Well, thank you, for attending Jefferies London Healthcare Conference. My name is Kelly Shi, one of the biotech analysts here. For this session, we are very pleased to have Mr. André Choulika, CEO from Cellectis, for this first session. Maybe we can start off with, the overarching debate of, autologous and allogeneic CAR T approaches. How do you see the opportunities for allo CAR T? Thank you. Well, personally, I have difficulty to see some future for autologous CAR T in the long run. One of the main reasons is the ability to find an apheresis center to treat patients. And today, you see that most of the sales and most of the CAR T that are developed, would it be Yescarta or Carvykti or Abecma, or also Kymriah. There is a plateau for all these things, and this is mainly gauged by apheresis center. You need to get your patient to an apheresis center, and this is not the business of pharma company to build apheresis center. At the top of this, you have all the clinical trials. At the top of this, you have not only the onco CAR T, but you have the autoimmune CAR T that are coming in. How we're gonna solve the problem of having all the patients funneled to apheresis center, getting the apheresis, sending the apheresis to a treatment center to the CAR T and send them back? All this logistics is something that seems, for me, unsolvable, not only on the short, but even in the mid or the long term. Therefore, I think allogeneic CAR T, when they will start hitting the market, will totally wipe out indication after indication, all autologous CAR T. And it seems crazy to me to continue to develop autologous CAR T in this space, would it be autoimmune or oncology, because I think that the limit of the sales will continue to plateau. I was talking, for example, with one of the commercial at Johnson & Johnson, and he's telling me, "Like, we can reach only 3% of the patient we can, we can treat," for the simple reason that they cannot reach apheresis center to be treated. And that's the limit. So I think at the end, on par with most of the data that autologous CAR T are showing, allogeneic CAR T are gonna flow in the space. Point taken. And, what is the differentiation of TALEN gene editing platform Cellectis actually develop, versus other, approach in realizing allogeneic CAR T therapies? Well, Cellectis gene editing platform is multiple. So we do nucleases, TALEN-based, like DNA cutters. We do also TALEN that can do like TALE-based, base editors. There's a lot of other things. One of the main power of a TALEN is the precision of the technology. It can cut right at the base almost, compared, for example, to CRISPR, that have a PAM constraint that can cut within the 70 base pairs most of the time, and if cannot do it, then you have to drop it. The second thing is that it promotes homologous recombination, DNA-targeted insertions in a very high rate. It's just not a knockout system. It's a repair system. Mm-hmm. It can insert, replace DNA, and it's very flexible in this term. And finally, one of the things we like on our side, especially in manufacturing CAR T, you have a very higher survival rate post-editing. So we think it makes way less damages to the genome, and also it promotes a lot of, like, good survival at the end, and the quality of the cells are better. And the quality of the cells, especially when you're manufacturing CAR T, is at the utmost importance. Terrific. And with this great intro, could you walk us through the pipeline candidates you currently focus? So we have, of course, products that are partnered either by Servier, Allogene for ALLO-501A in non-Hodgkin lymphoma. There is with Allogene, some products for multiple myeloma, but also for renal cell carcinoma. And we have, like, a program with Iovance on solid tumor CAR tumor-infiltrating lymphocytes that I'm let them talk about, but I'll mainly focus on our portfolio, which is essentially, the first product, which is UCART22, in BALLI-01 trial for to treat acute lymphoblastic leukemia, is currently switching from last year, when we showed data was like 50% complete response at DL3 from the product that was manufactured at the CDMO. We switched to internally manufactured fully internally manufactured product. So today, Cellectis manufacture 100% of the product, everything from raw materials to the final product, and we have today ability to produce clinical vials. But the objective is to make commercials, also vials, and the facility is set for this. And we're gonna show data at ASH for this, but I can already tell you what are the results because they were presented in the abstract that were revealed at the beginning of November. So with a dose that is five times lower than DL3, where we showed 5% overall response at last year at ASH. So with DL2, which is 1 million cells per kg versus 5 million cells per kg, we already have 67%- Mm-hmm. of overall response. We think this is a very encouraging data. We're gonna continue the dose escalation because so far we have no adverse effects, no ICANS, no CRS grade over Grade 3, no neurotox, nothing like that. And we believe that the potential for this product is that reaching very rapidly the what's called the RP2D next year, and declare RP2D and move on after the end of a phase 1 meeting into the expansion