Cellectis S.A. (ALCLS) Earnings Call Transcript & Summary

Good morning, everyone, and thank you for joining us today. So my name is Andre Choulika. I'm one of the founders and the CEO of Cellectis. And I'm extremely pleased to have you all here for this first R&D day for lasme-cel. And so Cellectis is mission is essentially to try to bring allogeneic CAR-T therapies for safer, more scalable, more accessible type of therapies to all patients. Allogeneic therapies have essentially been providing the same chance to every patient. And when I'm saying the same chances, for example, chemotherapy for now remains one of the main first-line treatment for acute lymphoblastic leukemia, and chemotherapies works really well. However, also, there is a high relapse in -- especially in adults, and it hurts very much immune system. And as much as chemotherapy remain one of the main first-line type of treatment for acute lymphoblastic leukemia, it will hurt also the immune system. And when you come for later lines of products, sometimes chemotherapy, but also sometimes other type of therapy sites such as immunotherapies that would rely on the immune system of the patient; then the immune system of the patient could be also hurt. So when we come up to a series of lines of therapies and the immune system of the patient has been battered, then every patient don't have the same chance. For example, autologous therapies depend upon the T-cells quality of the patient. Same thing, for example, T-cell engagers or the same thing for in vivo therapies. This is why we think that this allogeneic therapy is becoming a game changer in the acute lymphoblastic leukemia. So where is my -- so we're very excited today because today is the moment where Cellectis will reveal the first -- for the first time the data of the full Phase I of our BALLI-01 trial, trying lasme-cel in acute refractory relapse for acute lymphoblastic leukemia. And the first data that are going to be presented to you today are interesting because it's a CAR that targets not CD19, it's not yet another CD19 CAR. CD19 is an overcharged target, and it's very much used, and it works really well. But there is a need for an alternate target. And we believe also that CD22, especially for refractory relapse patient, is a game changer. So here is like today in just a few minutes, Dr. Adrian Kilcoyne and Professor Nitin Jain from MD Anderson Cancer Center, it's like the head Professor of the Department of the MD Anderson Cancer Center, will walk you through all the data of our Phase I for lasme-cel, but will also walk you through the design of the Phase II that we hope will translate into pivotal trial and will be accepted. This will be followed by a presentation of Arthur -- panel discussion of world experts in the field that will share with you their experience and the clinical data that has been generated. Then this will be followed after this by presentation by our Chief Financial Officer, Arthur Stril, who will tell you the lasme-cel and where we creating value with lasme-cel. And finally, we have the pleasure and also the honor to have AstraZeneca, our strategic partner, represented by Mark Cobbold, who's the Head of the Oncology Cell Therapy, AstraZeneca; will share with you also the insights on how AstraZeneca is becoming one of the game changers in the field of cell and gene therapy in general and especially in oncology and the use of this because they have like a very strong positioning in on this side and also parts of the collaboration we're having with them. And one of the things I would like to say also is like the event will end up at 10:30 sharp. With that, I will like to -- I lost my blue. So B-ALL is definitely one unmet medical need. First of all, there's roughly 10,000 patients worldwide -- not worldwide, but in the U.S. [ EU4 ] and the U.K. on a yearly basis. And most of the time, these patients are treated by chemotherapy as a first line. And as we just said before, we have a heavy relapse rate for adults essentially. ADCs have definitely an effect, but it's limited effect as there is a lot of relapses, especially using certain type of ADCs targeting CD50 -- CD22. CD19 directed therapies have 50% relapse also rate afterwards. And all these therapies, based on patient T cells, as said before, where the T cells can be unfit or scarce; have no solution. This is where it's important to come with healthy donor T-cells to try to treat these patients, and this is what we're going to share today. So why allogenic T cell? First of all, the quality of the T-cell can be very, very stable on this side. And healthier, less exhausted T-cells coming from healthy donors and preselected patients can give the same chance to every patient. The patient don't have T-cells, works the same. Patient has plenty of T-cells, it also works the same. The speed of the therapy as an off-the-shelf therapy in BLL, every day counts. We're not talking about like months 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 Cellectis mission in the way we design these products. And finally, CD22 complements also [ preempt ], for example, for CD19-naive or post-CD19 cells or even engaging CD22 could potentially rescue CD19 failures. You will see also that some people that are treated for [ product ] targeting CD22, we can still pick them up with an allogeneic CAR-T targeting CD22. So one of the things -- the prides of Cellectis is our manufacturing. People tend to forget about this. I've been talking about the importance of manufacturing for allogeneic T-cells and usually for all cell therapies. Most of the time, in cell therapies, the product is the most important thing because this is the thing that is going to make a change in the patient. And also at the time of the approval of the BLA, the quality of the production and the way to master the production is of an utmost important. This is why we decided in 2018 to integrate inside Cellectis all manufacturing, I would say, from A to Z because we do the buffers, we do the electroporation machines, we do the messenger RNA, the plasmid DNA, lentiviral 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 storage, 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 value chain. I think Adrian will walk you through P1 and P2. P1 is the process one that has been made at the CMO [ cell procure ] at this time. Since then, it has been acquired by Novartis and things change. You cannot, if you're a cell therapy company, give your manufacturing to someone else because they're not going to treat it the same way you will treat it yourself. And you will see the difference between P1 and P2 is essentially the fact that Cellectis just manufacture a process that we invented, and we make products that have no comparison there. And at the end, you have like an allogeneic T-cells, 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 COGS. And this is in the presentation of Arthur, is really important because if you want to have a product that is a pharmaceutical valuable product, means not with negative gross margin, then you need to control the COGS to make a very valuable product. And we believe that we have this type of product today. So lasme-cel, we're developing this first indication as a bridge to transplant that's going to be represented. 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 don't come back to the hospital, it's over, the patient is considered as cured. It secures -- so like lasme-cel will secure a window. You will see how we secure this, makes patient eligible for an HSCT. You need to be MRD negative for this, not only like as a CR. And this gives a clear path for an HSCT and long-term remission. And also, I will show you that's a very manageable safety profile, and this is something that is so much important. 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 lasme-cel works. Adrian?

