role. It's not particularly scalable. There's also a limited amount of people that take the types of approaches. This work is led by Harold Chester. this work is led by harold chester He's going to be introducing the concept of reset T cell development, immune development for patients with this deeply fixed autoimmune feature. he's going to be introducing the concept of reset t cell development, immune development for patients with this deeply fixed autoimmune feature Not all of these work here, but you can have very, very significant effects on those patients. not all of these work here but you can have very very significant effects on those patients We and other companies have actually shown similar data. we and other companies have actually shown similar data We presented some data, and in this year, EULAR is showing the AZD0120 , but actually, we have very similar data, so we believe in this. we presented some data and in this year eular is showing the azd0120 but actually we have very similar data so we believe in this We believe this is a game changer for the autoimmune space and the ability to disrupt and reset the immune response of the patient where the immune response is just gone astray, and so autologous has clearly had a significant role. we believe this is a game changer for the autoimmune space and the ability to disrupt and reset the immune response of the patient where the immune response is just gone astray and so autologous has clearly had a significant role It's not particularly scalable. it's not particularly scalable There's also a limited amount of people that take the types of approaches. there's also a limited amount of people that take the types of approaches Allogeneic approaches give you a much greater paintbox for which to create these kinds of regulations. I think in vivo is also very significant in this particular space, so we're very excited about this proposition and very enthusiastic about the cell therapy, and so in terms of where we're investing, we're investing in autologous. We're investing in our autoimmune platforms, particularly with Cellectis. We're investing in in vivo spaces, and I think there's room for these technologies to advance more. I think this is one of the most rapidly evolving spaces driven by the pace of technology and the pace of innovation, so I think what we are going to see, we're going to see some of these products that surpass others, but we'll also see many of them survive too, so this is the last slide, and this is kind of what our overall vision is. Allogeneic approaches give you a much greater paintbox for which to create these kinds of regulations. allogeneic approaches give you a much greater paintbox for which to create these kinds of regulations I think in vivo is also very significant in this particular space, so we're very excited about this proposition and very enthusiastic about the cell therapy, and so in terms of where we're investing, we're investing in autologous. i think in vivo is also very significant in this particular space so we're very excited about this proposition and very enthusiastic about the cell therapy and so in terms of where we're investing we're investing in autologous We're investing in our autoimmune platforms, particularly with Cellectis. we're investing in our autoimmune platforms particularly with cellectis We're investing in in vivo spaces, and I think there's room for these technologies to advance more. we're investing in in vivo spaces and i think there's room for these technologies to advance more I think this is one of the most rapidly evolving spaces driven by the pace of technology and the pace of innovation, so I think what we are going to see, we're going to see some of these products that surpass others, but we'll also see many of them survive too, so this is the last slide, and this is kind of what our overall vision is. i think this is one of the most rapidly evolving spaces driven by the pace of technology and the pace of innovation so i think what we are going to see we're going to see some of these products that surpass others but we'll also see many of them survive too so this is the last slide and this is kind of what our overall vision is We see the first CAR-T approved back in 2017, and today we've got a large number of cell therapy principally being used in the context of delivering hematology. Where we're going to tomorrow is expanding this into solid tumors, and I think the solid tumor data that's emerging is also very exciting, and also immunities, and then longer term we're going to have much safer medicines and much scalable, I hope, and I think deployable at most hospitals without expert teams and a very safe profile, and this will include off-the-shelf, allogeneic and in vivo. Those autologous. Okay. With that, I thank you very much. We see the first CAR-T approved back in 2017, and today we've got a large number of cell therapy principally being used in the context of delivering hematology. we see the first car-t approved back in 2017 and today we've got a large number of cell therapy principally being used in the context of delivering hematology Where we're going to tomorrow is expanding this into solid tumors, and I think the solid tumor data that's emerging is also very exciting, and also immunities, and then longer term we're going to have much safer medicines and much scalable, I hope, and I think deployable at most hospitals without expert teams and a very safe profile, and this will include off-the-shelf, allogeneic and in vivo. where we're going to tomorrow is expanding this into solid tumors and i think the solid tumor data that's emerging is also very exciting and also immunities and then longer term we're going to have much safer medicines and much scalable i hope and i think deployable at most hospitals without expert teams and a very safe profile and this will include off-the-shelf allogeneic and in vivo Those autologous. those autologous Okay. okay With that, I thank you very much. with that i thank you very much