that can be turned into a pivotal because ALL, when you look at CD22, it's the only allogeneic CAR T, only allogeneic CAR T. There is like an autologous CAR T, obviously, which made a lot of noise by the end of this year with data that are not on par with what we have. We'll also show some durability data with the first cohort that we've done with the CDMO product, with an allogeneic CAR T, with very good data. It's gonna go for, like, a pivotal trial. So that's the first thing. The second one is interesting also because we're showing data at ASH, and I invite you all to come and see our poster. It's the first dual CAR T, targeting CD22 and CD20 together, and we started with a flat dose that is 50 million cells per patient, with a preconditioning with cyclophosphamide, fludarabine, and alemtuzumab. Mm-hmm. As the cells don't have allogeneic knockout in CD52, you should count, like, around, like, 40 million cells per patient. Mm-hmm. That is super low dose. We have already 100% complete response overall response, and it's continuing. So these, the data for UCART22 and UCART20x22, are the data with a cutoff in May this year because, like, you have to submit the abstract end of July for ASH. So we're expect probably in the future after ASH to have more meaningful data that will be presented. And last but not least, UCART123 in acute myeloid leukemia. We're very excited by this CAR T because we showed last year data with a DL2 single-dose patient, for example, that have over one year of survival. Patient that had, like, weeks of life, over one year of survival with no bone marrow transplant, nothing. Today we're doing double dose, so two doses at DL2, 14 days apart, and then our intent is to increase the second dose. So the first dose at DL2 shows 6.25 × 10^5 cells/kg, essentially debulking dose. If you increase too much the dose, you have adverse effects. So, like, you go for, like CRS Grade 3 and 4, so that's a bit risky. At DL2, it's quite safe. You have a very meaningful blast reduction, and the second dose can be similar to DL2 or more massive- Mm-hmm ... where you won't have all these side effects. We'll treat the MRD positivity at the end and give a potential for the patient either to go for a bone marrow transplant or to stay without it, as like some of the patient decided, and have a longer survival. So we're super excited by these products, and we think that there will be meaningful data sets, like, in the coming weeks for ASH, and 2024 will be a very rich year for both of them. Terrific. And for UCART22 and also the dual CAR 20x22, do we expect a longer follow-up and also the next dose-level data at ASH compared to what's shown in the abstract? So given the context, I would say that is not the greatest context I've seen in the lifespan of biotechnology. And seeing a lot of companies putting data was not the expected. You know, I, I've seen some data from our competitors and, like, rejoiced in seeing them say, "Wow, this is fantastic!" I've seen some stocks dropping. I'm really considering if we will pull more data and burn this data at ASH or keep them maybe for better times in the coming months. So it's really communication concept, but we've been enrolling more patient. There are, like, exciting things that we'd like to show, but is this ASH the right moment to reveal these data or just stick to it? It's something that I think that the probably the second option would be the best, like, just to keep it where we are. Great. And what do you think of the bar on durability, for both? For example, the 3-month, 6-month CR rate, do you think, it should reach to the same level with the autologous has shown? I think it's gonna be better than autologous. Yes. Oh, so your bar is higher than- Yeah, it's higher. Absolutely. Currently, we have better data than autologous. And second, there is a start, like, for CD22 autologous, but essentially, I think it's gonna be non-Hodgkin lymphoma. For ALL, there is no frontal competition. I think it's the only CAR allogeneic CAR-T for ALL, and essentially it's compared with CD19, but comes after CD19. For 20 by 22, there is no comparables. Okay. So... Great. Mm-hmm. Regarding the lymphodepletion regimen, you mentioned alemtuzumab was added, and do you see additional safety signals actually from this regimen? Absolutely. I think there is, like, a better safety signal with preconditioning with FCA versus FC. We've done both cohorts, actually. We've shown this for UCART22 and for UCART123. We decided to abandon the arm without alemtuzumab, and we've seen absolutely no difference in, for example, an increase in infection or fungal infection or viral infection in patients receiving FCA. However, when you go for a treatment with alemtuzumab, adding on this, you probably tame a bit the cytokine release syndrome because it contains also the other cells. So we think that there is an added value to bringing alemtuzumab in terms of safety for the patient at the end. ... Great. That's essentially from, like, the AML trial. Okay, and I want to dig a little bit deeper into the dual CAR 20x22. First, can you actually share details on how many sites are open at the moment, and do you plan to expand the study sites in the near future? And the second question is, regarding the 20 and the 