Thank you, Andre. Thank you all for being here today. And a special thank you to our three investigators who've been so supportive of this trial for being here to talk 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 context. 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, lasme-cel. 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 lasme-cel. But I will give you a little bit of a snippet of -- sorry, wrong way, where we are with UCART22, which is now eti-cel. These are where we are at the current dose level. Now there will be more data shared at ASH 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. So -- 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 7 patients at the current dose level. Now I know you'll have lots of questions about this, but please, if we could hold that until 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 coming -- the last few years is there's been advances in ALL. But what we've seen is increased access to targeted therapies. So if we look at front line, 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 your response rates. And the mere exposure to many of these targeted therapies also changes your response rates to following targeted therapies. So when we 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 in this trial are very late stage. And we know that many of them have been heavily pre-exposed not only to chemotherapy, but multiple targeted therapies. So for most of our patients, the real next line for them is yet again salvage chemotherapy. And the only real chance they have of getting a long-term remission based on what's currently available is to achieve a transplant. But what we can see from these data here is that getting to deep responses with MRD negative is very challenging with what's currently available. 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, it will allow you to interpret it a little bit more carefully. But as Andre already said, we needed to answer a few questions. One, can we make better product than an external CDMO? We needed to answer that question. What is very topical at the moment is, is an anti-CD52 antibody necessary to optimize response? We have looked at this. Of course, we want to know what the RP2D is, and Professor Jain will share that with you. And of course, touching on what Andre has said, in the context of these very heavily pretreated patients, what is the best outcome measure? What is the best endpoint to reflect clinical value for patients? And we will share with you after we see the data, all of the clinical trial design and timelines, so you'll be very clear of what our path forward is. So this is the trial design. Now there's a number of questions to be asked. Now forgive the simplicity, but all the dosing schedules is in the box in the top left-hand corner. Dose level 3 is the relevant dose here, 5 by 10 to the 5 million cells per kilo. But as you can see, we started off with process 1, and as Andre said, that is our external manufacturer. And we did do dose escalation right up to dose level 3. But then we internalized our manufacturing for a number of reasons. And to Andre's point, nobody knows better how to make these living cells than we do. So we fundamentally believe that cell therapies like allogeneic cell therapies should be brought in-house. But what you will notice is as we transition from P1 to P2, we dose escalated. 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 spirit of maintaining safety, we deescalated and reescalated back up to dose level 3. That's the first part. So throughout the data, you will see a cut of P1 and a cut of P2. Also, you'll see on the bottom, we have FC versus FCA. Now this is very topical. FC is Flu/Cy standard conditioning lymphodepletion. FCA is Flu/Cy plus alemtuzumab. And we will -- okay. Sorry. I'm going to -- I need to keep the microphone close to my map. 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 and 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 for 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 in advance of what Professor Jain will show. Hopefully, it's very clear to you that there is 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.

