Cellectis S.A. Q2 FY2022 Earnings Call

Good morning, everyone, and welcome to the Cellectis Second Quarter 2020 Earnings Call. At this time, all participants are in listen-only mode. Later, we will conduct a question-and-answer session and instructions will follow at that time. Please be aware that today's conference call is being recorded. I'd now like to introduce the first speaker, Arthur Stril, Chief Business Officer. You may begin.

Good morning, and welcome, everyone to Cellectis second quarter 2022 corporate update and financial results conference call. Joining me on the call today with prepared remarks are Dr. Andre Choulika, our Chief Executive Officer; and Dr. Bing Wang, our Chief Financial Officer. Dr. Brownstein is absent on today's call, so I will be speaking about our CAR-T program update. Yesterday evening, Cellectis filed its interim report and issued a press release reporting its financial results for the second quarter and six months period ended June 30, 2022. The report and press release are available on our website at cellectis.com. As a reminder, we will make statements regarding selective financial outlook in addition to its manufacturing, regulatory, and product development plans. These forward statements, which are based on our management's current expectations and assumptions and on information currently available to management, including information provided or otherwise publicly reported by our licensed partners, are subject to risks and uncertainties that may cause actual results to differ from those forecasted. A description of these risks can be found in our most recent Form 20-F filed with the SEC and the financial report, including the management report for the year ending on December 31, 2021, and subsequent filings Cellectis makes with the Securities and Exchange Commission from time to time. I would now like to turn the call over to Andre.

Thank you, Arthur. Good morning, and thank you, everyone, for joining us today. I would like Cellectis to make progress enrolling patients in our three sponsored Phase I dose escalation trials and take notable steps forward with our preclinical data and programs. This week, we are proud to announce the FDA clearance of our investigational new drug application for UCART20x22, our product candidate being developed for patients with relapsed or refractory non-Hodgkin's lymphoma. The UCART20x22 program is very exciting and will be the selective first tool targeting allogeneic CAR-T cell product candidate to enter the clinical trial. Targeting CD20 and CD22, those validated targets in B-cell malignancies, has the potential to enhance tumor cell killing and increase the breadth of antigen targeting. These advantages may increase the addressable patient population and provide a potential therapeutic alternative to CD19-directed therapy. UCART20x22 will also be our first product candidate with fully integrated in-house development, showcasing our transformation into an end-to-end cell and gene therapy company from discovery to product development and transfer into GMP manufacturing and clinical development. This quarter, we're also pleased to publish research data on our novel immune-evasive universal CAR T cell in Nature Communications following our oral presentation at the American Society of Cell and Gene Therapy. These immuno-evasive universal CAR T cells are very promising, and they may address the main challenges of allogeneic CAR T cells, the first of which is depletion by the host immune system via the host versus graft reaction, followed by enabling the proliferation of cells without attacking host tissue through the graft versus host reaction. While the prevention of graft versus host reaction can be readily addressed by inactivation of T cell receptor T-alpha expression in CAR T cells, our engineering approach could enable the universal CAR T cell to become transiently invisible to natural killer cells and allogeneic T cells, allowing them to eradicate tumor cells before being rejected by the patient immune system. This could enable the broad use of universal CAR T cells in allogeneic settings for the benefit of a wider population of patients. This quarter, we also continue to expand our incredible leadership team, Cellectis announced during our Annual Shareholders Meeting that Axel-Sven Malkomes and Dr. Donald Bergstrom have been appointed as Directors of the Company's Board of Directors. We are very pleased to continue our work with Dr. Bergstrom and to welcome Mr. Malkomes to the Board. They are both seasoned leaders in the healthcare industry who bring decades of experience in both the healthcare and financial services sector to Cellectis. We are confident that they will provide meaningful and valued perspectives as we continue to progress toward becoming one of the few end-to-end cell and gene therapy companies. Now I would like to turn the call over to Arthur Stril, our Chief Business Officer, who will give an overview of the three sponsored clinical trials and preclinical product timeline. Arthur, please go ahead.

