Cellectis SA (CLLS) 2022 Q2 法說會逐字稿

Good morning, everyone, and welcome to the Cellectis Second Quarter 2022 Earnings Call. (Operator Instructions) 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 for 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 6-month 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 Cellectis' financial outlook in addition to its manufacturing, regulatory and product development plan. 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 license 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 reports, 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. Cellectis continues to make progress enrolling patients in our 3 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 selective first feel targeting allogeneic CAR T-cell product candidate to enter clinical trials. Targeting CD20 and CD22, both validated targets in B-cell malignancies has the potential to enhance tumor cell killing and increases the breadth of antigen targeting.

These advantages may increase the addressable patient population and provide a potential therapeutic alternative to CD19-directed therapies. UCART20x22 will also be our first product candidate with full integrated in-house development, showcasing our transformation into an end-to-end cell-and-gene therapy company from discovery and 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 communication following our oral presentation at the American Society of Cell and Gene Therapy. These novel immuno-evasive universal CAR T-cells are very promising, and they may address the main challenges of allogeneic CAR T-cell, 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 issue beyond the graph versus host reaction. While the prevention of graft versus host reaction can be readily addressed by an inactivation of T-cell receptor, T alpha expression in CAR T-cells, our engineering approach could enable the reversal CAR T-cell to become transit invisible to natural tumor 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-cell in allogeneic setting for the benefit of wider population of patients.

This quarter, we also continued to expand our incredible leadership team. Cellectis announced during our annual shareholders meeting that Axalta Malcom and Dr. Donald Bergstrom has been appointed as Director for the company's Board of Directors. We are very pleased to continue our work with Dr. Bergstrom and to welcome Mr. Malcom to the selective Board. There are both seasoned leaders to the health care industry who brings decades of experience in both the health care and financial services sector to Cellectis. We're confident that they will provide meaningful and valued perspective as we continue to progress to becoming one of the few end-to-end cell and gene therapy company.

Now I would like to turn the call over to Arthur Stril, our Chief Business Officer, who will give an overview of the 3 sponsored clinical trials and preclinical product pipeline. 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 regimens. We look forward to sharing clinical data from at least 1 of these 3 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 tailored mediated disruption of both the track then 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 NatHaLi-01 study, evaluating UCARTx22 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 ALPHA2 trial in heavily pretreated patients with relapsed/refractory large B-cell lymphoma.

Allogene previously announced that enrollment in the Phase I 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 prepared to launch the pivotal Phase II 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 midyear 2022, with FDA discussions directed at finalizing clinical trial design and chemistry manufacturing and controls requirements.

In May, 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-in-human study of IOV-4001. IOV-4001 is a PD-1 inactivated TIL therapy that incorporates the tail and gene editing technology. IOV-4001 may leverage the combination of TIL and interruption of PD-1 signaling within a single therapy. In the murine model of melanoma the antitumor activity of IOV-4001 was superior to non-edited cell products, whether alone or in combination with an anti-PD-1 antibody.

The IOV-GM1-201 study includes 2 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 3 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 IOV-4001, several targets for genetic modifications are in preclinical studies using the gene editing talent technology, including double genetic knockout program.

Our research and development collaboration with Cytovia to develop TALEN-edited induced pluripotent stem cell 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 a 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 equivalent, current financial asset, 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 equivalent 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 6 months of 2022, partially offset by a $10 million capital raise at Calyxt and $5 million of cash received related to research tax credit prefinancing of Cellectis.

The net loss attributable to shareholders of Cellectis, excluding Calyxt, was $47 million in the first 6 months of 2022 compared to a loss of $43 million in the first 6 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 of R&D expense of $4 million.

The consolidated net loss attributable to shareholders of Cellectis, including Calyxt, was $51 million, or and $1.12 per share in the first 6 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, excluding noncash stock-based compensation expenses, was $43 million or $0.95 per share in the first 6 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 trial and our upcoming milestones for the remainder of 2022. To date, close to 200 patients have been treated with allogeneic CAR T-cell utilizing technology developed by Cellectis, both in Cellectis' sponsored clinical studies and those of our license partner, Allogene and Servier. We continue to make progress with our pipeline with our 3 ongoing clinical trials in hematological malignancies this quarter as we make 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, our technology and our in-house manufacturing capabilities will lead us to the paradigm shift for patients with hard-to-treat cancer, positioning us at the forefront of this promising medical and scientific field.

With that, I would like to open the call for Q&A.