All right. Thank you. And I guess I don't need it. Good morning, everyone. I hope this mic is working. So let me take you with the data here. Let's see. All right. You use the microphone, sorry. Okay. I didn't. Further on, I got it. All right. So good morning, everyone. So we just discussed this slide. So as it's kind of shown here, we started the study with the FC process, then dose level 1, dose level 2, then we added lemtuzumab, went to dose level 3, then the process changed to P2, as we just discussed. And then we had 3 dose levels, DL2, DL2i and DL3. And you can see the actual doses of the cell ranging from 1 to [ 10 5 ]. Right now, our DL3, which is our current dose, is 5 million cells per kilogram. So that's why overall, the study design had been over the course of last several years. So in terms of the key inclusion criteria for this trial, patient age 15 to 70 years. So we had some pediatric population to say, 15 to 18 years of age, good performance status. And obviously, this is a CD22 CAR, so CD22 expression more than 70%, at least -- more than 2 prior lines of therapy. And obviously, these patients were transplant ineligible getting into the study because they had kind of active disease with the eventual goal that many of these patients hopefully can go to transplant and remission. The key secondary key outcomes included, obviously, the safety of the product, investigator-assessed clinical response, recommended Phase II dose and also PK of alemtuzumab. And then we had several exploratory objectives looking at the CAR-T expansion, persistence and also immune reconstitution. 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 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, was 4. So these are heavily pretreated patients. And you can -- again, if you look at the entire group of 40 patients, you can see 45% had prior allo transplant, 55% had prior inotuzumab, 80% had prior blinatumomab and actually half of the patients had failed a prior -- had a prior CD19 CAR T-cell therapy, which they had failed. And then also I 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 -- especially we are looking at DL3P2. So this is the dose level 3 at the process 2, where we have treated 12 patients overall. And also, we want to specifically highlight the 9 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 high out of 5 prior lines of therapy for this group of patients. And again, you can see the bone marrow blast count of, so far, 60%. So I think that point remains that these are really heavily pretreated patients, who had failed most of these standard therapies, which are available, and then they are looking for next line of therapy. The same thing is kind of exemplified here in this kind of figure here. Again, heavily pretreated patient population, 4 to 5 prior lines of therapy, 80% had prior blinatumomab, 55% had prior inotuzumab and then half of the patients had CD19 CAR T-cell therapy, either TZ-cell or [ buxa-cel ]. 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 makes the 40-patient cohort, the total patients we treated. And as Adrian has showed 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 overall response rate, which includes CR/CRi as well as what is called MLFS. So I should -- 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 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 shows within the CR/CRi population, how many patients were MRD negative versus MRD positive. As you can see that majority of the patients who achieved their remission were also MRD negative. Again, it kind of shows the kind of the same data kind of in a similar way. Again, we are split by P1, P2, specifically targeting dose level 3, 12 patients and then the 9 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 9 patients. We talked about the 9 patients who are at the target Phase II population. So again, to remind everyone, these are process 2, dose level 3, less than 50 years of age. So we happen to have 9 patients in the study who we are [ treated ] in this. And this shows the kind of the swimmer 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 [ CST ] is a patient who had then a transplant. And then the arrows, which are for the 3 patients who are still live and they are censored at that time. So as you can see that -- I mean, in this cohort, all actually 9 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 we have done. The patient #1 or the patient -- the top patient who has the longest follow-up had a transplant and then doing well now close to 19, 20 months kind of down the line. So now this shows the overall survival. This is not censored for transplant. So that's what our goal is to get the patients to transplant. You can see the summary at the bottom here that the median survival for patients who achieved MRD-negative remission was 14.8 months. And again, if you look specifically at the kind of the graph on the right side there, overall, for P2, the median survival was 9.4 months. But if you look at, again, at the dose level 3 patients or the less than 50-year age group patients, the median survival, again, this is a group of patients who had 4 or 5 prior lines of therapy; the median survival was about 14 months. Now one of the important aspect here was to get the patients to transplant, so this -- because we know that for these patients who are multi relapsed refractory at the endpoint 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, you really need to be in remission for patients with BLL. So the goal here and what we are kind of mentioned here is that the Phase II target population, which is those 9 patients we talked about, all of them either have received or are eligible to get a stem cell transplant for this patient population. And then again, it's kind of shown here kind of graphically that if you look at the last bar here, which is the 9 patients, 80% had proceeded with the transplant and the remaining 20% are still in kind of works, the more recent data for these patients. So I think majority of the patients are able to get to transplant, which is kind of the goal for the study. And the transplant does seem to improve the outcome. Certainly, patients who are able to get to transplant, they are doing better than versus patients who are not. Kind of makes sense because then they're able to drive long-term benefit from the transplant. So you can see the curve. The top curve here is patients who -- this is the patients who received dose level 3 process 2. So these are the 12 patients, and then patients were able to go to transplant versus not. Now as we're thinking about designing kind of the Phase II part, one of the things we also wanted to look at is the number of prior lines of therapy. Certainly, when we split the number of patients by 4 or less lines of therapy, there doesn't seem to be a bit of a difference in terms of the survival seems to be the same with less than 4 versus 4 or more prior lines of therapy in this patient population. Now as was mentioned before, right, I mean, these days, everyone, at least moving forward, getting blinatumomab in the first-line setting because of approval of blinatumomab in the first-line setting. Obviously, inotuzumab is approved in the relapsed/refractory setting. So most patients who come to the trial have -- generally have received blinatumomab, have received inotuzumab and many times, they may have received CD19 CAR T-cell therapy as well. Because inotuzumab is also a CD22-targeting drug and obviously, UCART22 is also target CD22, we wanted to specifically look at the outcomes of patients who had prior inotuzumab. And again, as you can see, it doesn't -- it appears to work in patients who had prior inotuzumab as well. Obviously, all these patients, before study entry, were required to have at least 70% CD22 expression. This again shows the CR/CRi rate 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 rates among the patients who had prior inotuzumab. Now you also wanted to look at the group of patients who really had all target therapies. So obviously, these patients had chemotherapy because that's pretty much default for everyone who gets ALL these days, patients who had inotuzumab, patients who blinatumomab and also patients who had a prior CD19 CAR T-cell therapy. So the number of patients become relatively small here. But if you just focus on the P2 dose level 3, 5 and then at the target population, 4 patients, again, these are the patients who have received all 3 kind of approved target agents in the context of B-cell ALL; it appears to be responding to this therapy. And this shows again the same kind of a patient population. Again, the numbers are small, but these are all patients who have received [indiscernible] and CD19 CAR T-cell therapy. And again, this shows a CR/CRi rate. These patients are responding, and they're MRD negative. So like, for example, 4 patients at the target dose, 3 out of 4 responded with CR/CRi and they had -- they were MRD negative. Obviously, we talked about the efficacy part. The next part is the toxicity part, how this CAR-T product is doing. This shows the CRS and ICANS, first for the overall population, all 40 patients who have been treated and this specifically for the 18 patients at dose level 3, which have been treated. So as you can see, in general, I mean, most of the CRS events were Grade 1 and Grade 2. Similarly, same thing for the ICANS, Grade 1 and Grade 2. You can see the Grade 3, 2.5% in the overall population for CRS and then 5% for ICANS in the overall population for Grade 3. And then the right part shows specifically for the 18 patients had DL3, kind of overall low rates of Grade 3 or higher toxicity. Now one of the other things which have been talked about is the IEC-HS, which has been associated with some other CAR T kind of CD42 targeting agents. But in this, we had one patient who had IEC-HS, which was -- which resolved with ara dexamethasone. And so we haven't seen a higher incidence except this one patient who had the IEC-HS. This shows -- these are the -- specifically the related serious adverse events, which was 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 I talked about the overall CRS and ICANS incidents. Only 2 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 graft-versus-host disease, there's only just one patient, which was at the process 1 who had a Grade 2 graft-versus-host disease of the skin, but we haven't seen that in GvHD in the process 2. Now obviously, this is -- the product uses CD52 antibody, so -- which can increase the risk of infections. This shows all Grade 3 or higher infections, which were related to CD52 exposure. So this kind of shows the process 1 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 -- you can see there were 6 patients who had CMV reactivation, again, at the dose level and the process they had. And the investigator assessed the relation to alemtuzumab, cyclophosphamide or fludarabine. Now as we mentioned in the -- how the study started very early on, initially, we were only using FC without alemtuzumab. This is when the trial started with process 1. Then we moved process 1 with FCA and then process 2 with FCA. 5 patients were treated. The first 5 patients on the study were with FC alone. And at that time, we really didn't see any response in these 5 patients, making a point that, at least for this product, I think alemtuzumab is important. I think that is my part of the study. So I'll hand it back to Adrian. Thank you.