Thank you, Andre. Our clinical stage allogeneic CAR-T cell product candidates continue to make progress in the clinic. The BALLI-01 study evaluating UCART22 in patients with relapsed or refractory B-cell acute lymphoblastic leukemia is currently enrolling patients at dose level 3, 5 million cells per kg, with fludarabine, cyclophosphamide, and alemtuzumab preconditioning regimen. We plan to initiate the administration of UCART22 batches manufactured fully in-house from our Raleigh facility in the second half of this year. The MELANI-01 study, evaluating UCARTCS1 in patients with relapsed or refractory multiple myeloma, is currently enrolling patients at dose level 1, 1 million cells per kg, with fludarabine and cyclophosphamide preconditioning regimen. We look forward to sharing clinical data from at least one of these three programs by the end of the year when we will have a robust and meaningful data set to present. Lastly, as Andre mentioned, we are pleased to announce the FDA IND clearance for our product candidate UCART20x22, the first allogeneic dual CAR T cell product candidate being developed for patients with relapsed or refractory non-Hodgkin lymphoma. UCART20x22 features TALEN-mediated disruptions of both the attract gene that has been shown to reduce the risk of graft versus host disease and the CD52 gene to permit use of the CD52-directed monoclonal antibody in preconditioning to enhance CAR-T engraftment, expansion, and persistence. We are extremely excited to start the NATALEE 01 study, evaluating UCART20x22 in patients with relapsed or refractory non-Hodgkin lymphoma in the second half of this year. This quarter, our partnerships also proved to be an exciting highlight for Cellectis. In June, Allogene announced that the FDA granted Regenerative Medicine Advanced Therapy Designation to ALLO-501A in relapsed/refractory large B-cell lymphoma. The RMAT designation was based on the potential of ALLO-501A to address the unmet need for patients who have failed other therapies and follows positive data from the Phase I ALPHA 2 trial in heavily pretreated patients with relapsed/refractory large B-cell lymphoma. Allogene previously announced that enrollment in the Phase 1 portion of the ALLO-501A ALPHA2 trial in relapsed/refractory large B cell lymphoma reopened with the goal of offering ALLO-501A to patients while Allogene prepares to launch the pivotal Phase 2 ALPHA2 trial. They also previously said that the single-arm pivotal ALPHA2 trial of ALLO-501A in relapsed/refractory large B-cell lymphoma is on track to begin mid-year 2022 with FDA discussions directed at finalizing clinical trial design and Chemistry Manufacturing and Controls requirements. In May 2022, Allogene also announced that the FDA granted Orphan Drug Designation for ALLO-605 for the treatment of relapsed/refractory multiple myeloma. Allogene previously announced that enrollment had resumed in trials targeting BCMA for the treatment of patients with relapsed/refractory multiple myeloma and targeting CD70 for patients with advanced or metastatic clear cell renal cell carcinoma. Enrollment also resumed in the UNIVERSAL trial with ALLO-715 and the IGNITE trial with the TurboCAR™ candidate, ALLO-605. I will now move on to our research collaboration with Iovance and Cytovia. This quarter, Iovance began site activation and patient recruitment for the IOV-GM1-201 first human study of IOV-4001. IOV-4001 is a PD-1 inactivated cell therapy that incorporates the TALEN gene editing technology. IOV-4001 may leverage the combination of TIL and interruption of PD-1 signaling within a single therapy. In a murine model of melanoma, the antitumor activity of IO-4001 was superior to non-edited cell products, whether alone or in combination with anti-PD-1 antibodies. The IOV-GM1-201 study includes two patient cohorts: advanced melanoma patients who were previously treated with anti-PD-1 therapy and metastatic non-small cell lung cancer patients whose disease has progressed after up to three lines of prior therapy. Iovance announced it looks forward to dosing the first patients in the study in the second half of this year. Finally, Iovance has a robust research pipeline advancing towards the clinic. Following the success of IO-4001, several targets for genetic modifications are in preclinical studies using the gene editing TALEN technology, including double genetic knock-out programs. Our research and development collaboration with Cytovia to develop TALEN edited induced pluripotent stem cells, NK and CAR-NK cells is progressing. Cellectis has developed custom TALEN which Cytovia is using to edit iPSCs in a safe and effective manner. Additionally, Cytovia has generated promising preclinical data of TALEN-edited iPSC-derived NK cells that it expects to present at upcoming scientific conferences later this year. These announcements reiterate once more that TALEN is the technology of choice for gene editing, which continues to provide the company with expanded business opportunities. With that, I would like to hand the call over to Dr. Bing Wang, Cellectis Chief Financial Officer, for an overview of our financials for the second quarter of 2022.