Speaker 2: Thank you very much for the presentation and my all your voices because we're definitely going to see things. We've got to a science fiction, but we're making it real. As we said, we might have updates soon, and it's going to be really interesting. Thank you very much for the presentation and my all your voices because we're definitely going to see things. thank you very much for the presentation and my all your voices because we're definitely going to see things We've got to a science fiction, but we're making it real. we've got to a science fiction but we're making it real As we said, we might have updates soon, and it's going to be really interesting. as we said we might have updates soon and it's going to be really interesting So I'm going to make a quick conclusion on the presentation we did this morning. And then we're going to open Arthur, myself, and Adrian to questions for the Q&A session. So Adrian presented this slide. A few takeaways that I think are extremely important in this slide. We're deep believers in the fact that allogeneic CAR-T therapy fits definite needs in various spaces in oncology and potentially beyond oncology, as Mark has showed it, in autoimmune disease and maybe beyond. And it's interesting for the simple reason that you get a really standardized program. And this is all the difficulty is to make it super stable and standard and reproducible. And this is something Cellectis knows how to do. We've been doing this for more than 10 years. We've seen those difficulties. Remember the first patient we ever dealt with was 10 years ago with autologous CAR-T. So I'm going to make a quick conclusion on the presentation we did this morning. so i'm going to make a quick conclusion on the presentation we did this morning And then we're going to open Arthur, myself, and Adrian to questions for the Q&A session. and then we're going to open arthur myself and adrian to questions for the q&a session So Adrian presented this slide. so adrian presented this slide A few takeaways that I think are extremely important in this slide. a few takeaways that i think are extremely important in this slide We're deep believers in the fact that allogeneic CAR-T therapy fits definite needs in various spaces in oncology and potentially beyond oncology, as Mark has showed it, in autoimmune disease and maybe beyond. we're deep believers in the fact that allogeneic car-t therapy fits definite needs in various spaces in oncology and potentially beyond oncology as mark has showed it in autoimmune disease and maybe beyond And it's interesting for the simple reason that you get a really standardized program. and it's interesting for the simple reason that you get a really standardized program And this is all the difficulty is to make it super stable and standard and reproducible. and this is all the difficulty is to make it super stable and standard and reproducible And this is something Cellectis knows how to do. and this is something cellectis knows how to do We've been doing this for more than 10 years. we've been doing this for more than 10 years We've seen those difficulties. we've seen those difficulties Remember the first patient we ever dealt with was 10 years ago with autologous CAR-T. remember the first patient we ever dealt with was 10 years ago with autologous car-t We made CAR-T before 2018. It's now like alpha-1, not alpha-1a, but alpha-1. And this is something that we're extremely proud of. And since then, we've been working and working and working and improved the process to something that is extremely stabilized. And we believe we know how to make the pharmaceutical commercializable program. We'll give two chances to every patient. Give them chances to every patient. Remember, you have T cells. You have no T cells. It works. Why, for example, an ABC works differently than a CAR-T? So you know the hierarchy. It's like a monoclonal antibody will kill a cell if there is more than 100,000 tumor-associated antigen on the surface of the autologous cell. Or an ABC, it stands out. Below 10,000, it's not going to work. We made CAR-T before 2018. we made car-t before 2018 It's now like alpha-1, not alpha-1a, but alpha-1. it's now like alpha-1 not alpha-1a but alpha-1 And this is something that we're extremely proud of. and this is something that we're extremely proud of And since then, we've been working and working and working and improved the process to something that is extremely stabilized. and since then we've been working and working and working and improved the process to something that is extremely stabilized And we believe we know how to make the pharmaceutical commercializable program. and we believe we know how to make the pharmaceutical commercializable program We'll give two chances to every patient. we'll give two chances to every patient Give them chances to every patient. give them chances to every patient Remember, you have T cells. remember you have t cells You have no T cells. you have no t cells It works. it works Why, for example, an ABC works differently than a CAR-T? why for example an abc works differently than a car-t So you know the hierarchy. so you know the hierarchy It's like a monoclonal antibody will kill a cell if there is more than 100,000 tumor-associated antigen on the surface of the autologous cell. it's like a monoclonal antibody will kill a cell if there is more than 100,000 tumor-associated antigen on the surface of the autologous cell Or an ABC, it stands out. or an abc it stands out Below 10,000, it's not going to work. below 10,000 it's not going to work This is why, for example, some failures of ADC give the same chance for the CAR because it will be a few hundreds. We don't know exactly the number of tumor-associated antigen that needs to be expressed on the surface, can still take them, and this is what makes the difference between being able to bring a patient to MRD negativity versus not, and that's where CAR-T cells are a real game changer. They come in with something even if you don't have a consolidation and a few blood cells, it works, so we're excited about this, and also, we're excited about the strategy that has been developed and also endorsed by William Blair in terms of making this first program the best chances for patients both for the future. This is something that is totally innovative and a game changer. This is why, for example, some failures of ADC give the same chance for the CAR because it will be a few hundreds. this is why for example some failures of adc give the same chance for the car because it will be a few hundreds We don't know exactly the number of tumor-associated antigen that needs to be expressed on the surface, can still take them, and this is what makes the difference between being able to bring a patient to MRD negativity versus not, and that's where CAR-T cells are a real game changer. we don't know exactly the number of tumor-associated antigen that needs to be expressed on the surface can still take them and this is what makes the difference between being able to bring a patient to mrd negativity versus not and that's where car-t cells are a real game changer They come in with something even if you don't have a consolidation and a few blood cells, it works, so we're excited about this, and also, we're excited about the strategy that has been developed and also endorsed by William Blair in terms of making this first program the best chances for patients both for the future. they come in with something even if you don't have a consolidation and a few blood cells it works so we're excited about this and also we're excited about the strategy that has been developed and also endorsed by william blair in terms of making this first program the best chances for patients both for the future This is something that is totally innovative and a game changer. this is something that is totally innovative and a game changer So the first patient will be recruited this year, by the end of the year. We'll have next year an interim analysis for the patient. And then it will continue up to general enrollment. And then we'll have the BLA in 2020. So a lot of things to do in the meantime, of course, like opening 75 sites, et cetera. But we have a clear road to success. Well, the strategic roadmap, something that we need to keep in mind for Cellectis, we're not all about TALEN stuff. We're super excited. We believe TALEN is a game changer. We believe it's a program that definitely fits the size of Cellectis. And we really just need to run a program like this with a very valuable program and something that has given fantastic market value creation for a company outsized and at the stage where we are really considered. So the first patient will be recruited this year, by the end of the year. so the first patient will be recruited this year by the end of the year We'll have next year an interim analysis for the patient. we'll have next year an interim analysis for the patient And then it will continue up to general enrollment. and then it will continue up to general enrollment And then we'll have the BLA in 2020. and then we'll have the bla in 2020 So a lot of things to do in the meantime, of course, like opening 75 sites, et cetera. so a lot of things to do in the meantime of course like opening 75 sites et cetera But we have a clear road to success. but we have a clear road to success Well, the strategic roadmap, something that we need to keep in mind for Cellectis, we're not all about TALEN stuff. well the strategic roadmap something that we need to keep in mind for cellectis we're not all about talen stuff We're super excited. we're super excited We believe TALEN is a game changer. we believe talen is a game changer We believe it's a program that definitely fits the size of Cellectis. we believe it's a program that definitely fits the size of cellectis And we really just need to run a program like this with a very valuable program and something that has given fantastic market value creation for a company outsized and at the stage where we are really considered. and we really just need to run a program like this with a very valuable program and something that has given fantastic market value creation for a company outsized and at the stage where we are really considered The second thing that you have to keep in mind is after UCART22, you have Epicel. Talk a bit about Epicel. We'll see where it goes, but it's 20x22. It's still not the 19. Still a very high unmet need with a program that has double targeting, and you have a very nice strategy because you can grab even two targets instead of only one, CD20 and CD22, and you will have also a bit of information by the end of this year. So keep an eye on that, but that will be the end of phase I in refractory r/r B-cell ALL in 2026. And also some data on trials that we are doing that will be probably very exciting. I'm very excited about it, and we're definitely looking forward to presenting. The second thing that you have to keep in mind is after UCART22, you have Epicel. the second thing that you have to keep in mind is after ucart22 you have epicel Talk a bit about Epicel. talk a bit about epicel We'll see where it goes, but it's 20x22. we'll see where it goes but it's 20x22 It's still not the 19. it's still not the 19 Still a very high unmet need with a program that has double targeting, and you have a very nice strategy because you can grab even two targets instead of only one, CD20 and CD22, and you will have also a bit of information by the end of this year. still a very high unmet need with a program that has double targeting and you have a very nice strategy because you can grab even two targets instead of only one cd20 and cd22 and you will have also a bit of information by the end of this year So keep an eye on that, but that will be the end of phase I in refractory r/r B-cell ALL in 2026. so keep an eye on that but that will be the end of phase i in refractory r/r b-cell all in 2026 And also some data on trials that we are doing that will be probably very exciting. and also some data on trials that we are doing that will be probably very exciting I'm very excited about it, and we're definitely looking forward to presenting. i'm very excited about it and we're definitely looking forward to presenting And finally, a bit of the peak of the pre-clinical proof of concept 2026 of in vivo gene therapy. Gene therapy has been always very complex. You know, to take the cells out, it's complicated, et cetera. But if you take a pair of mRNA packages, it's something tha And finally, a bit of the peak of the pre-clinical proof of concept 2026 of in vivo gene therapy. and finally a bit of the peak of the pre-clinical proof of concept 2026 of in vivo gene therapy Gene therapy has been always very complex. gene therapy has been always very complex You know, to take the cells out, it's complicated, et cetera. you know to take the cells out it's complicated et cetera But if you take a pair of mRNA packages, it's something tha but if you take a pair of mrna packages it's something tha It's something that is going to go in vivo and is going to be a shock with something that can also have very powerful and decent cut and that will give probably also something that we know on the other side of the company and allow it to develop. So that's going to be a revolution in medicine, and we're here to bring revolution in medicine. This is our mission and our path. We will bring it. With that, I would like to thank you again for attendance. I'd like to open to questions for the viewers. Adrian and Arthur, please, so we'll start by Gina. I don't know. It's something that is going to go in vivo and is going to be a shock with something that can also have very powerful and decent cut and that will give probably also something that we know on the other side of the company and allow it to develop. it's something that is going to go in vivo and is going to be a shock with something that can also have very powerful and decent cut and that will give probably also something that we know on the other side of the company and allow it to develop So that's going to be a revolution in medicine, and we're here to bring revolution in medicine. so that's going to be a revolution in medicine and we're here to bring revolution in medicine This is our mission and our path. this is our mission and our path We will bring it. we will bring it With that, I would like to thank you again for attendance. with that i would like to thank you again for attendance I'd like to open to questions for the viewers. i'd like to open to questions for the viewers Adrian and Arthur, please, so we'll start by Gina. adrian and arthur please so we'll start by gina I don't know. i don't know