(Operator Instructions) Our first question comes from the line of Gena Wang with Barclays.

Congrats on the R&D clearance. Now since your UCART20x22 can start clinical trial second half this year. Would you be able to share a little bit more color regarding the clinical trial design, including initial thoughts or initial dose and also the patient population that specifically related to which line or whether they will have a prior CD19 CAR-T therapy?

And then my second question is regarding the -- your Nature Comm publication. It is very impressive data. So wondering, do you have a -- what kind of IP you have for your dual approach (inaudible) knocking and beta-2m knockout?

Thank you so much, Gena, for these 2 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 in relapsed/refractory Non-Hodgkin Lymphoma patients. And 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 allo CAR-T in the NHS space, in particular, because of the dual targeting approach and the fact that it is strongly differentiated versus the 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 a strong protection on the CD52 knockout approach for heme malignancies CAR-T. And we definitely have protection as well around the beta-2m HLA approach that we recently disclosed the Nature Comm. And we think this is indeed exciting to have a very strong arsenal of persistence, enhancing technologies that allow us to adjust and that depending on the indication that we target, be it in the heme space or in the solid tumor space.

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

This is [Ashik Mubarak] on for Yigal. For 20x22, just as you're thinking about starting the study, I'm just curious how you're thinking about 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 where you think you'll start maybe relative to those other cell therapies out there. Just more generally how dual antigen targeting might make your dose escalation different, if at all?

Yes. 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 [CAR] force into the clinical trial design, both in terms of the starting dose as well as the lymphodepletion regimen, indeed, due to the dual targeting nature of the field of the CAR-T. So at this stage, again, we are not disclosing the exact dose. I think what we can say safely is this will be a standard dose escalation, dose expansion design. But since this is a very competitive field right now, in particular 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 1 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 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 -- maybe do some comparability work for those regions, if there are any further ones?

And these are excellent questions on UCART22. I think Andre reconnected. So Andre, do you want to take this?

Apparently not. So I will again take the question on UCART22. So basically, on UCART22, you're absolutely right. The product on what we have seen is 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 definitely -- we have had an intense discussion with the FDA on comparability and what will happen with the dose escalation. And there is a possibility that the FDA ask us to deescalate. 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 obviously 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.

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

This is Dev on for Kelly. So just a quick question on overall plan for the next 12 months. You said you will be disclosing at least 1 set of data. So apart from that investors should look forward in next 12 months. Additionally, can you add color on milestones from allogene on pivotal trials of ALLO-501 and ALLO-715 data update?

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

And thank you for -- actually, can you hear me?

Yes.

Yes.

Okay. Okay. So the Well, we know that Allogene is starting their clinical trial, their pivotal phase very soon. And of course, there are milestones, there are stage that our preclinical milestone -- like a clinical milestone up to the BLA and post-commercialization milestones. And 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. The other thing is also, we expect potentially next year to have also the BCMA trial from Allogene to start pivotal trial and also to receive milestones. These are like $185 million in total up to the BLA and post-commercial milestones and about the detail also are not disclosed and are part of the confidential at the company as well as Allogene. But we're very excited by the data that they have a pain with both CAR-T. We think that ALLO-501A is not only first-in-class allogeneic CAR-T, but is also part of the first-in-class autologous and allogeneic all of the CD19 CAR-T.

And we think that this act is going to totally wipe out the competition in the space. And we're very excited by the start of the development 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 the data definitely matches and is better than (inaudible). Of course, there are like other type of BCMR CAR-T autologous. Given all the difficulty and the logistics, we believe that also the performance, the commercial performance and the potential for physicians of these 2 CAR-T being on the shelf will definitely change -- will be game changer in the state.

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

Andre, I might suggest, I know you're helping get some of that product out in 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, team, on the data at the end of the year from one of the projects and then maybe looking to next year. The trials for 123, CS1 and UCART22 have been designed with like a dose expansion with if you've seen a really good signal in some tumor type to maybe go to a pivotal trial. Are you still thinking of those 2 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 so much, Hartaj, for the question. Always great, as usual. Do you want to take this, Andre?