Thank you, Arthur. I will provide a brief overview of our financials for the second quarter of 2022. I would like to highlight that our financials, the cash, cash equivalents, current financial assets and restricted cash position of Cellectis, excluding Calyxt, as of June 30, 2022, was $123 million compared to $177 million as of December 31, 2021. This difference mainly reflects $56 million of net cash flow used in operating, investing, and lease financing activities and $4 million of negative foreign exchange impact, partially offset by $5 million of cash received related to research tax credit prefinancing. Based on the current operating plan and financial projections, this cash position is expected to be sufficient to fund Cellectis stand-alone operations into early 2024. The consolidated cash, cash equivalents, and current financial assets and restricted cash position of Cellectis, including Calyxt, was $135 million as of June 30, 2022, compared to $191 million as of December 31, 2021. The net cash flow used in operating capital expenditure and leases were $56 million at Cellectis and $30 million at Calyxt in the first six months of 2022, partially offset by a $10 million capital raise at Calyxt and $5 million of cash received related to research tax credit and prefinancing at Cellectis. The net loss attributable to shareholders of Cellectis, excluding Calyxt, was $47 million in the first six months of 2022 compared to a loss of $43 million in the first six months of 2021. This $4 million increase in net loss between 2022 and 2021 was primarily driven by a decrease in revenue and other income of $18 million, partially offset by an increase in net financial gain of $8 million and a decrease in R&D expense of $4 million. The consolidated net loss attributable to shareholders of Cellectis, including Calyxt, was $51 million or $1.12 per share in the first six months of 2022 compared to a loss of $52 million or $1.17 per share in 2021. The consolidated adjusted net loss attributable to shareholders of Cellectis, excluding Calyxt and excluding noncash stock-based compensation expenses, was $43 million or $0.95 per share in the first six months of 2022, compared to a loss of $38 million or $0.86 per share in 2021. Based on current plans, we anticipate our cash runway will take us into early 2024. We are focused on spending our cash, developing our deep pipeline of wholly owned product candidates in the clinic, and operating our state-of-the-art manufacturing facilities in Paris and in Raleigh. Our focus remains on maintaining an efficient corporate infrastructure that will enable us more limited growth in G&A spend. Thank you very much, and back to Andre.

Thank you, Bing. To close out this call, I would like to reiterate how excited we are about the continued progress of our clinical trials and our upcoming milestones for the remainder of 2022. To date, close to 200 patients have been treated with allogeneic CAR T cells utilizing technology developed by Cellectis. Most in Cellectis-sponsored clinical studies and those of our licensed partners, Allogene and Servier, we continue to make progress with our pipeline and our three ongoing clinical trials in hematological malignancies. This quarter, as we take steps closer to becoming a true end-to-end cell and gene therapy company. These updates clearly show our potential and ability to advance the field of allogeneic CAR T cell therapy. At Cellectis, we strongly believe that our product candidates, technologies, and our in-house manufacturing capabilities will lead us to a paradigm shift for patients with hard-to-treat cancers positioning us at the forefront of this promising medical and scientific field. With that, I would like to open the call for Q&A.

Thank you. Our first question comes from Gena Wang with Barclays. Please proceed with your question.

Thank you for taking my questions. Congrats on the R&D clearance. Now since your UCART20x22 can start clinical trial in the second half of this year, would you be able to share a little bit more color regarding the clinical trial design, including initial thoughts on the initial dose and also the patient population that is specifically related to which line or whether they will have a prior CD19 CAR T therapy? And then my second question is regarding your Nature Communications publication. It is very impressive data. So wondering, do you have - what kind of IP you have for your due approach HLA-E-knocking and beta 2-M knockout?

