Cellectis SA (CLLS) 2021 Q4 法說會逐字稿

Good morning, everyone, and welcome to Cellectis Fourth Quarter 2021 and Year-End Conference Call. (Operator Instructions)

Please be aware that today's conference call is being recorded.

I would now like to introduce the first speaker, Arthur Stril, Chief Business Officer. You may begin.

Good morning, and welcome, everyone, to Cellectis Fourth Quarter 2021 Year-end Corporate Update and Financial Results Conference Call. Joining me on the call today with prepared remarks are Dr. Andre Choulika, our Chief Executive Officer; Dr. Carrie Brownstein, our Chief Medical Officer; and our new Chief Financial Officer, Dr. Bing Wang.

Yesterday evening, Cellectis filed its annual report and issued a press release reporting its financial results for the fourth quarter and year ended December 31, 2021. 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 plans. These forward-looking 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. Andre?

Thank you, Arthur. Good morning, and thank you, everyone, for joining us today. 2021 was a productive year for Cellectis. We are proud of the progress we've made as it relates to our corporate milestones as we evolve to become a full end-to-end cell and gene therapy biopharmaceutical company. We have progressed on the clinical front with escalating doses of our product candidates. We completed our manufacturing plants, and that gives us control of products, quality and supply lines. We continue to innovate. We have been working on our first dual-targeted UCART product, UCART20x22 and plan to bring it to the clinic into 2022. We have been able to leverage our valuable TALEN platform to provide Cellectis with business opportunities in the future cell therapy field outside of our core allogeneic CAR T area. Regulatory issues that had posed some of our partnered programs have been resolved. It is clear that none of these issues are due to Cellectis TALEN technology. And our financial position is secure.

Based on our current plans, our cash takes us not just through 2023, but to early 2024. First, I will touch on some of the clinical progress. Carrie Brownstein, our Chief Medical Officer, will give additional details later. We have trials running in 3 different forms of hematological cancers. At the annual meeting of the American Society of Hematology held in December 2021, we released encouraging preliminary efficacy and safety data from our BALLI-01 trial, evaluating UCART22 in patients with relapsed or refractory B-cell acute lymphoblastic leukemia. These patients received fludarabine, faclofospamib and alemtuzumab a lymphodepletion regimen and provides us strong confidence that we are moving into the right direction. These results showed that our preconditioning regimen that includes alemtuzumab was well-tolerated and promoted the expansion of clinical activity of our UCART22 in patients with relapsed or refractory B cell lymphoblastic leukemia.

Currently, in the BALLI-01 trial, we are enrolling patients at the highest dose so far, dose level III. We also added alemtuzumab to the preconditioning regimen in another blood cancer clinical trial, AMELI-01, in acute myeloid leukemia. So in the clinic, we're moving into 2022, confident in our ability to execute our ambitious new program focused on product development and patient recruitment into our 3 ongoing multicenter dose escalation clinical trial, BALLI-01, AMELI-01 and MELANI-01.

We also plan to file a new IND for our new product candidate, UCART20x22 for patients with relapsed or refractory non-Hodgkin's lymphoma. With this road map, our cash runway takes us into Q1 2024. Let's turn now to the progress we have made in manufacturing. In 2021, Cellectis made a meaningfully powered becoming one of the few end-to-end cell and gene therapy companies. Back in 2018, Cellectis made the decision to internalize the manufacturing of its therapeutics product candidates, providing the company with independence and a stronghold over its cell and gene therapy processes. We are thrilled to say that this goal has been achieved in 2021.

Our two manufacturing sites in Raleigh, North Carolina and Paris, France are both now fully operational, We produce our own cell libraries, our own plasma DNA, our own messenger RNA. We produce 2 type of vectors, AAVs and recombinant lentiviruses. We are set up to produce our own clinical-grade allogeneic CAR T-cell product. In fact, in the second half of 2022, we plan to initiate dosing patients in the BALLI-01 trial with clinical supplies of UCART22 manufactured in-house in Raleigh, and UCART20x22 in non-Hodgkin lymphoma trial.

We're becoming self-sufficient in clinical supplies. This reduces our dependence on outside suppliers. These derisks our path to the market. This removes bump into the road. Cellectis is positioned to capitalize on clinical and commercial success of its product candidates. I already mentioned our plan to file an IND of a new product candidate, UCART20x22 in non-Hodgkin's lymphoma. This is a very exciting product for the at least two reasons. First, UCART20x22 will potentially be our first dual allogeneic CAR T to enter clinical trial. It is designed to hit 2 validated targets in B-cell malignancy. The product candidate is also the first product candidate Cellectis has designed in-house, developed in-house and manufactured in-house.

In addition, the power of UCART20x22 is that it goes beyond overcrowded CD19 antigen on B-cells. We believe it's a real allogeneic CAR-T alternative to the crowded of all CD19 targeting product.

I want to say a word now about our partner product pipeline, which remains important to Cellectis as a validation of our technology-based source of future revenues. In January this year, Allogene announced that the United States Food and Drug Administration has removed the clinical hold on all of the Allogene's clinical trials, which was announced on October 7, 2021. Allogene reported that after investigation, it was determined that the chromosomal abnormality detected in some UCART cells of the single patient treated with ALLO-501A was unrelated to TALEN gene-editing in B-cells cells.

Allogene has announced that it has resumed clinical studies activities on TALEN gene-edited product candidate, ALLO-715 and ALLO-605, targeting BCMA for relapsed or refractory multiple myeloma. Allogene has resumed clinical studies activities on TALEN gene-edited ALLO-316, targeting CD70 for advanced or metastatic clear cell renal cell carcinoma and began enrolling patients earlier this month.