Well, you want trying to get started, I can continue the 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 2 blocks, dose escalation and dose expansion, that could have, depending on data and the indication, the potential of being registrational. We think, for example, that for UCART22, because there is a high unmet need and a scarcity of options beyond CD19 autologous, there is definitely room for the dose expansion phase of the trial once we found the recommended Phase II dose with our Raleigh internal manufactured product, for the -- 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 would like to -- like 1 thing. First of all, it's a great question. But the thing is that we've been developing a series of CARs and allogenic CARs and numbers of years from now, like UCART19 that has been renamed ALLO-501. We started dosing the first patients 6 years ago, like in 2015, like 7 years ago, by the way, more than 7 years ago. And then -- since then, there was like the BCMA CAR-T. So '19 was license to survey, we started with Pfizer then became Allogene, and Allogene is very brilliantly developing these 2 CAR-T. Then we went for 123 then CS1, then 22. And we think it's a lot of things on our plate. And now like we're moving to 20x22.

There are like certain targets that are let's say, derisked targets such as 19 and BCMA, but there is plenty of them. Some are derisked targets, such as CD22 or CD20, and this is why we think the 2 CAR-T 20x22 and plan like versus 22 fairly straightforward, the ones that like you should see a potential jokers in the gain which are 123 for AML and TS1 for multiple myeloma. Of course, there are 2 MLs hard-to-treat indication and the target is complex target that is being challenged several times. And we expect potentially to see some data in the future in this space we have to play.

Our next question comes from the line of Jack Allen with Baird.

Congratulations on the progress. I just have 2 quick questions. 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 want 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 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, Jack, and I can start and Andre can definitely chime in. So for UCARTs, 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 cells 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's definitely 1 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 second line, there is very limited options and a very limited target opportunities. And so we've taken the 2 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 the 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, we're DL1, like the enrollment is not very fast, but there is a lot of trials in the space in the U.S. So we have -- there is a scarcity of available patients, and it's not the fastest trial we are having currently for numerous regions. The enrollment in the United States, and you talk to a lot of physicians, is something that is difficult. So like maybe the plan also is to expand to other countries.

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

I also want to add my congratulations to the current progress. So 2 quick questions for me, Andre. So the first question is just around credit UCART22. Could you just remind us how many patients have been enrolled in dose level 3 with the FCA pre-commissioning regimen so far? And then second question is just around the data expectations in the second half of this year. I know you're going to be providing some updates from all the programs. So just can you just position us in terms of what kind of data to expect?

Andre, you want to take this?

Is it -- like it depends on like UCART22, actually, I missed the little piece of it. So on -- Okay. So on the FDA, you -- there is 3 patients per level DL1, DL2, DL3 and completed DL3, . So its the plan trying to bridge with few patients with the product that has been made at in-house. So at our Raleigh facility, but globally, all the SCE part and SCA part has been completed with the full cohort on both sides. So that's the whole thing that has been done. But now we're expecting potential to start dosing patients for the global Raleigh and then move to the expansion. And we hope, of course, we believe this (inaudible) also. If that answers your question, I think you can do the math.

And our next question comes from the line of Silvan Tuerkcan with JMP Securities.

Congrats on the quarter. Maybe 1 question, you 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? So what are the mechanics of interactions with the regulators here? And I think, last time, we were talking about the potency assay for the assets 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, recently, there was a deal with Roche and obviously Poseida and as part of that, rather large deal and interest in that roses getting into the CAR-T space now, there was a CD19/CD20 CAR-T. Could you just tell us a little bit about the differences, obviously, in 19, retargeting of 19, why would you do that? And why is 20x22, perhaps a better idea?

Thank you so much, Silvan. Great questions, and I can start on the Raleigh one. So definitely, as mentioned before, we've had interactions with regulators to understand exactly what they would be looking for in seamlessly transitioning from our CMO manufactured product to the Raleigh manufactured product. This -- 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, their IRBs, so that we can then safely administered product. So 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 the...Yes, Andre, please go ahead.

Yes. On the size of the potency assays, it's 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 that'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 like the potency of release of perforin and granzymes and the number of recycling that it could do the time of the recycling between 2 releases, the expansion potential of the cells, the number of like cell division they can do, the interferon gamma assays, et cetera, and all of this gives you quite a broad idea of the performance of these type of products.

And well, I think it's good, but the performance that we obtain is totally not that bad, and we're very excited to see that they're very performant program, but definitely the comparability doesn't stand, it's not totally comparable. So that's why there is a potential rule necessity of potentially do quite like a few doses below and spend after you don't do a full cohort, but that's what you give. There was a technical question like the beginning of the 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, retargets basically CD19. Just what are the rationale there? And why?