Thank you, Professor Jain. So I'm now going to talk you through the next steps as we're transitioning to our pivotal 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 our end of Phase I and scientific advice meetings with both the EMA and the FDA. And these were very encouraging meetings. They all -- they both agreed that this was an area of specific unmet 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 endpoints 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 of 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 that 3 months between day 28 and day 84. You will notice from Professor Jain's presentation that our Phase I program covered patients 15 to 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 aged 12 to 50. And this does two things. One, it gets us a registrational data, but it also satisfies a significant portion of our pediatric investigation plan, which we're also working on right now. And we'll talk about that in a couple of slides. Now we also -- 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 mode of action of a CAR-T, do we need higher levels of expression like we've seen in the INNOVATE trial, et cetera, 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 INNOVATE trial, for instance, I think the median CD22 positivity was in the region of 98%. So we know that we'll -- 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 2 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 20 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 inferentially seamless design. So the patients in the dose optimization at 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 will be based on CR/CRi at 3 months following full recruitment. You will note that we have a follow-up analysis for overall survival, which will be up to 2 years because as you've seen from Professor Jain's presentation, we believe that one of the challenges we've had in our 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 3 months, most patients had already had a transplant. And because we were sensoring for transplant, it's very difficult to show durability of response. Moving forward, because we won't be sensoring 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 pediatric investigation plan. The current Phase II program will capture patients from 12 to 50, but we will also have almost parallel pediatric plan looking at patients from 0 to 12. So we are capturing the majority of patients from 0 to 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 -- the protocol has been submitted to the regulatory authorities. We are now open -- we are now setting up our study to -- and because we want to accelerate this, we have increased the number of sites we are 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 towards. We are, of course, hoping that we can beat those timelines, but we anticipate towards 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 in recruiting. The second interim analysis comes fairly quickly after in second quarter of 2027. And that will be at 50% of the pivotal cohort. By Q3 '27, we anticipate we will have completed enrollment. And then we know that we have our 3-month follow-up for CR/CRi, we will -- should have our primary analysis complete, allowing for that in 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 2 BLAs because throughout this, we have 2 investigational products. We have lasme-cel, but we also have alemtuzumab. So by second half of 2028, we will be submitting not 1, but 2 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 Hospital 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 Cannon -- awesome. Sorry. 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 2022. So his insights are really helpful to us. So what we wanted 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 need that we're addressing? Maybe we can start with you to get a European perspective, Professor Boissel. Talk About the unmet need of these particular patients.

So yes, let's start with European point of view. So we're not so far from what our colleagues here in the U.S. are doing for patients in children and adults. We are, of course, now exposing our patient to blinatumomab frontline. So all the patients, including in first or second relapse, have been exposed to blinatumomab, CD22-targeted inotuzumab and also CAR T-cells. So may be surprised to speak about first-line ALL because it's not something that we -- that has been usual in prior study, but that's the reality now. So we have a lot of drugs to propose to our patients and mostly CD19 targeted. What is probably also changing now in Europe is because of the use of blinatumomab frontline, we will postpone allogeneic stem cell transplant to second line. So we were traditionally more transplanting patients frontline that our colleagues here in the U.S., but I think we will come closer to -- in terms of practice because of the use of targeted or immunotherapy frontline. And so obviously, the patient we will have to deal with in terms of relapse or refractory status will be exposed to CD19-targeted therapy with 2 different profiles, those who will lose the target, so will be CD19 negative; and those are not completely identifying so far as those who are an immune system that is unfit either to respond to blinatumomab or to provide efficient CAR-T, even it's something that is still unclear. So there is always a question about the fitness of the T-cell of this patient exposed frontline or at relapse. So I think that yes, the first surprise about these results is how the patients were exposed or have the high rate of prior exposure to immunotherapy, I think none of the study or pivotal study we have done for ALN in relapsed/refractory setting showed this kind of profile of prior exposure. So it's clear that fourth line and 80% of blinatumomab, I don't remember exactly, 55% or 60% of inotuzumab and the high rate of transplant is something we have never seen before. And so clearly, these patients will require to have, yes, such innovating strategy as presented before. So of course, I think that the agency is required to move to relapsed/refractory setting. But when you are addressing the question of unmet need 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 because the E1910 study that led to the approval of blinatumomab frontline was for MRD-negative patients. So there were MRD-negative, good responders to chemo and then bridged to blinatumomab. So there are good responders. But we know also from European studies then if you consider the overall population of patients, we will identify very rapidly patients that are so not refractory but MRD positive of the chemo and that do not convert to MRD negativity and especially with the high sensitive MRD tool that we are using now. So -- and this patient, we know that they have a quite high risk of progression and that in this situation, it's not a good option to bridge them to allogeneic stem cell transplant with this MRD-positive status. So it is clear that also this kind of population, so early phase or early line patients will benefit from a strategy like lasme-cel.

Great. Thank you. And Dr. Ramakrishnan, you've put a number of patients on the trial recently. Well, you're probably the most recent recruiter of the trial, so thank you for that. What's your general -- you've seen the days on now. And with your experience, what's your general view of the products with lasme-cel, UCART22? And how you see its role in therapy?