Speaker 8: Yes, yes, yes. Okay, so first, I wanted to say congratulations. It's a great update. You really cover a lot of the questions that I've invested in. It's very impressive data, so I have tried to limit myself. Yes, yes, yes. yes yes yes Okay, so first, I wanted to say congratulations. okay so first i wanted to say congratulations It's a great update. it's a great update You really cover a lot of the questions that I've invested in. you really cover a lot of the questions that i've invested in It's very impressive data, so I have tried to limit myself. it's very impressive data so i have tried to limit myself I know a lot of the questions will be asked. I'll limit myself to two to three questions. One is the lasme-cel, the pivotal study, just want to confirm. The trial design is confirmed, agreed upon by the FDA and the EMA. Then the question is for the two doses, I assume one including dose level three, and the other doses are higher or lower dose. Then what is the definition of success given the kind of endpoints, CRs, CRis, CR? So that's one question. So I'll get to it. Then the other question is about the manufacturing and also to AstraZeneca. So the manufacturing will have to share the sq ft. But what is the capacity here? The current capacity and future peak capacity, I assume that will also be part of the topic of AstraZeneca and certain products. I know a lot of the questions will be asked. i know a lot of the questions will be asked I'll limit myself to two to three questions. i'll limit myself to two to three questions One is the lasme-cel, the pivotal study, just want to confirm. one is the lasme-cel the pivotal study just want to confirm The trial design is confirmed, agreed upon by the FDA and the EMA. the trial design is confirmed agreed upon by the fda and the ema Then the question is for the two doses, I assume one including dose level three, and the other doses are higher or lower dose. then the question is for the two doses i assume one including dose level three and the other doses are higher or lower dose Then what is the definition of success given the kind of endpoints, CRs, CRis, CR? then what is the definition of success given the kind of endpoints crs cris cr So that's one question. so that's one question So I'll get to it. so i'll get to it Then the other question is about the manufacturing and also to AstraZeneca. get to it then the other question is about the manufacturing and also to astrazeneca So the manufacturing will have to share the sq ft. so the manufacturing will have to share the sq ft But what is the capacity here? but what is the capacity here The current capacity and future peak capacity, I assume that will also be part of the topic of AstraZeneca and certain products. the current capacity and future peak capacity i assume that will also be part of the topic of astrazeneca and certain products And then the question is, when will we see the pipeline of the collaboration on AstraZeneca? When will we see the data from Cellectis collaboration? And then the question is, when will we see the pipeline of the collaboration on AstraZeneca? and then the question is when will we see the pipeline of the collaboration on astrazeneca When will we see the data from Cellectis collaboration? when will we see the data from cellectis collaboration