Well, I don't see the rationale behind the fact that most of the patients receive the 19 CAR-T at start. And they arrive, they will probably deliver in a space of a full end of CD19 CAR-T allogenic hematologists. Of course, the Allogene CAR-T will be approved by then. Of course, you have Yescarta, Kymriah, et cetera, et cetera, et cetera. And then you come with yet another CD19 CAR-T, where you see the performance are already quite good. So either you show a superiority compared to the other CD19 CAR-Ts and added CD20, or I think it's way more interesting to have a CD20x22, where there are all the relapses of 19 are not going to give them another CD19 CAR-T. So it's better to give them a CAR-T that we believe the performance is really high, but don't have CD19. So I'm surprised of the reaction of this type of approach.

Our next question comes from the line of Nicholas Abbott with Wells Fargo.

First just on just on UCART22. So have you filed the IND amendment? And if not, when do you intend to do that?

Andre?

It broke up a bit at the time, actually, like can you just repeat the question, excuse me?

Yes. Andre, I'm asking whether you have for UCART22, if you filed the IND -- if you filed the IND amendment? And if not, when you think you'll do that?

For 22?

Yes.

Well it's -- well, you should expect to see patient dosing, I hope, sooner than later. We haven't disclosed it, but we are not delayed. We are on time.

I may have missed it. I didn't hear -- I think it was asked his prepared comments on 1, 2, 3. But I seem to 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, yes, actually, we've been very cautious with this type of CAR because we had a series of CRS in the past. And we think that dose level 2 could be an interesting dose so far, and we are concerned by dose level 3 that being too high dose. So we are trying an intermediate dose. And potentially, I think that maybe there is like an intermediate between the 2 like giving a repeat dose on 2 or something like this because it's quite a reactive target, and it started easy disease. So I'm not going to go through all the details of this, but I think we're in orders that are interesting for the dose level, DL2 or -- and that maybe it can be high waters on DL3. So this is not a simple CAR T to be dosed.

Right. Understood. So then maybe you filed like an amendment to try -- do you need to file an amendment to try dose Level 2.5 or repeat dosing?

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

Our next question comes from the line of Brooke Schuster, William Blair.

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 the UCART20x22 uses the same allogeneic CAR-T manufacturing platform that we developed at Cellectis. So the same manufacturing process as 123, 22, CS1 with all the improvements that come from manufacturing it in-house from our Raleigh facility. There is 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 allogeneic -- to put the allogeneic approach. And 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. So there was definitely a lot of process improvements to cater for 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 UCART20x22, if you don't write exactly on the 2, for example, containing the antiviral vector for CD20x22 versus 22, you will not realize. So it's exactly the same process. The only thing that defers is in the QC at the end to be sure that both CARs has expressed or like the killing on 20 and on 22, notwithstanding the fact that the other targets are not present, et cetera. So there is a QC process. It's slightly more complex for UCART20x22 to be sure that you have the jewel. But during the manufacturing process itself, if you don't know what's contained in the lenti then you don't know. It's exactly the same.

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

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, Matt. Great questions. Andre?

Well, the patient enrollment so far has been slow for numerous reasons across the 3 trials. So 22 -- acute lymphoblastic leukemia is a rare disease compared to Non-Hodgkin's Lymphoma, there's like 120,000 patients in the U.S. -- patient every year in the U.S. versus like 6,000 -- 120,000 versus 6,000. So it's quite huge. So it's been -- the enrollment has been slow.

On TS1, as I said before, also, there are a lot of products in this space. So the trials are like recruiting patients that fit the criteria, and there are like tight criteria for numerous reasons also is quite lower DL1. We have completed DL3 for P1 for 22, but we're still at DL1 for CS1 following the hold. And 123 is a difficult disease to treat. So also like the patient selection and is something that slows down their enrollment. And we are like completed DL2 and we will DL2I have 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 is a lot of trials that are ongoing, and we are opening other countries, and we believe that other countries have less of these complex cell and gene therapy trials. So there is more potential in recruiting patients that we believe so. And UCART20x22, which is not touching lymphoma is opening in multiple countries, not altogether because the U.S. is faster, but potentially we'll see a 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 to dial as opposed to an on-off like (inaudible). 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 the right safety benefit ratio. So you're spot on, and I think this is what we love about the CD52 approach is its inherent tunability.

And we have reached the end of the question-and-answer session. I'll 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. And I think they're all like very great question. Of course, 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, in-house manufactured, UCART20x22 in-house manufactured product. Also, we are also progressing on CS1 and 123 and the thing is like, we'll definitely keep you updated on these trials in the near future. And 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.