Thank you so much, Gena, for these two great questions to start this call. This is Arthur, and I think I will hand over the questions to Andre. So I don't think we can hear Andre for now. So I will take the first question. So on the UCART20x22, we're indeed extremely excited to have the IND cleared. This is the first allogeneic CAR-T developed, designed, and manufactured end-to-end at Cellectis. So it's a fantastic milestone for the company, and we definitely look forward to administering this product to patients. We haven't disclosed the full clinical trial design yet. We have said that this will be for relapsed/refractory non-Hodgkin lymphoma patients. We will be disclosing the full clinical trial design later this year as the trial is getting started. But we do believe that this will be a very strong differentiated AlloCAR T in the NHL space, particularly because of the dual targeting approach and the fact that it is strongly differentiated versus CD19 targets. So on your other question around IP, I mean, definitely, we strive to protect all the innovation that we're doing at Cellectis. We have strong protection on the CD52 knockout approach for hem malignancies CAR-T. We definitely have protection as well around the HLA-E approach that was disclosed in Nature Communications. We think this is indeed exciting to have a very strong arsenal of persistence-enhancing technologies that allow us to adjust that depending on the indications we target in the gene space or in the solid tumor space.

Thank you.

Our next question comes from the line of Yigal Nochomovitz with Citi. Please proceed with your question.

Hi, team. This is Ashiq Mubarack on for Yigal. Thanks for taking my questions. For 20x22, just thinking about starting the study. I'm just curious how you're thinking about dose escalation generally. I think we've seen kind of a wide range of starting doses from some of the other cell therapies. So I'm just kind of curious if you can comment at all on where you think you'll start, maybe relative to those other cell therapies out there? And just more generally, how dual antigen targeting might make your dose escalation different at all?

Yeah. Thanks a lot for this question. So Andre has disconnected, so I will take it, this is Arthur. So I think it's a great question, and we've put a lot of thought into the clinical trial design, both in terms of starting dose as well as the lympho-depletion regimen due to the dual targeting nature of the CAR-T. So at this stage, again, we are not disclosing the exact dose. I think what we can safely say is this will be a standard dose escalation and dose expansion design. But since this is a very competitive field right now, especially for dual targeting, we are not yet disclosing the trial design and we'll do so in due course when the trial has started.

Okay. Makes sense. And then maybe if I can ask one more about UCART22. I think you've indicated that you're switching to your fully in-house manufactured version. And I think you've previously alluded to this version being more potent compared with the product you've used before. So I was just wondering, as you switch over, if you'll need to make any adjustments to the dose escalation or maybe even dose deescalate a bit. And is this version the commercial-ready version? Or will there be additional iterations down the road? And will you have to do some comparability work for those regimens if there are any further ones? Thanks.

Thank you. And these are excellent questions on UCART22. I think Andre reconnected. So Andre, do you want to take this? Currently not, so I will again take the question on UCART22. So basically on UCART22, you're absolutely right. The product is, from what we've seen, more potent than what we had manufactured at our CMO in the past. So this is definitely a big milestone and testimony to our Raleigh internal manufacturing capabilities. We have had internal discussions with the FDA on comparability and what will happen with dose escalation. There is a possibility that the FDA might ask us to de-escalate. But if that's the case, this will be to acknowledge that the product is more potent and therefore a smaller dose could lead to the same effect with the added benefit of reduced cost of goods. So if that happens, this will not delay the trial, and we will still be able to rely on the data from the previous version of UCART22 that was manufactured at our CMO.

Okay. Great. Thanks for all the color.

Our next question comes from the line of Kelly Shi with Jefferies. Please proceed with your question.

Hi. This is Dave on for Kelly Shi. Thank you for taking our question. So just a quick overall plan for the next 12 months. You said you will be disclosing at least one set of data, so from that what investors should look forward in the next 12 months. Additionally, can you add color on milestones from Allogene on pivotal trials of ALLO-501 and ALLO-715 data updates? Thank you.