Speaker 1: So I will take the first question. There's probably going to be five questions and then Gina's going to answer. That's a great question. So yes, we're completely aligned with the regulatory authorities. The biggest issue is you're finding the right endpoint. I think we've got that. And get agreement that really this is a trial. So yes, there's a bit of clarification from my end. And sorry if I didn't make it clear. There's no dose optimization for AstraZeneca. It's dose level three. That's our recommended phase II dose. The dose optimization is actually for alemtuzumab, where they want us to try to make sure we've got a dose. So I will take the first question. so i will take the first question There's probably going to be five questions and then Gina's going to answer. there's probably going to be five questions and then gina's going to answer That's a great question. that's a great question So yes, we're completely aligned with the regulatory authorities. so yes we're completely aligned with the regulatory authorities The biggest issue is you're finding the right endpoint. the biggest issue is you're finding the right endpoint I think we've got that. i think we've got that And get agreement that really this is a trial. and get agreement that really this is a trial So yes, there's a bit of clarification from my end. so yes there's a bit of clarification from my end and And sorry if I didn't make it clear. and sorry if i didn't make it clear There's no dose optimization for AstraZeneca. there's no dose optimization for astrazeneca It's dose level three. it's dose level three That's our recommended phase II dose. that's our recommended phase ii dose The dose optimization is actually for alemtuzumab , where they want us to try to make sure we've got a dose. the dose optimization is actually for alemtuzumab where they want us to try to make sure we've got a dose And they want us to try a lower dose as well within the dose optimization. And that'll be that for the patients. We will not be testing any alternative doses of AstraZeneca. Those are my questions. And they want us to try a lower dose as well within the dose optimization. and they want us to try a lower dose as well within the dose optimization And that'll be that for the patients. and that'll be that for the patients We will not be testing any alternative doses of AstraZeneca. we will not be testing any alternative doses of astrazeneca Those are my questions. those are my questions

Speaker 8: What is the definition of success? Defining the development of Servier. Yes. So what is defining the success? Within the two hours, would that be frozen at two hours or would it be with the reflection when it reaches a certain severity? What is the defining of the success? What is the definition of success? what is the definition of success Defining the development of Servier. defining the development of servier Yes. yes So what is defining the success? so what is defining the success within the two Within the two hours, would that be frozen at two hours or would it be with the reflection when it reaches a certain severity? within the two hours would that be frozen at two hours or would it be with the reflection when it reaches a certain severity What is the defining of the success? what is the defining of the success

Speaker 1: So first thing in our trial, there's always the same wording for the regulators. It has to be compelling. So right now, there's an assumption in the background these patients have, I think, generously a CR/CRi rate maybe of 20%, although what we've seen with you, that that is probably a threshold many patients will meet. So first thing in our trial, there's always the same wording for the regulators. so first thing in our trial there's always the same wording for the regulators It has to be compelling. it has to be compelling So right now, there's an assumption in the background these patients have, I think, generously a CR/CRi rate maybe of 20%, although what we've seen with you, that that is probably a threshold many patients will meet. so right now there's an assumption in the background these patients have i think generously a cr/cri rate maybe of 20% although what we've seen with you that that is probably a threshold many patients will meet We have exceeded that quite significantly as our marker of success, and that's been generally agreed as it is, so we believe that threshold is probably the data we have here, if we hit this, we will certainly surpass our threshold. Yes, yes, so for the manufacturing question, yes, we share the square footage. That's, of course, something that is not relevant for the manufacturing capacity that we have. First of all, you're all invited to visit our site in Raleigh, but the nice picture of this building that you see is the entrance of our building in Raleigh. Some of you have visited. Friendly faces that have visited the site, but definitely, it's something that will show you how powerful and efficient and well-organized it is and if it's set for successful production. We have exceeded that quite significantly as our marker of success, and that's been generally agreed as it is, so we believe that threshold is probably the data we have here, if we hit this, we will certainly surpass our threshold. we have exceeded that quite significantly as our marker of success and that's been generally agreed as it is so we believe that threshold is probably the data we have here if we hit this we will certainly surpass our threshold Yes, yes, so for the manufacturing question, yes, we share the square footage. yes yes so for the manufacturing question yes we share the square footage That's, of course, something that is not relevant for the manufacturing capacity that we have. that's of course something that is not relevant for the manufacturing capacity that we have First of all, you're all invited to visit our site in Raleigh, but the nice picture of this building that you see is the entrance of our building in Raleigh. first of all you're all invited to visit our site in raleigh but the nice picture of this building that you see is the entrance of our building in raleigh Some of you have visited. some of you have visited Friendly faces that have visited the site, but definitely, it's something that will show you how powerful and efficient and well-organized it is and if it's set for successful production. friendly faces that have visited the site but definitely it's something that will show you how powerful and efficient and well-organized it is and if it's set for successful production We have currently one suite that is active and allows us potentially to produce up to 4,000 doses a year, which covers way more than what is being built in terms of the 20%-87%. We're opening our collaboration with AstraZeneca. We decided to enable a second suite, and we'll have the same capacity. We have thoughts with two other suites, four in total, on one side of the building, but the second side of the building can be cloned on the other side. That would allow two other suites. We will have two suites that will be ready to go by the end of next year and for early 2027, but it's something they will be supposed to be by the end of next year. That's the completed capacity. We have currently one suite that is active and allows us potentially to produce up to 4,000 doses a year, which covers way more than what is being built in terms of the 20%-87%. we have currently one suite that is active and allows us potentially to produce up to 4,000 doses a year which covers way more than what is being built in terms of the 20%-87% We're opening our collaboration with AstraZeneca. we're opening our collaboration with astrazeneca We decided to enable a second suite, and we'll have the same capacity. we decided to enable a second suite and we'll have the same capacity We have thoughts with two other suites, four in total, on one side of the building, but the second side of the building can be cloned on the other side. we have thoughts with two other suites four in total on one side of the building but the second side of the building can be cloned on the other side That would allow two other suites. that would allow two other suites We will have two suites that will be ready to go by the end of next year and for early 2027, but it's something they will be supposed to be by the end of next year. we will have two suites that will be ready to go by the end of next year and for early 2027 but it's something they will be supposed to be by the end of next year That's the completed capacity. that's the completed capacity Not only this, but the numbers that I'm giving you can be augmented pretty meaningfully because today, we don't have the need to have that many vials. But once we believe that we can supply the whole world in terms of the two products that we have and eventually also some of the products that we will be producing for AstraZeneca, there is no limit. So the Raleigh site can fill with multiple products. There is global need for even larger in the future. And then the last step. Yeah, so Mark said it, 2026, maybe the first piece on the things that we're doing, right? But you know, I think under the control of Astra, it's like 26, they say, "Oh, no, we don't want you to share this stuff. Not only this, but the numbers that I'm giving you can be augmented pretty meaningfully because today, we don't have the need to have that many vials. not only this but the numbers that i'm giving you can be augmented pretty meaningfully because today we don't have the need to have that many vials But once we believe that we can supply the whole world in terms of the two products that we have and eventually also some of the products that we will be producing for AstraZeneca, there is no limit. but once we believe that we can supply the whole world in terms of the two products that we have and eventually also some of the products that we will be producing for astrazeneca there is no limit So the Raleigh site can fill with multiple products. so the raleigh site can fill with multiple products There is global need for even larger in the future. there is global need for even larger in the future And then the last step. and then the last step Yeah, so Mark said it, 2026, maybe the first piece on the things that we're doing, right? yeah so mark said it 2026 maybe the first piece on the things that we're doing right But you know, I think under the control of Astra, it's like 26, they say, "Oh, no, we don't want you to share this stuff. but you know i think under the control of astra it's like 26 they say "oh no we don't want you to share this stuff Let's do it," so then we'll not share because they are our partners and we'll do what our partners are willing to do. Let's do it," so then we'll not share because they are our partners and we'll do what our partners are willing to do. let's do it," so then we'll not share because they are our partners and we'll do what our partners are willing to do