Well, I think my perspective always comes from a transplant perspective because that's my background. So any tool that helps me bridge my patient to transplant, which can cure them, especially if we get them into an MRD-negative state, the advances in transplant regimens and toxicity management; we have very good outcomes. So getting them into an MRD-negative state is quite critical. Regarding that, the 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 and actually activity, it's very, very encouraging. I think the other thing, I've worked with some allogeneic CAR-T therapies for some years now. And I want to highlight what Andre said, the manufacturing, I think, is very critical because 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 a 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. It's 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 going through this process. So it's been very encouraging.

I think I will just send 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 autologous CAR T-cell therapy, which have 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 -- you cannot collect. There's nothing to collect. I mean there are no T -- circulating T cells. So I think -- and that's a challenge specifically for BLL, maybe not so much for NHL. I mean, maybe, but because BLL is a bone marrow disease. So I think that's also a point that I think for -- specifically for BLL and allogeneic CAR T-cell therapy would have a point because you don't need to worry about blood counts. So the cells are already premade. So I think that's another important point we sort of routinely run into issues in our department trying to say, "Oh, let's do CAR T-cell therapy. But oh, the white count is 0.2. Okay, we can -- we're talking about autologous CAR T standard of care and oh, we cannot do that because there are no cells to collect." So I think that is a potential challenge for BLL as well.

What was really interesting when I met with you a few weeks ago, and 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 rates, if I'm being honest. So maybe we'll start back with you, Professor Boissel.

Yes. The question was, I think, obvious because we have the experience about the CD19 and repeated CD19 targeted therapy, so blinatumomab and then CAR T-cells, and we have now nice data also emerging from real-life experience here in the U.S., where we know that prior exposure may have an impact on the early response, but also on the risk of progression of the response to CD19 targeted CAR-T. But the mechanism are a little bit different in terms of [ CD22 expression modulation ] between CD19 and CD22. But we know that -- and also from daily experience, exposure to CD22 with inotuzumab may modulate sometimes transiently the expression of CD22. So we start to have some data, but I think it was very important to have this analysis done. And so yes, I was indeed surprised by the results you showed me yesterday because it doesn't seem to number quite small. But yes, we have to confirm that, but there is no clear evidence that prior exposure to inotuzumab may modulate the response to lasme-cel. So yes, it's something that is encouraging, clearly.

Yes. Dr. Ramakrishnan, would you have a view on that?

Yes. So I would concur. I think with a lot of blin usage, what you see is downregulation of 19, and those patients are no longer eligible for CD19 CAR-T because we can't detect the target. So I was a little surprised with prior inotuzumab. And the majority of patients are getting it. Perhaps the mechanism of resistance is a little bit different in the targets is still -- I mean, it is a different type of approach. It's an ADC versus a T cell redirecting agent. So -- but it's very encouraging that I can tell you, I had patients with heavy [ ino ] exposure that went into an MRD-negative remission. So very encouraging.

Yes, I think continuing the same thoughts, I think for -- as was mentioned, I think for CD19, it's more of an issue because of the loss with blina and obviously, after CD19 CAR T-cell therapy. I think for CD22 with inotuzumab, yes, there could be some loss, but it's not very as frequent as has been described with CD19. So I think in that sense, I think it's in a way good because you're preserving your target even after prior exposure to inotuzumab, but also the fact that -- which is encouraging is that, yes, you had prior exposure to inotuzumab, but all these patients are still sensitive to another CD22 targeting kind of agent. So -- and I think moving forward, I think it's quite likely that I think at least in the U.S., certainly, I think a lot of patients will have prior [ blinatumomab ] for sure. And I think a lot of these patients, as we saw in the study, will have prior [ inotuzumab ] exposure before they go into the CAR T-cell therapy.

So I think we also have to address the alemtuzumab issue. Now we have seen that alemtuzumab appears to be very important in achieving a response. 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 to get your view on using it. Maybe we can mix it up. We'll start you first.

So when I first took on the study again, alemtuzumab, I heard that -- and 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 letermovir for prophylaxis. And that's pretty much gotten rid of that issue for the most part. We also have other drugs. So I think that the key aspect there is having those anti-infectious prophylaxis and being on top of that so that you manage that with your patient good antifungal prophylaxis with posaconazole and 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 product.

Yes. So I think my previous -- we use alemtuzumab for a different disease T-cell PLL at a much higher doses for much longer. And there are certainly -- I think CMV reactivation and all these is an issue, is a challenge. But here, as we kind of discussed, we're using much shorter duration. Overall dose is much lower than what we use for PLL. And again, I think with the infectious prophylaxis, monitoring the patients closely, I think, thankfully, the infectious issues have not been a major issue with alemtuzumab. And it appears, as we just discussed, at least for this product, use of alemtuzumab appears to be quite important in terms of cell expansion.

A few things to add. We are also using alemtuzumab for some transplant or I think we used to manage this infectious AEs that are not that impressive in terms of viral events in the first patients here. Of course, the randomization of the Phase II will be important to explore the 2 dose levels. And I think it was -- yes, it was required by the agencies, but it seems wise. And yes, so happy to go forward with this kind of questions.

Good. Thank you. I suppose I have maybe one more question. I'm mindful of time. When we look -- and I know the numbers are really small, and we have to contextualize -- we have to interpret it based on the small numbers. We have those really heavily pre-exposed to targeted therapies, getting those level of MRD-negative responses, which we 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, be it the next available salvage therapy, if at all? So maybe we'll start with you first, Professor Jain.