Great. Thank you so much. We will try Andre another time. Andre, are you on the line?

Thank you, Arthur. Well, we know that Allogene is starting their clinical trial, their pivotal phase very soon. And of course, there are milestones, there are stage, preclinical milestones, like clinical milestones up to the BLA and post-commercialization milestones. These total approximately $410 million in total, but the details have not been disclosed, and part of the confidentiality we have between us and them. I think we expect potentially next year to have also the BCMA trial from Allogene to start pivotal trial and also to receive milestones, there are like $185 million in total to the BLA and post-commercial milestones, and about the detail also are not disclosed and are part of the confidentiality that the company has with Allogene. But we're very excited by the data that they have been able to obtain with both CAR-T. We think that ALLO-501A is not only the first allogeneic CAR T but is also part of the first implant, autologous and allogeneic of the CD19 CAR-T, and we think that this is going to totally change the pace. We're very excited to see this trial seeing the data. On the BCMA part, we are also very excited by the data that has been obtained by Allogene. We definitely believe that this data best matches some of the others. Of course, there are like other trials like BCMA CAR T autologous. Given all the difficulty in the logistics, we believe that also the performance, the commercial performance, and the potential for physicians of these two CAR-T being on the cell will definitely change and begin to change the industry.

Thank you.

Our next question comes from the line of Hartaj Singh with Oppenheimer. Please proceed with your question.

Great. Thank you for the question. And Andre, I might suggest, I know you're helping get some of that product out of the door there, down in Paris, but you might want to move away from those steel tanks, reception-wise. But just a quick question, Andre, and team on the data at the end of the year from one of the projects and then maybe looking to next year, the trials 104, 123, CS1, and CART22 have been designed with like a dose expansion with - if you've seen a really good signal in some tumor types to maybe go to a pivotal trial. Are you still thinking of those two projects in that regard? And then how could we see that play out, assuming you have some good data readouts essentially over the next 12 months? Thank you for the question.

Thank you so much, Hartaj, for the question. Always great. As usual, do you want to take this, Andre?

Well, I want to try to get started, I can continue, no problem.

Okay. I can get started. So Hartaj, you're spot on, and I think this will be not only very indication and very data specific. But definitely, we've designed the Phase I/II trials in two blocks, the dose escalation and dose expansion that could have, depending on data and the indication, the potential of being registrational. We think, for example, that UCART22, because there is a high unmet need and the scarcity of options beyond CD19 autologous, there is definitely room for the dose expansion phase of the trial once we find the recommended Phase II dose with our Raleigh internal manufactured product for those expansions to be potentially registrational. And that's why we decided to switch the product to our Raleigh facility so that when we get closer to BLA, we don't have to switch from a CMO, and we completely control the production, and we can file our own facility in the BLA. I don't know, Andre, if you want to add any additional color to that?

Yes. I'd like to add one thing. First of all, it's a great question. The thing is that we've been developing a series of CART from allogeneic CAR, n numbers of years from now, like UCART19 that has been renamed ALLO-501, we started dosing the first patients six years ago, like in 2015, like seven years ago, by the way, more than seven years ago. And since then, there were like the BCMA CAR-T, so 19 was licensed to Servier, we partnered with Pfizer, then became Allogene, and Allogene is very brilliantly developing these two CAR-T. Then we went from 1 to 3, then CS1, then 22. And we think it's a lot of things on our plate. Now like we're moving to 20x22. There are like certain targets that are, let's say, derisked targets like such as 19 and BCMA, but there's plenty of them. Some are derisked targets such as CD22 or CD20, and this is why we think these two CAR-Ts, 20x22 and 20x22, plan like more 22 are fairly straightforward, the ones that like you should see a potential Docer and again, which are 123 for AML and CS1 for multiple myeloma. Of course, there are two hard-to-treat indications, and the target is a complex target that is being challenged several times. We expect potentially to see some data in the future in this space.

Great. Thanks, Andrew. Thanks, everyone, for the answers in the call.