Speaker 9: Thanks for taking my question. I'm Allen. I work with the Baird. I was wondering if I can ask questions to the doctors, if any of them would like to comment. I was wondering, in terms of using the AstraZeneca, would the doctors use it exclusively after for inotuzumab ozogamicin, or if there are scenarios where they can use it because this is to be followed by a transplant, right? I mean, essentially, it would be used as a result followed by a transplant and an alternative to either Blincyto or oncology. Perhaps Lisa can clarify that. Thanks for taking my question. thanks for taking my question I'm Allen. i'm allen I work with the Baird. i work with the baird I was wondering if I can ask questions to the doctors, if any of them would like to comment. i was wondering if i can ask questions to the doctors if any of them would like to comment I was wondering, in terms of using the AstraZeneca, would the doctors use it exclusively after for inotuzumab ozogamicin , or if there are scenarios where they can use it because this is to be followed by a transplant, right? i was wondering in terms of using the astrazeneca would the doctors use it exclusively after for inotuzumab ozogamicin or if there are scenarios where they can use it because this is to be followed by a transplant right I mean, essentially, it would be used as a result followed by a transplant and an alternative to either Blincyto or oncology. i mean essentially it would be used as a result followed by a transplant and an alternative to either blincyto or oncology Perhaps Lisa can clarify that. perhaps lisa can clarify that

Speaker 2: Yeah, I think right now, as you know, Blincyto is a proven first-line setting. Yeah, I think right now, as you know, Blincyto is a proven first-line setting. yeah i think right now as you know blincyto is a proven first-line setting So practically, every patient in the U.S. is getting Blincyto or inotuzumab in the first-line B-ALL setting. So practically, all patients will have exposure to Blincyto and to the medicine. In terms of whether they need to be on CD19 refractory, in the trial, you saw 50% of the patients had a prior CD19 bispecific therapy. But as I said during the session, there are patients who cannot get a lot of those apheresis collection done because their counts are too low. There are no apheresis to collect. Or there are many situations where you want a quick CAR-T. There's no time for bridging, cell collection, root operations. All those things take too much time where you want to go quickly to a cell product where the allogeneic product is helpful. So I don't think it's a requirement per se that you must fail at CD19 CAR-T for this. So practically, every patient in the U.S. is getting Blincyto or inotuzumab in the first-line B-ALL setting. so practically every patient in the u.s is getting blincyto or inotuzumab in the first-line b-all setting So practically, all patients will have exposure to Blincyto and to the medicine. so practically all patients will have exposure to blincyto and to the medicine In terms of whether they need to be on CD19 refractory, in the trial, you saw 50% of the patients had a prior CD19 bispecific therapy. in terms of whether they need to be on cd19 refractory in the trial you saw 50% of the patients had a prior cd19 bispecific therapy But as I said during the session, there are patients who cannot get a lot of those apheresis collection done because their counts are too low. but as i said during the session there are patients who cannot get a lot of those apheresis collection done because their counts are too low There are no apheresis to collect. there are no apheresis to collect Or there are many situations where you want a quick CAR-T. or there are many situations where you want a quick car-t There's no time for bridging, cell collection, root operations. there's no time for bridging cell collection root operations All those things take too much time where you want to go quickly to a cell product where the allogeneic product is helpful. all those things take too much time where you want to go quickly to a cell product where the allogeneic product is helpful So I don't think it's a requirement per se that you must fail at CD19 CAR-T for this. so i don't think it's a requirement per se that you must fail at cd19 car-t for this But I think there will be some situations where some maybe kind of prefer just the logistics issue and how good you want to go with it. But I think there will be some situations where some maybe kind of prefer just the logistics issue and how good you want to go with it. but i think there will be some situations where some maybe kind of prefer just the logistics issue and how good you want to go with it

Speaker 10: Thank you to the company. I think you talked about the greater quality agreed with the importance of the FDA. But in the label, so in the trial design, how is that reflected? Will the label, because CR/CRi, that's the FDA, right? Would that reflect in the DOR that will be officially recognized in the label or in the document? Thank you to the company. thank you to the company I think you talked about the greater quality agreed with the importance of the FDA. i think you talked about the greater quality agreed with the importance of the fda But in the label, so in the trial design, how is that reflected? but in the label so in the trial design how is that reflected Will the label, because CR/CRi, that's the FDA, right? will the label because cr/cri that's the fda right Would that reflect in the DOR that will be officially recognized in the label or in the document? would that reflect in the dor that will be officially recognized in the label or in the document

Speaker 1: That's a great question. So yes, we agreed with them. They wanted to see efficacy first, which is CR/CRi. That's what they want to try to implement. However, within the design, we're including key secondary endpoints. We will be capturing CR efficacy for transplant-eligible. And that will allow us then to capture for the patients following up. That's a great question. that's a great question So yes, we agreed with them. so yes we agreed with them They wanted to see efficacy first, which is CR/CRi. they wanted to see efficacy first which is cr/cri That's what they want to try to implement. that's what they want to try to implement However, within the design, we're including key secondary endpoints. however within the design we're including key secondary endpoints We will be capturing CR efficacy for transplant-eligible. we will be capturing cr efficacy for transplant-eligible And that will allow us then to capture for the patients following up. and that will allow us then to capture for the patients following up We will not be mandating a transplant, but all patients entering the trial would be considered to benefit from transplant, and that is the goal of the treatment. So I think the design has allowed us to capture. But consider that at the more traditional endpoint, with, however, the aspirational endpoint of showing that getting these patients to transplant with the follow-up and improving the overall survival, that actually gives the label this. We will not be mandating a transplant, but all patients entering the trial would be considered to benefit from transplant, and that is the goal of the treatment. we will not be mandating a transplant but all patients entering the trial would be considered to benefit from transplant and that is the goal of the treatment So I think the design has allowed us to capture. so i think the design has allowed us to capture but But consider that at the more traditional endpoint, with, however, the aspirational endpoint of showing that getting these patients to transplant with the follow-up and improving the overall survival, that actually gives the label this. but consider that at the more traditional endpoint with however the aspirational endpoint of showing that getting these patients to transplant with the follow-up and improving the overall survival that actually gives the label this