So I think if you're talking about patients who have 3 or 4 prior lines of therapy and who have failed, obviously, chemotherapy, blina INO and maybe a CD19 CAR T-cell therapy, I think then we are really -- there's no approved available agents. I mean chemotherapy at that time will have a less than 20% 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 are talking about, again, response rates of, I don't know, hopefully, 20%, 30% response rate where we hoped and then they're MRD negative and then they can take them to transplant. So I think if you go -- I think -- and that's an important point. I think also, I think in the ALL, I think if you go 4 or 5 prior lines of therapy, these are really -- I mean, I think -- I don't think there's anything standard here, and we are talking about really very dismal outcomes, unfortunately. So...

I would concur. I think I typically -- when I see these patients, I 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, if we don't have anything, I call Nitin and send the patient to him to 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 2-year-old kid. And just imagine sitting in front of that person and telling them, "Yes, we got nothing else." And to be able to take that type of individual and give them a product that gets them MRD negative, gets them to transplant and 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 give patients that type of outcome.

Yes, it's a difficult question, but -- and I'm not surprised because other study have shown that when you treat a median of 4 line and you compare less than 4 line and more than 4 line, you don't see any difference. So it's important for this drug, of course, to move forward and -- particularly and come back to the MRD-positive population of patients first or also second line because we have to deal also with this kind of patients in second line. And I'm very happy to see the results of this kind of strategy. I think they are built also for this kind of patient and of course, not only to be used in third or fourth line, so advanced phase of the disease.

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, where CD19 CAR is coming earlier in the line of treatments. And -- 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 need 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 can get durable remissions. 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 need to wait to see. It's early days, but also encouraging so far.

Great. Well, thank you so much. In the spirit of time, I would say thank you to our three investigators. Thank you for your ongoing support. And I'd like to hand over to Arthur Stril, our Chief Financial Officer and Chief Business Officer.

Thank you, Adrian. So good morning, everyone. Thank you so much for being here. None of what you've seen today, and we'll see in the coming months, would be possible without your support. So 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 lasme-cel’. What are we talking about in terms of sales and commercial opportunity? Now if you have to take two key 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 is peak sales from autologous therapies with razor-thin margins and individualized complicated therapies to scale. And there is 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 this is this kind of peak sales that Cellectis is bringing forward today. So you've heard a lot about lasmo-cel. 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 fully internalized manufacturing, which will be highly beneficial for a fast uptake upon BLA -- 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 a [ BESPONSA ], it's an ADC. So it doesn't fully 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 lasme-cel’ 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 [ AUTO19 ], 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 lasme-cel 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 incidents 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 2/3 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, annually. And then finally, we apply a last cutoff 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 that 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 cells would be about 1,900 patients. Now of course, this is the addressable market. And to get into peak cells, you have to have an estimate of what is going to be the preference for lasme-cel. So as you have heard during the panel from Adrian and our physician experts, we think that lasme-cel will be a very promising opportunity for the third line and above markets. Lasme-cel is an alternative target to CD19. It benefits from the convenience of a one-off dosing. It's obviously an off-the-shelf availability, so no need to extract T cells, 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 setting. So we estimate based on oncology precedence, but also interviews from physicians, preference 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, which is the case of chemotherapy, as we have just heard, would not be the prominent therapies once lasme-cel is approved. Second, we think that lasme-cel 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 -- an anchor price in 2025 of the average price of the approved therapies, Tecartus and Kymriah, and we project a flat pricing until a year of peak sales, so 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, Aucatzyl and Tecartus, the 3 autologous CAR-Ts that were approved. The current anchor price for 2025 has been about USD 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 USD 840,000, now we are going to bring this all together, looking at the target patient population, the expected price and the expected preference share. So if you look at the initial addressable patients, you come back to about 1,900 patients, which is the number that was -- that came from the previous slides, about 1,100 in the U.S. and 840 in EU4 plus U.K. 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 480 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 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 expand lasme-cel in other areas. We think that lasme-cel has the potential to have a place in the second line and we think that lasme-cel has the potential to have in first-line MRD positive consolidation in place, pretty much like Blincyto, especially as you're going in earlier lines of treatments where patients are more fit. So if you factor in an additional opportunity for these label expansions in the future, we believe that peak sales could increase to up to $1.3 billion with this additional label expansion. So to put it all together, we think that lasme-cel again, has a very strong commercial opportunity. This 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 sale 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 peak sales territory. So thank you very much for your attention. And I will hand it back to Andre for the next steps.