22 expression level, how does it compare to CD19? And the third question is, do you see potential for this dual CAR in the post-CD19 autologous CD19 CAR settings? Well, it's three great questions. I'll try to remember them, so - I'll repeat. I'll repeat, don't worry. Yes, like, we have, like, many sites now. I think, like, we're close to 10 sites in the U.S. We have, like, many—like, few countries that are open in Europe. For example, we have, like, France, Spain, et cetera. And our plan is also to expand because we think that very rapidly, we're gonna reach the RP2D next year and go for an expansion with this. And it might not be like a pivotal expansion, but it might be an expansion. And, we're gonna continue to open essentially the big five in Europe and more sites in the U.S. There is a lot of appetite for this product because it is not a 19. Mm-hmm. So, like, to come back to the question of CD19, we're, no, it's not positioned as a post-CD19 treatment. Mm-hmm. First of all, yes, we received today, at the time of the dose escalation, a lot of patients that have most of the patients have received the CD19 because there is so many patients in non-Hodgkin lymphoma that are treated by CD19 CAR-T, that have failed CAR-T CD19, and then respond to CD20x22. I remember the second question now. And we think that the performance of this CAR-T and the fact that it's a allogeneic CAR-T will make it being used in a lot of different indication, patients, 19 or non-19. So I think it's gonna move up the lines. The same thing, for example, for the Allogene product, we're super excited about the data they have, and I think that ALLO-501 will start to compete with autologous CAR T, but will start beating the autologous CAR T. Just for the first question you asked, like the apheresis center- Mm-hmm. Patient that have no time to be treated will be will receive ALLO-501A. This is what's gonna happen. And for UCART20x22, it will be in the same case here. And the interesting thing is that, yeah, of course, the expression of 20 and 22 is not as early as 19. I think it's one step before, but there's wobbling in all these genes. So the wobbling is like the genes can express high or low or super low. If you go below a certain cutoff- Mm-hmm. Then that's where you have the relapse and an escape, an MRD positivity post-treatment and the relapse of the patient. If you have two genes, that's why the dual CAR T are extremely powerful, the wobbling of the two genes doesn't happen at the same time. For example, if you have 20 that is down in expression, 22 will be high. So you can wipe out all the cells and get rid of this. And we're expecting probably a longer, better, survival curve and less of relapse with dual CAR T in general. I think this concept is probably one of the concept that we'll continue to build and, on our side, and we believe very strongly that the potential is very different than a plain CD19. you know, CD19 is an overcharged target, and we see it when we open the site, for example, in the U.S. Mm-hmm. A lot of the physicians say, "Oh, if it's a 19, it's no, we have too many of this." I say, "No, it's a 20 by 22." They say, "Oh, that's cool. We take it." So that's why, like, also opening sites is something that is interesting, and the enrollment is pretty quick. Makes sense. So, so you think this dual targeting strategy have a better coverage than CD19 for patients' expression pattern? It's different. Okay. It's not better, it's different. Okay. But the fact is that, yes, like the fact of having two CARs that is expressed allows to compensate for the wobble for one gene. Okay, great. We also recently heard news that you formed partnership with AstraZeneca. Would you like to elaborate on the deal, and what is the technology attract pharma actually to form partnership? What is the development plan for the future? So yes, actually, we're really excited by this partnership. We're very proud of being selected by AZ for, like, AstraZeneca for this partnership. One of the main thing that really attract me towards AstraZeneca is that at the top level of the company, they have a deep strategy- Mm-hmm ... to go into cell and gene therapy in general, and I think this is like a cross-company strategy that would like to move forward. And it's not something where they would like to go, just like, you know, for the next two or three years. No, they would like to make an effort over a long period of time to become real leaders, and they're trying to place every kind of like pieces of the puzzle to come to this point. And this real strategy, I think Cellectis is one of these pieces. They already got excited by this. First of all, Cellectis is kind of a one-stop shop in this space of cell and gene therapy. Well, we have many different type of technologies concerning gene editing, going from like, DNA cutters to base editors, and also pretty wide extensive experience and success in this space. We filed up to 10 INDs, us and our partners, with gene-edited products so far. Okay. We've treated over 270 patients between us and our partners, and that's pretty convincing, and the data are really interesting. The second thing is that Astra is interested in gene therapy, so rare diseases using gene editing. The second thing is immunology, for