Speaker 10: Great. Thank you. Great. great Thank you. thank you Thank you so much. Congrats on all the updates here. Very impressive data. I guess maybe the first one to the physicians, I'd love to get some more context around how many transplant-eligible patients have access to a transplant. Is the match rate very high in B-ALL? And how do you think about that when you're looking at clinical treatments that can be bridged to transplant? Thank you so much. thank you so much Congrats on all the updates here. congrats on all the updates here Very impressive data. very impressive data I guess maybe the first one to the physicians, I'd love to get some more context around how many transplant-eligible patients have access to a transplant. i guess maybe the first one to the physicians i'd love to get some more context around how many transplant-eligible patients have access to a transplant Is the match rate very high in B-ALL? is the match rate very high in b-all And how do you think about that when you're looking at clinical treatments that can be bridged to transplant? and how do you think about that when you're looking at clinical treatments that can be bridged to transplant

Speaker 2: Probably worthwhile getting the U.S. and the European view on this. So maybe for Liz, what's that? Do you want that? Prob ably worthwhile getting the U.S. and the European view on this. prob ably worthwhile getting the u.s and the european view on this So maybe for Liz, what's that? so maybe for liz what's that Do you want that? do you want that

Speaker 11: Yeah, that's not different. It's not different. It's not different. So Dr. Riedell, my question, you're in the community setting. So perhaps as far as getting a donor for a transplant, the era where we match is going away. In fact, we're doing clinical trials right now where we're doing mismatch-friendly donor transplants and having similar success rates. So six out of eight to seven out of eight, or even a trial with a deceased bone marrow registry source that we can use for transplants. So pretty much in this era, almost every patient has a donor. It's very rare that we have to send someone. We don't do cord blood transplants in our center. Very few centers are doing it. Yeah, that's not different. yeah that's not different It's not different. it's not different It's not different. it's not different So Dr. Riedell, my question, you're in the community setting. so dr riedell my question you're in the community setting So perhaps as far as getting a donor for a transplant, the era where we match is going away. so perhaps as far as getting a donor for a transplant the era where we match is going away In fact, we're doing clinical trials right now where we're doing mismatch-friendly donor transplants and having similar success rates. in fact we're doing clinical trials right now where we're doing mismatch-friendly donor transplants and having similar success rates So six out of eight to seven out of eight, or even a trial with a deceased bone marrow registry source that we can use for transplants. so six out of eight to seven out of eight or even a trial with a deceased bone marrow registry source that we can use for transplants So pretty much in this era, almost every patient has a donor. so pretty much in this era almost every patient has a donor It's very rare that we have to send someone. it's very rare that we have to send someone We don't do cord blood transplants in our center. we don't do cord blood transplants in our center Very few centers are doing it. very few centers are doing it If we do, in the rare occasion we have to do that, we send in the additional online committee at your site, and that pretty much covers everybody. I think you can pretty much guarantee 100% if you needed a transplant, there's nowhere else to. Great. That's great context and incredible to see the patient in that phase, and then maybe to Adrian, the design of the phase III study. I guess you mentioned that it incurs with 20%-25% complete response rate, but also I think earlier you talked about still looking at the literature. I'm not sure if that's pinned down that external control, and if there are any changes in the assumptions around that external control that dictate the size of the study as well. If we do, in the rare occasion we have to do that, we send in the additional online committee at your site, and that pretty much covers everybody. if we do in the rare occasion we have to do that we send in the additional online committee at your site and that pretty much covers everybody I think you can pretty much guarantee 100% if you needed a transplant, there's nowhere else to. i think you can pretty much guarantee 100% if you needed a transplant there's nowhere else to Great. great That's great context and incredible to see the patient in that phase, and then maybe to Adrian, the design of the phase III study. that's great context and incredible to see the patient in that phase and then maybe to adrian the design of the phase iii study I guess you mentioned that it incurs with 20%-25% complete response rate, but also I think earlier you talked about still looking at the literature. i guess you mentioned that it incurs with 20%-25% complete response rate but also i think earlier you talked about still looking at the literature I'm not sure if that's pinned down that external control, and if there are any changes in the assumptions around that external control that dictate the size of the study as well. i'm not sure if that's pinned down that external control and if there are any changes in the assumptions around that external control that dictate the size of the study as well Was it an 80-patient study locked in, or could you go lower, or if you had a lower response rate based on the literature? Was it an 80-patient study locked in, or could you go lower, or if you had a lower response rate based on the literature? was it an 80-patient study locked in or could you go lower or if you had a lower response rate based on the literature