Next question comes from the line of Jack Allen with Baird. Please proceed with your question.

Thank you so much for taking the question and congratulations on the progress. I just have two quick questions. On the CS1 program, I was hoping you could add some more color as to how enrollment is going? It sounds like you're at dose level 1. And I just wanted to hear about how many patients maybe have been given dose level 1 and what you're looking for to advance additional doses potentially in that study? And then on 20x22, I know the study design is going to be disclosed as you enter the clinic. But I'd love to hear any thoughts you have as far as how quickly we could reach proof of concept with that asset as well. Thank you so much for taking the question.

Thank you so much, Jack, and I can start and Andre can definitely chime in. So for UCART CS1, again, we're not disclosing individual patient numbers. I think the thing that we can say is that DL1, as mentioned in the call, is 1 million per kg. So it's already quite high compared to the other dose levels of the other CAR T. So we started that trial at the dose level that was higher. So that is definitely one indication we can give towards the overall trial by itself. And then for UCART20x22, I think, again, without going into specifics of clinical trial design, what we can safely say is there is a very large patient population and unmet need at this stage because once patients are refractory to the CD19 options that have actually moved to the second line, there are very limited options and very targeted opportunities. And so we've taken the two most derisked targets that are not CD19, CD20 and CD22 to offer a meaningful alternative not only to patients that will relapse from 19 but also for patients that could potentially not receive a 19, in particular in the autologous field. So we believe there is a large patient population, a large opportunity, and this could be conducive to a swift enrollment. Andre, any thoughts to add?

Yes, like for CS1, yes, for DL1, the enrollment is not going very fast. But there are a lot of trials in the space in the U.S. So we have – there are CAR Ts available for patients, and it's not the fastest enrollment we are having currently for numerous reasons. The enrollment in the United States is something that is difficult. So like maybe the plan also is to expand to other countries.

Great. Thanks a lot. Great color.

Our next question comes from the line of David Dai with SMBC. Please proceed with your question.

Great. Thanks for taking my question and I also want to add my congratulations to the current progress. So two quick questions for me, Andre. So the first question is just around the 20x22, could you just remind us how many patients have been enrolled in dose Level 3 with the FCA conditioning regimen so far? And then the second question is just around the data expectations in the second half of this year. I know you're going to be providing some from one of the programs. So just can you position us in terms of what data to expect? Thank you.

Andre, you want to take this?

Unlike UCART22, actually, I missed the little piece of it. Okay. So on the FCA, there are three patients per level, DL1, DL2, DL3 completed DL3, so the plan is to bridge with a few patients with the program that has been made in-house. So at our Raleigh facility globally, all the FCA and SCA Park has been completed with the full goal on both sides. That's the whole thing that has been done. But now we're expecting the potential to start dosing patients in Raleigh and move to the expansion. We hope, of course, we believe that this will follow in going forward also. If that answers your question. I think you can do the math.

Our next question comes from the line of Silvan Tuerkcan with JMP Securities. Please proceed with your question.

Yeah, hello. Congrats on the quarter and thanks for taking my question. Maybe one question about UCART22. Could you just remind us of the exact mechanics of what still needs to be done to get the Raleigh material into the clinic, and what are the mechanics of interactions with the regulators here? And I think the last time we were talking about the potency assay or the assays required for comparability. Are they now all in place? It would be great if you could provide some more color there. And then my second question is around recent deal with Roche, and obviously, to say that. And as part of that rather large deal and interesting that Roche is getting into the other CAR-T space now. There was a CD19 CD20 CAR-T. Could you just tell us a little bit about the differences, obviously, 19, we target 19, why would you do that? And why is 20x22 perhaps a better idea? Thank you.

Thank you so much, Silvan. Great questions, and I can start on the Raleigh one. So definitely, as mentioned before, we had interactions with regulators to understand exactly what they would be looking for in timely transitioning from our CMO manufactured product to the Raleigh manufactured product. We have a good understanding, and basically, the steps are filing an IND amendment with the FDA in order to approve the Raleigh manufactured product. This then has to go through the clinical centers and their IRBs so that we can then safely administer the product. All of this is undergoing. We have all the assays in place to make that happen, and we're confident that we'll be able to dose the first patients with the Raleigh product in the second half of this year. And I think on, yes, Andre, please go ahead.