Thank you very much, Arthur, and hold your horses because you're definitely going to see things you thought with science fiction, but we're making it real. As we said, we might have like an update soon, and that's going to be really interesting. So I'm going to make a quick conclusion on the presentation that we saw this morning. And then we're going to open Arthur, myself and Adrian, question for -- like Q&A session and answer your questions. So Adrian presented this slide, a few takes away that I think are extremely important on your side, we're deep believers in the fact that allogenic CAR-T therapies fits definitely needs in various spaces in oncology and potentially beyond oncology, as Mark has just showed it, in autoimmune disease and maybe beyond this. And it's interesting for the simple reason that you get a really standardized product. And this is all the difficulty is to make it super stable and standard and reproducible. And this is something Cellectis know how to do. We've been doing this for more than 10 years with CDMOs, some difficulties. Remember, the first patient we ever dosed was UCART19 10 years ago with an allogeneic CAR-T. So we made the CAR-T before 2015. So that was 10 years ago. And like UCART19 like is now like ALLO-501, not ALLO-501-A, but ALLO-501, 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 a pharmaceutical commercializable product that would give the same chances to every patient. Same chances to every patient. Remember, you have T cells, you have no T cells, it works. Why, for example, an ADC 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 a T cell -- of the target cell. For an ADC, it's 10,000. Below 10,000 is not going to work. This is why, for example, some failures of ADCs gives the same chance for a CAR because it will be few hundreds. We don't know exactly the number of tumor-associated antigen that needs to be expressed under surface, can still take them down. 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 and coming with something even if you don't have T cells, the patient have like few blood cell counts still works. So we're excited about this. And also, we're excited by the strategy that has been developed and also endorsed by regulatory bodies in terms of making this first product the best chances for a patient go for bridge to transplant. This is something that is totally innovative and a game changer. So first patient would be recruited this year by the end of the year, we'll have next year an interim analysis for patients and then it will continue up to the enrollment and then we'll have the BLA in 2028. So lot of things to do in the meantime, of course, like opening 75 sites, et cetera, but we have a clear road to success for this. Well, the strategic road map, something that you need to keep in mind for Cellectis, we're not all about lasme-cel. We're super excited. We believe lasme-cel is a game changer. We believe it's a product that definitely fits the size of Cellectis and the ability to develop a product like this with a very valuable product. And something that have given asymmetric value creation for a company our size, and at the place, where we are today. So I really consider this. The second thing that you have to keep in mind that after lasme-cel, you have eti-cel, talked a bit about eti-cel. There is like a bit of a peak on where it goes, but it's 20/22, still not in 19, still a very high unmet medical need with a product that has a dual targeting and like a very nice strategy because you can grab even 2 targets instead of only 20 -- CD20 and CD22, and you will have also a bit of information by the end of this year at ASH. So keep an eye on ASH. But that will be end of Phase I in refractory relapsed non-Hodgkin lymphoma 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 present this. And finally, a bit of a peak of the preclinical proof of concept in 2026 of in vivo gene therapy. Gene therapy has been always very complex, have to take the cells out, it's complicated, et cetera. But if you take a pair of mRNA, package it. It's something that can bring this to the right cells inside the body and can do this as an injection IV, who had RNA in vector that was injected in the blood in the room here. I'm not asking the question to raise your hand, but it's something that has been acceptable since many years now, like probably 4 -- 3 or 4 years. And so it's something that is going to be the game changer in vivo gene therapy, and we believe that our technology, and I should say, our technologies because we go beyond nucleases, base editors, modifiers, epigenetic modifiers, et cetera, is something that is going to go in vivo and is going to be a shot with something that can be -- also have very powerful and decent CoGs and that would give probably also something that would play more on the EBITDA at the end of a company and allow us 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 task, and we're doing this. With that, I would like to thank you again for your attendance, and I'd like to open the questions for the audience. Adrian and Arthur, please.

So we'll start by Gina.

Is it working?

I don't know. Yes, yes, that's working. Yes, go ahead. That's working.

First, I wanted to say congratulations. It's a great update. You really covered a lot of the questions and that's very impressive data. So I have -- I'll try to limit myself. I know a lot of questions will be asked. I will limit myself to 2 to 3 questions. One is about lasme-cel pivotal study. I just want to confirm the trial design is confirmed, agreed by the FDA and EMA. And 1 question is for the 2 doses. I assume, one, including dose level 3 and the other dose is a higher or lower dose. And then what is the definition of success given the primary endpoint strengthening CR? So that's 1 of the questions, sorry. And then the other question is about manufacturing and also AstraZeneca. So the manufacturing, I think you share the square footage. So what is the capacity here, current capacity and future peak capacity. And I assume, will be also part of helping AstraZeneca providing certain products, right? And then related question is when will we see the pipeline of the collaboration from AstraZeneca? And will we see the data from Cellectis collaboration?

So I may take first question. There's probably really 5 questions. That's a great question. So yes, we're completely aligned with the regulatory authorities. The biggest issue is really finding the right end point, and I think we've got there and get agreed with that really, this is a single-arm trial. So yes, there is with that. There's a bit of clarification from my end and sorry if I didn't make it clear. There's no dose optimization for lasme-cel. It's dose level 3. That's our recommended Phase II dose. The dose optimization is actually for alemtuzumab, where they want us 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 will be that first CAR-T patients. So we will not be testing any alternative doses of lasme-cel. There was another question that was there.

I think that's it. And what is the definition of success for primary endpoint? Because you only say CR is like 3 months, right? So what is defined as you have 2 arms. Is that comparison of the 2 arms or FDA set a threshold, you have to reach a certain CR rate in order to define as a success.

So for a single-arm trial, there's always the same wording from 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 when you -- that, that is probably a threshold many patients wouldn't meet. We have exceeded that quite significantly as our marker of success, and that's been generally agreed as appropriate. So we believe the threshold is probably -- the data we have here, if we hit this, we will certainly surpass our threshold.

So for the manufacturing question, yes, we share the square footage. Well, 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. It's like the nice picture of this building that you see is the entrance of our building in Raleigh. Some of you have visited, I see some 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 it is set for commercial production. We have currently 1 suite that is active and allows us potentially to produce up to 4,000 doses a year, which covers way more than what is needed in terms of completing, for example, lasme-cel and eti-cel, et cetera. We're -- as we're opening our collaboration with AstraZeneca, we decided to enable a second suite that will have the same capacity, and we have spots for 2 other suites, so 4 in total on 1 side of the building, but the second side of the building can be cloned on the other side that would allow 2 other suites. So we will have 2 suites that will be ready to go within -- by the end of next year and -- or early '27, but it's something -- but it's supposed to be by the end of next year. So it will increase the 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 like that many vials. But once we believe that we can supply the whole world in terms of the 2 products that we have, and potentially also some of the product that we will be producing for AstraZeneca, and there is no limit for this. So the Raleigh site can fill with multiple products, the global needs for even larger indications also. And then the last -- so Mark said it 2026, maybe a first peak on the things that we're going to do, right? But I speak under the control of Astra. It's like 26 -- "Oh, no, we don't want you to share this [ because it looked ] so great, then we'll not share because they're our partners, and we do what our partners are willing to do.