Speaker 1: So that's a great question. The size of our trial is not really driven by our assumed efficacy. It's actually driven by the size of the safety data patient on ELA. And if we were to power our trial based on efficacy, it would be much smaller. So that is the first point. So even if there's any change in numbers, we have so much room. We're very confident regardless of what we see in our control arm. We're very much overpowered to demonstrate the efficacy required. In terms of the synthetic control arm, and we've been talking to our investigators here about it. I don't want to dismiss this as being easy. It's not. So that's a great question. so that's a great question The size of our trial is not really driven by our assumed efficacy. the size of our trial is not really driven by our assumed efficacy It's actually driven by the size of the safety data patient on ELA. it's actually driven by the size of the safety data patient on ela And if we were to power our trial based on efficacy, it would be much smaller. and if we were to power our trial based on efficacy it would be much smaller So that is the first point. so that is the first point So even if there's any change in numbers, we have so much room. so even if there's any change in numbers we have so much room We're very confident regardless of what we see in our control arm. we're very confident regardless of what we see in our control arm We're very much overpowered to demonstrate the efficacy required. we're very much overpowered to demonstrate the efficacy required In terms of the synthetic control arm, and we've been talking to our investigators here about it. in terms of the synthetic control arm and we've been talking to our investigators here about it I don't want to dismiss this as being easy. i don't want to dismiss this as being easy It's not. it's not This is a very specific group of patients that will require both an element of retrospective and prospective data collection. We have pretty much designed most of our propensity score matching and how we're going to capture them. There is really what is required for us now, and we have a little bit of time, is where are we going to get these patients from? Is it a mixture of databases versus academic institutions? It's going to have to be an element of capture both in Europe and in the U.S. It's complex, but I think we have a very good plan. This is a very specific group of patients that will require both an element of retrospective and prospective data collection. this is a very specific group of patients that will require both an element of retrospective and prospective data collection We have pretty much designed most of our propensity score matching and how we're going to capture them. we have pretty much designed most of our propensity score matching and how we're going to capture them There is really what is required for us now, and we have a little bit of time, is where are we going to get these patients from? there is really what is required for us now and we have a little bit of time is where are we going to get these patients from Is it a mixture of databases versus academic institutions? is it a mixture of databases versus academic institutions It's going to have to be an element of capture both in Europe and in the U.S. it's going to have to be an element of capture both in europe and in the u.s It's complex, but I think we have a very good plan. it's complex but i think we have a very good plan

Speaker 11: I agree. And then maybe just one last one on the pivotal study design. You mentioned the Helms-Tewson ad dose that they're going to test in the pivotal is going to be a dose down. I agree. i agree And then maybe just one last one on the pivotal study design. and then maybe just one last one on the pivotal study design You mentioned the Helms-Tewson ad dose that they're going to test in the pivotal is going to be a dose down. you mentioned the helms-tewson ad dose that they're going to test in the pivotal is going to be a dose down I'd just love to hear any context you provide around contribution to components and those discussions with the FDA and their reassurances of the ability to show that the current plan that you're playing out here? I'd just love to hear any context you provide around contribution to components and those discussions with the FDA and their reassurances of the ability to show that the current plan that you're playing out here? i'd just love to hear any context you provide around contribution to components and those discussions with the fda and their reassurances of the ability to show that the current plan that you're playing out here

Speaker 2: Yeah, we've had a lot, as you may expect. We've had a lot of conversation with the regulatory bodies in terms of how are we going to differentiate between two doses of Helms-Tewson ad in the context of patients who are incredibly unwell. From a disease perspective itself, they get a lot of toxicities. But we believe that the doses we've chosen are differentiated enough. But however, we will be monitoring. This is still open label. We want to make sure that patients are not underexposed to Helms-Tewson ad. Yeah, we've had a lot, as you may expect. yeah we've had a lot as you may expect We've had a lot of conversation with the regulatory bodies in terms of how are we going to differentiate between two doses of Helms-Tewson ad in the context of patients who are incredibly unwell. we've had a lot of conversation with the regulatory bodies in terms of how are we going to differentiate between two doses of helms-tewson ad in the context of patients who are incredibly unwell From a disease perspective itself, they get a lot of toxicities. from a disease perspective itself they get a lot of toxicities But we believe that the doses we've chosen are differentiated enough. but we believe that the doses we've chosen are differentiated enough But however, we will be monitoring. but however we will be monitoring This is still open label. this is still open label We want to make sure that patients are not underexposed to Helms-Tewson ad. we want to make sure that patients are not underexposed to helms-tewson ad What we've done over the last year is we've done a tremendous amount of modeling as to what is the right dose, what does underexposure and overexposure look like. Because what we've tried to get, and I think it's one of the learnings you can have having had so many patients treated with alemtuzumab in this context, we can start to see a picture of what is the right level. What dose levels are too low so you get very close T-cell reconstitution and you don't get your expansion. So we're coming into our phase II really better informed. So I think our two doses, we will be able to differentiate between the two. And as always, if we can get away with a lower dose of alemtuzumab, maintaining efficacy and minimizing toxicity, that is a good outcome for patients. What we've done over the last year is we've done a tremendous amount of modeling as to what is the right dose, what does underexposure and overexposure look like. what we've done over the last year is we've done a tremendous amount of modeling as to what is the right dose what does underexposure and overexposure look like Because what we've tried to get, and I think it's one of the learnings you can have having had so many patients treated with alemtuzumab in this context, we can start to see a picture of what is the right level. because what we've tried to get and i think it's one of the learnings you can have having had so many patients treated with alemtuzumab in this context we can start to see a picture of what is the right level What dose levels are too low so you get very close T-cell reconstitution and you don't get your expansion. what dose levels are too low so you get very close t-cell reconstitution and you don't get your expansion So we're coming into our phase II really better informed. so we're coming into our phase ii really better informed So I think our two doses, we will be able to differentiate between the two. so i think our two doses we will be able to differentiate between the two And as always, if we can get away with a lower dose of alemtuzumab, maintaining efficacy and minimizing toxicity, that is a good outcome for patients. and as always if we can get away with a lower dose of alemtuzumab maintaining efficacy and minimizing toxicity that is a good outcome for patients

Speaker 11: Great. Thanks so much for taking the questions. Great. great Thanks so much for taking the questions. thanks so much for taking the questions

Speaker 5: Clara Dong, Jefferies. Congratulations on all the amazing progress and support for the patient from the CRC team and Mark in the panel discussion. So I just want to follow up on the question Jack asked about the external control arm. So what are the key design considerations for this external control arm, whether you're going to discuss with the FDA and EMA on the key design elements? And then maybe also want to ask the KOLs here that how do you think about the comfort level from community-based doctors to handle the addition of alemtuzumab, given the data you showed today, that the importance of the FCA regimen here and the company's vision of community-based delivery of the product in the future? Clara Dong, Jefferies. clara dong jefferies Congratulations on all the amazing progress and support for the patient from the CRC team and Mark in the panel discussion. congratulations on all the amazing progress and support for the patient from the crc team and mark in the panel discussion So I just want to follow up on the question Jack asked about the external control arm. so i just want to follow up on the question jack asked about the external control arm So what are the key design considerations for this external control arm, whether you're going to discuss with the FDA and EMA on the key design elements? so what are the key design considerations for this external control arm whether you're going to discuss with the fda and ema on the key design elements And then maybe also want to ask the KOLs here that how do you think about the comfort level from community-based doctors to handle the addition of alemtuzumab, given the data you showed today, that the importance of the FCA regimen here and the company's vision of community-based delivery of the product in the future? and then maybe also want to ask the kols here that how do you think about the comfort level from community-based doctors to handle the addition of alemtuzumab given the data you showed today that the importance of the fca regimen here and the company's vision of community-based delivery of the product in the future