On the size of the potency assay, it is quite straightforward. I'm not going to get into the details of this for numerous reasons. First of all, I think that there's - I'm not sure it's really interesting for anyone. And plus, I don't want to disclose everything we're doing to do these type of comparabilities. Globally, it's essentially killing potency, so the number in the potency of release of perforins and granzymes and the number of recycling that it could do the time of the recycling between two releases, the expansion potential of the cells, the number of cell divisions they can do, the interferon gamma assays, etc. All of this gives quite a broad idea of the performance of these type of products. And well, I think it’s good. The performance that we obtain is totally not bad, and we're very excited to see that they're very performing products, but definitely, the comparability doesn't stand. It's not totally comparable. So that's why there is a potential necessity to potentially do a few doses below, and we extend that or you do not do, that's what you get. There was a technical question, like the beginning of your question was about what like Silvan, excuse me.

There was a question around the Roche partnership and their dual targeting CAR-T, which also targets – retargeting basically CD19; just what are the rationale here and why?

I don't understand why most patients received the CD19 CAR-T treatment initially. They will likely provide a combination of the full CD19 CAR-T, whether it’s allogenic or autologous. Naturally, the allogenic CAR-T will be approved by them. There's also a lot of noise around this topic. Then, there is another CD19 CAR-T with decent performance already on the market. The challenge is whether you can demonstrate superiority over the existing CD19 CAR-T or if it's more beneficial to develop a CD20x22 approach, considering that relapses after CD19 treatment won't result in another CD19 CAR-T being administered. Instead, it would make more sense to offer a CAR-T that we believe has excellent performance but doesn't include CD19. I'm surprised by the reaction to this strategy.

Great. Thank you. Thanks for taking my questions.

Our next question comes from the line of Nicolas Abbott with Wells Fargo. Please proceed with your question.

Good morning. Thanks for taking the questions. The first one, just on UCART22. So have you filed the IND amendment and if not, when do you intend to do that?

Andre?

It broke up at the time actually, could you just repeat the question, excuse me.

Yes. Andre. The first one you have filed for UCART22, if you filed the IND amendment and if not, when do you think you'll do that?

For 22? Well, it's - well, you should expect to see patient dosing, I hope sooner than later. We are not delayed.

Okay. I may have missed it. I didn't hear - it was Arthur's prepared comments on 1, 2, 3. But I think you recall that you had completed dose level 2. The next dose was going to be an intermediate sort of dose level 2.5 before jumping to dose level 3. Can you just provide us an update on precisely where you are with 1, 2, 3?

Well, actually, we've been very cautious with this type of CAR-T because we had a series of CRS in the past. We think that dose level 2 could be an interesting dose so far, and we are concerned that dose level 3 may be too high. So we are trying an intermediate dose. Potentially, I think there may be like an intermediate between the two, like giving a repeat dose on 2 or something like this because it's quite a reactive target, and it's not an easy disease. I'm not going to go through all the details of this, but I think we're in orders that are interesting for dose level DL2 or DL3, so simple CAR-T to be dosed.

Right. Understood. So then maybe you filed like an amendment to try to dose level 2.5 or repeat dosing?

For DL2, just like - how you can do this, but to do a repeat, you need to file an amendment, and we're not delayed on this. It still remains a challenging approach, and we've been very cautious with that. It's something we're not considering, but we're just doing it.

Our next question comes from the line of Brooke Schuster with William Blair. Please proceed with your question.

This is Brooke Schuster on for Raj Prasad. I had a question regarding the manufacturing of UCART20x22. I was wondering if you could provide more color on how the manufacturing process for dual differs from the single-target products? And any details on the run yields between the two?