I'm from Wells Fargo, and thanks for the invitation to the R&D Day. I was wondering if I can ask a question to the doctors. If any of them would like to comment, I was wondering in terms of using lasme-cel, would the doctors use it exclusively after Blincyto and autologous CAR-T? Or is there scenarios where they can use it because this is to be followed by transplant, right? And essentially, will they use lasme-cel followed by transplant as an alternative to either cycle?

Perhaps, Nitin, you can take?

Sure. Yes. I think right now, as you know, Blincyto is approved in the first-line setting. So practically, every patient in the U.S. is getting Blincyto or blinatumomab in the first-line ALL setting. So practically all patients will have been exposed to Blincyto coming onto the lasme-cel. In terms of the -- whether they need to be a CD19 refractory, in the trial, you saw 50% of the patients had a prior CD19 CAR-T cell therapy, but as I said, during the discussion, there are patients who cannot get an autologous T-cell collection done because the counts are too low, there are no T cells to collect or there may be situations where you want a quick CAR-T -- there's no time for bridging and like cell collection or leukapheresis, all those things are taking too much time and where you want to go quickly to your cell product, where the having an allogeneic product is helpful. So I don't think it's a requirement per se that you must fail in CD19 CAR-T to go into this. But I think -- and there will be some situations where certainly this may be kind of preferred just because of the logistics issue and how quickly you want to go to the CAR-T.

And also to a company, I think you talked about regulatory bodies agree with the importance of transplant, but in the label or in the trial design, how is that reflected? Will the label because CR/CRI, that's transplant, right? Would that reflect or will that be officially recognized in the label?

Yes. It's the great question. So yes, we agreed with them. They wanted to see efficacy first, which is CR/CRi. That's what they want as the primary endpoint. However, within the design with including key secondary endpoints, we will be capturing the proportion of patients who become transplant eligible. And that will allow us then to capture those patients following up. We will not be mandating a transplant, but all patients entering the trial would be considered to be -- to benefit from transplant, and that is the goal of the treatment. So I think the design has allowed us to capture what I would consider a more traditional endpoint with, however, the aspirational endpoint of showing that getting these patients to transplant with the follow-up and improvement in overall survival would that actually give us the label that we are seeking.

Jack?

Congrats on all the obvious very impressive data. I guess maybe the first 1 is for 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 T cells ALL? And how do you think about that when you're looking at potential treatments that can be bridged to transplant?

It's probably worthwhile getting a U.S. and a European view on this. So maybe Professor Boissel, do you want to...

It's not different to Europe.

It's not different. Okay. It's not different. So you -- Dr. Ramakrishnan, you're in the community setting. So perhaps there's a...

As far as getting a donor for transplant, the era where we need to match is going away. In fact, we're doing clinical trials right now, where we're doing mismatched-unrelated donor transplants and having similar success rates. So 6 out of 8, 7 out of 8 or even a trial with deceased bone marrow registry source that we can use for transplant. 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, have to do that, we send a [indiscernible] MD Anderson and that pretty much covers everybody. I think you can pretty much guarantee 100% if you needed a transplant, there's a donor out there for you.

Great. That's great context and incredible to see the innovation in that space. And then maybe to Adrian on the design of the Phase III study. I guess you mentioned that maybe the comparator is on the 20% to 25% response rate, but also, I think earlier you talked about still looking at the literature. I'm not sure if that pinned down that external control. And if there is any changes in the assumptions around that external control, would that dictate the size of the study as well. Is that ENVISION study locked in? Or did you go lower 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 database required for BLA. 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 we're going to get these patients from? Is it a mixture of databases versus academic institutions, there'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.

Great. And maybe just 1 -- last 1 on the study design. You mentioned that alemtuzumab doses that are going to be tested in the pivotal study are going to be dosed down. I just want to hear any context you can provide around contribution to components in those discussions with FDA and their reassurances of the ability to show that with your current plan.

Yes, 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 2 doses of alemtuzumab 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 it. If this is still open label, we want to make sure that patients are not underexposed to alemtuzumab. 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 is underexposure and over exposure look like because what we've tried to get, and I think it's 1 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 early host 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 2 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.

So congratulations on progress and presentations. So just 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 environment or agency or 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 show today, the importance of the FCA regimen here and the company's vision.

Yes. I'll take the first one, and Dr. Ramakrishnan, since you are kind of a community-based practice, he can answer the second question for you. So in terms of 1 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 comparator arm looks like. So it will require a significant amount of propensity score matching. Now as we're looking at our databases, we decide, well, how many patients do we need in the database to qualify 1 patient in our external controller. 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, but it's actually fairly 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 we'll be able to fulfill the requirements. And Dr. Ramakrishnan?

So the question was...

Alemtuzumab and [indiscernible] toxicities.

I think the -- more than that, I think 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 alemtuzumab, I think that itself, I'm not too concerned about toxicity-wise, has been around for a long time. People have used it. We have patients in the community with T-PLL who are getting alemtuzumab. They're not getting it at academic centers and community physicians are treating them and are knowledgeable if they're educated on toxicity management, infection prophylaxis.

Thank you. Well, the event have reached 10:33. We'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, et cetera. Cellectis would be extremely happy to take more questions in the future. But I think that for here like we need to clear the room. Again, thank you very much for your time. It's been a great pleasure and a great moment for Cellectis because it's the first time we're sharing this kind of data. And keep it by the end of the year, plenty of things are going to happen in the meantime. There's a lot of data points that you'll have to see and '26 will be extremely rich. We are going to present and continue to flow you with information and innovation for the next years. So stay put on Cellectis. Thank you very much.