Speaker 2: Yeah, I'll take the first one. Dr. Ramakrishnan, question. Since you are a community-based practice, I think that's an accepted question for you. Yeah, I'll take the first one. yeah i'll take the first one Dr. Ramakrishnan, question. dr ramakrishnan question Since you are a community-based practice, I think that's an accepted question for you. since you are a community-based practice i think that's an accepted question for you So in terms of one of the key considerations for the external control arm, which I think was your question, it is not easy to develop this control arm. We acknowledge that because there's not a lot of standard of care for these patients. These patients have had so heavily pretreated. There's not enough clarity on what the comparative arm looks like. So it will require a significant amount of efficacy score matching. Now, as we're looking at our databases, we decide, well, how many patients do we need in the database to qualify one patient in our external control arm? And that is actually far more reassuring than I thought it was going to be. I thought it was going to be a pretty big number. It's actually pretty small. So in terms of one of the key considerations for the external control arm, which I think was your question, it is not easy to develop this control arm. so in terms of one of the key considerations for the external control arm which i think was your question it is not easy to develop this control arm We acknowledge that because there's not a lot of standard of care for these patients. we acknowledge that because there's not a lot of standard of care for these patients These patients have had so heavily pretreated. these patients have had so heavily pretreated There's not enough clarity on what the comparative arm looks like. there's not enough clarity on what the comparative arm looks like So it will require a significant amount of efficacy score matching. so it will require a significant amount of efficacy score matching Now, as we're looking at our databases, we decide, well, how many patients do we need in the database to qualify one patient in our external control arm? now as we're looking at our databases we decide well how many patients do we need in the database to qualify one patient in our external control arm And that is actually far more reassuring than I thought it was going to be. and that is actually far more reassuring than i thought it was going to be I thought it was going to be a pretty big number. i thought it was going to be a pretty big number It's actually pretty small. it's actually pretty small So I think based on our initial analysis, we have enough patients in existing databases, both clinical trial databases, registries, and academic institutions that I believe will be able to fulfill the requirement. And Dr. Ramakrishnan, a question. So I think based on our initial analysis, we have enough patients in existing databases, both clinical trial databases, registries, and academic institutions that I believe will be able to fulfill the requirement. so i think based on our initial analysis we have enough patients in existing databases both clinical trial databases registries and academic institutions that i believe will be able to fulfill the requirement And Dr. Ramakrishnan, a question. and dr ramakrishnan a question

Speaker 3: So the question was efficacy and efficacy. More than that, I think cell therapy right now. Cell therapy right now, I mean, we're in the community, but we're a specialized center. I don't see anyone doing cell therapy in the community at this point. But if you think about access, most of the care is delivered in the community. I think we have to figure out ways how to expand that. As far as Helms-Tewson ad, I think that itself, I'm not too concerned about toxicity-wise. I've been around for a long time. People have used it. We have patients in the community with T-PLL who are getting Helms-Tewson ad. So the question was efficacy and efficacy. so the question was efficacy and efficacy More than that, I think cell therapy right now. more than that i think cell therapy right now cell therapy right Cell therapy right now, I mean, we're in the community, but we're a specialized center. now cell therapy right now i mean we're in the community but we're a specialized center I don't see anyone doing cell therapy in the community at this point. i don't see anyone doing cell therapy in the community at this point But if you think about access, most of the care is delivered in the community. but if you think about access most of the care is delivered in the community I think we have to figure out ways how to expand that. i think we have to figure out ways how to expand that As far as Helms-Tewson ad, I think that itself, I'm not too concerned about toxicity-wise. as far as helms-tewson ad i think that itself i'm not too concerned about toxicity-wise I've been around for a long time. i've been around for a long time People have used it. people have used it We have patients in the community with T-PLL who are getting Helms-Tewson ad. we have patients in the community with t-pll who are getting helms-tewson ad They're not getting it at academic centers, and community physicians are treating them. Our knowledge will. If they're educated on toxicity management, it touches both lines. They're not getting it at academic centers, and community physicians are treating them. they're not getting it at academic centers and community physicians are treating them Our knowledge will. our knowledge will If they're educated on toxicity management, it touches both lines. if they're educated on toxicity management it touches both lines

Speaker 5: Thank you. Thank you. thank you

Speaker 2: Well, the event has reached 10:33. You've been extremely generous with your time. I would like to thank you. This doesn't mean that we can't continue the discussion after with further meetings and etc. Like this, we'd be extremely happy to take more questions in the future. But I think that we're here on the need to fill the room. Again, thank you very much for your time. It's been my great pleasure and a great volunteer to like this because it's the first time I'm showing this kind of data, and keep up by the end of the year. Plenty of things are going to happen. Well, the event has reached 10:33. well the event has reached 10:33 You've been extremely generous with your time. you've been extremely generous with your time I would like to thank you. i would like to thank you This doesn't mean that we can't continue the discussion after with further meetings and etc. Like this, we'd be extremely happy to take more questions in the future. this doesn't mean that we can't continue the discussion after with further meetings and etc like this we'd be extremely happy to take more questions in the future But I think that we're here on the need to fill the room. but i think that we're here on the need to fill the room Again, thank you very much for your time. again thank you very much for your time It's been my great pleasure and a great volunteer to like this because it's the first time I'm showing this kind of data, and keep up by the end of the year. it's been my great pleasure and a great volunteer to like this because it's the first time i'm showing this kind of data and keep up by the end of the year Plenty of things are going to happen. plenty of things are going to happen In the meantime, there are a lot of data points that you will have to see. N26 will be extremely rich. We are going to present and continue to grow this information innovation for the next year. So thank you very much. In the meantime, there are a lot of data points that you will have to see. in the meantime there are a lot of data points that you will have to see N26 will be extremely rich. n26 will be extremely rich We are going to present and continue to grow this information innovation for the next year. we are going to present and continue to grow this information innovation for the next year So thank you very much. so thank you very much