Thank you, Brooke. This is a great question, and I can definitely start. So we - the UCART20x22 uses the same allogeneic CAR-T manufacturing platform that we developed at Cellectis, so the same manufacturing process as 123, 22, and CS1 with all the improvements that come from manufacturing it in-house from our Raleigh facility. There are definitely some specificities in the viral vector construct due to the dual targeting. So we use a bicistronic construct to carry both CARs, and we found that this was the most optimal construct for the allogeneic approach. We have found that this does not modify at all the value proposition of allogeneic, which is getting significant yields in order to get the true off-the-shelf therapy that can be distributed at an industrialized scale. There were definitely a lot of process improvements to cater for this dual targeting approach. But we have found that we could get to similar yields and to the hundreds of doses per manufacturing campaign that we're getting for the other CAR Ts.

If you take a technician that is making UCART22 or dual UCART20x22 if you don't try it exactly on the two, for example, containing lentiviral vector for CD20 by 22 versus 22, you will not realize. So it's exactly the same process. The only thing that differs is in the QC at the end to be sure that both CARs are expressed, or like the tailing on 20 and on 22 notwithstanding the fact that other targets are present, etc. So there is a QC process that's slightly more complex for UCART20x22 to be sure that you have both CARs, but during the manufacturing process itself, if you don't know what's contained in the lentivirus, then you don't know. It's exactly the same.

And our last question comes from the line of Salveen Richter with Goldman Sachs. Please proceed with your question.

Hey, good morning. This is Matt on for Salveen. Could you elaborate on the rates of patient enrollment across the portfolio? Are there any headwinds we should be aware of? And then on CD20x22, given the CD52 gene disruption, are you able to use a less toxic preconditioning regimen? Thank you.

Thank you, Matt. Great questions. Andre?

Well, the patient enrollment so far has been slow for numerous reasons across the three trials. So 22 in acute lymphoblastic leukemia is a rare disease compared to non-Hodgkin's lymphoma. There's like 120,000 patients in the U.S. - patients every year in the U.S. versus like 6,000. 120,000 versus 6,000. So it's quite huge. The enrollment has been slow. On the CS1, as I said before, also, there are a lot of products in this space. The trials are recruiting patients that save the criteria, and there are tight criteria for numerous reasons that are also quite lower DL1. We have completed DL3 for Q1 for 22, but they're still a done for CS1 following the hole. And 1, 2, 3 is a difficult disease to treat. So also, the patient selection is something that slows down the enrollment, and we have completed DL2. And the DL2 has difficulty to jump to DL3, as I described before. And that takes also a lot of time. Now, one of the things we're doing, we're expanding to other countries because, like in the U.S., there are a lot of trials that are ongoing. We are opening other countries, and we believe that in other countries, there are fewer complex cell and gene therapy trials. There is more potential in recruiting patients that we believe. And UCART20x22, which is Non-Hodgkin lymphoma is opening in multiple countries also, not altogether, because the U.S. is faster, but potentially, we'll see the trial expanding to other countries that should accelerate also the trials.

And I think, Matt, on the CD52 knockout, I think what's super interesting with this approach compared to others is that you can definitely tune the lymphodepletion because you can dial up or down the level of administration of this anti-CD52, which is true for the single dose, but which could also be true in a redosing regimen. So we really have a dial as opposed to an on-off approach. We really have a dial that will definitely allow us to fine-tune the lymphodepletion in a single and potentially a repeat dose setting exactly to achieve the right safety-benefit ratio. So you're spot on, and I think this is what we love about the CD52 approach: its inherent tunability.

Great. Thank you very much.

And we have reached the end of the question-and-answer session. I will now turn the call back over to Andre Choulika for closing remarks.

Thank you very much for all of you for supporting the company and asking questions. I think they're all like very great questions. Of course, we're super excited by the start of UCART20x22. I think the company is heading at a very interesting moment. In the near future, UCART22 is moving to P2 and enhancement factor UCART20x22 in-house manufactured product. Also, we are also progressing on CS1 and 1, 2, 3, and the thing is like we'll definitely keep you updated on these trials in the near future. With that, I would like to thank all of you and wish you a very great day.

This concludes today's conference, and you may disconnect your lines at this time. Thank you for your participation.