example, autoimmune diseases, and finally, oncology. That's an interesting agreement within AZ because it's a horizontal, across-the-company deal, while usually it's, like, pretty siloed in every, like, pharma company, and that was really interesting. Finally, I like the deal because, of course, it like all our main assets, preclinical and clinical assets that we're talking about- Mm-hmm. remain outside the deal. So we can continue to develop the three assets that we have, and we can continue to develop the preclinical assets that we have that are not part of the deal to remain Cellectis' property, and this is, like, really exciting for us. It also lifts, of course, like, the financing overhang for the company, so we can present the data more peacefully and not each time you produce data, "Oh, they're gonna finance at the back of this," and so you can go more smoothly with that. Terrific. Next, I would like to discuss the big push on manufacturing front that is Cellectis, Cellectis has undertook. Maybe, can you talk about... I mean, you have manufacturing sites both in U.S. and Europe, and how would you supply the three allogeneic CAR-T programs you just mentioned? And then also, what is the target of capacity by the end of 2024, 2025, and also the estimated manufacturing success rate? Well, first of all, I think if we would have not invest in manufacturing today, I think the company would be a very, in a very, very difficult situation. First of all, I think the agreement with AstraZeneca would have not been effective because they're really interested by manufacturing, and we have, like, an end-to-end manufacturing. So what do we manufacture in Cellectis? We do buffers, we do plasmids, we do messenger RNA, we do AAVs, we do lentiviral vectors, and we do final cells, and we manufacture also our own electroporation devices. All of this is done internally. If you don't do this, if we wouldn't have done this, still working with CDMOs, the quality of the product was so much whimsical. It means one batch is here, the second batch is there, et cetera. How can you make a reproducible product at the end, where allogeneic is supposed to give the same dose and the same type of things? This is not possible. The second thing, you're captive at the time. It means when you get into the pivotal trial with a CDMO, you're married for life. It's over. Like, you cannot switch like this in a cell therapy with, like, another CDMO just on the snap of finger. It's not a small molecule, it's a complex thing, so you need to control all of this. And then finally, we see it on CD22, so like, UCART22, with a dose that is five times higher, we have less CR rates or, or, like, overall response in general than the product that's manufactured internally. Now, like, one of the things I'm inviting people that are going to ASH is watch the cells through translational data, how they expand the ferritins and also the CD4+ and CD8+ cells. We go up to 600 cells per microliter at day 11, post-injection. All of these cells are CAR-T. This is data that even with autologous CAR-T, you cannot obtain. So how you can give this to someone else manufacturing this? I remember I have someone that was, like, quite startled by the... a different company, quite startled by the data and said, "How you do it, André? How is that possible?" We've been doing this for more than 12 years now. We've been investing tremendous amount of time and energy in trying to crunch one batch after the other. You want to transfer all this know-how to the third company? That's not possible. Now, all the investment has been made. We've been doing batches after batch, like the last campaign was this summer in for UCART123, and while the success rate is extremely high, I think there was, like, one batch that didn't work because for a deficiency in one apparatus that didn't work, but was not a human thing. And I think the success is unprecedented in this space, and I think that also drops the cost very low because you don't screw up batches. Excuse my French. Terrific. And, lastly, could you lay out the catalyst for the next twelve months for investors? So the thing you have to watch, of course, like the three trials, like for AstraZeneca agreement, I think we have to wait probably for a bit more, so like, not within the 12 months, because we're gonna be working hard. It's like it's gonna occupy us, like, very much. We're really excited by all these new programs, but not on the longer run. It's you will have, I hope, data. But for Cellectis, there is... Of course, we're excited by our partners. I hope that there will be data that will be shown by Allogene- Mm-hmm ... and potentially also by Iovance. But on our side, I hope we'll declare RP2D for UCART22 next year and move into expansion. That could turn pivotal, and probably for extension for UCART20x22 by 2022. We'll see for UCART123 because we'll have to go to see how the double dose, like an increase in the doses. It takes a bit more time because, like, the delay of the doses that we have. But yet it will be rich for UCART22 and UCART20x22 in the next years, and potentially maybe more of different type of indication than oncology. We'll see. Okay. Terrific. Thanks for great discussion, and thanks, everyone, for attending. Thank you.