Allogene also announced that -- and its partner, Servier will resume their clinical activities on CD19. During the 2021 Annual Meeting of the American Society of Hematology in December 2021, Allogene in collaboration with Servier reported that the results from Alpha and Alpha 2 clinical data continue to support the promises, ALLO-501 and ALLO-501A, to be safe and durable alternative to approve autologous CAR-T therapy in patients with relapsed or refractory non-Hodgkin's lymphoma.

Allogene announced its intent to initiate a Phase II pivotal trial on ALLO-501A in relapsed or refractory large B-cell lymphoma is on track to commence midyear 2022 pending FDA discussion. On the business development front, -- the utility of Cellectis TALEN gene-editing system continue to provide the company with expanded opportunity.

In February 2021, we entered into strategic research and development collaboration with Cytovia Therapeutics to develop TALEN gene-edited products a new type of cells, iPS NK and CAR-T NK for a series of different types of tumors. In November 2021, that collaboration with Cytovia expanded to include a new CAR target and development in China by Cytovia joint venture entity, CytoLynx Therapeutics. Financial terms include either a cash payment and/or equity stake totaling $20 million, depending on the satisfaction of certain conditions by December 31, 2021. Cellectis is in discussion with Cytovia regarding a potential extension of the deadline for such conditions to be met. The agreement also provides us up to $805 million of development, regulatory and sales milestone and a single-digit royalty payment on the net sales of all partnered products commercialized by Cytovia. After Allogene and Iovance Biotherapeutics, partnerships that we have signed, the collaboration with Cytovia in another cell therapy modality highlights TALEN as a gene editing technology of choice for cell therapy applications.

We have also expanded our general management team and Board committee with top talent. Firstly, Cellectis recently appointed Dr. Bing Wang, our new Chief Financial Officer. I would like to take this moment to welcome Bing to our Executive Committee and to Cellectis. Bing is a highly accomplished executive, who brings extensive global finance experience in the biotechnology industry, including a background with global public companies in corporate finance. He comes to us from Refuge Biotechnologies, a cell therapy in oncology biotechnology company, leveraging synthetic biology and gene engineering, where he was Co-Founder and the Chief Executive Officer. Bing's extensive experience in financing clinical stage biotech companies will be critical as we enter our next stage of development of our clinical trials. Welcome to Cellectis team, Bing.

Secondly, Cellectis appointed Dr. Donald Bergstrom as an observer on the company's Board of Directors in November 2021. Dr. Bergstrom brings with him 15 years of experience in the biopharmaceutical and medical industry and serves as Head of Research and Development at Relay Therapeutics, a clinical stage precision medicine company. They join a team executive clear plan to transform opportunities in cellular biology to the production of multiple focused clinical candidates. We already have a place of many of the elements that Cellectis needs as it products prove themselves. We have invested in the future, and we have the resources to continue to push forward that future.

Now I would like to turn the call over to Dr. Carrie Brownstein, our Chief Medical Officer, to give an overview of our three sponsored clinical trials and preclinical product pipeline. Carrie, please go ahead.

Thank you, Andre. As Andre mentioned, 2021 has been a productive year for Cellectis with our proprietary clinical programs, making substantial progress. I would like to start with UCART22, our CD22-directed TALEN gene-edited allogeneic off-the-shelf CAR T-cell product candidate currently being evaluated in patients with relapsed refractory B-cell acute lymphoblastic leukemia. We presented preliminary data at the 63rd Annual Meeting of the American Society of Hematology in December 2021. The presentation included data from patients who received UCART22 after lymphodepletion with fludarabine, cyclophosphamide and alemtuzumab. Alemtuzumab was added to the fludarabine and cyclophosphamide to deepen and sustain host lymphocyte suppression, thereby promoting UCART22 expansion and persistence.

As of the clinical cutoff date of October 1, 2021, 12 patients had received lymphodepletion, 11 were administered UCART22, of which 6 received UCART22 and fludarabine, cyclophosphamide, alemtuzumab, 3 patients at the dose level II and 3 patients at dose level II intermediate. UCART22 after FCA lymphodepletion was well-tolerated. No patients experienced protocol-defined dose limiting toxicities, immune effector cell-associated neurotoxicity syndrome nor UCART22-related severe treatment-emergent adverse events. Three patients experienced mild to moderate cytokine release syndrome. One patient reported Grade II GVHD of the skin in the setting of cryoallogeneic transplant donor stem cell reactivation. Encouraging antileukemic activity was observed in two patients in the FDA cohort. Both patients, one at dose level II and one at dose level II intermediate, achieved blast reduction to less than 5%, 0.4% and 0%, respectively, by day 28, accompanied by measurable UCART22 expansion and changes in relevant inflammatory markers.

Overall, UCART22, after fludarabine, cyclophosphamide and alemtuzumab lymphodepletion demonstrated promising signs of antileukemic activity without unexpected or significant treatment-related toxicity. The addition of alemtuzumab to fludarabine and cyclophosphamide was well-tolerated, improved host lymphocyte suppression and promoted UCART22 expansion, which was associated with anti-leukemic activity.

These data are encouraging and support the further development of UCART22 for patients with relapsed or refractory BALL, who remain in dire need of additional treatment options, particularly those who have failed CD19 therapy. BALLI-01 is currently enrolling patients at dose level III with FCA lymphodepletion.

Next, I'll move on to UCARTCS1. CS1-directed TALEN gene-edited allogeneic CAR T-cell product candidate being evaluated in patients with relapsed or refractory multiple myeloma. Early preliminary data from the first patients enrolled in the MELANI-01 trial was presented at the American Society of Gene & Cell Therapy, 24th Annual Meeting. These data validate CS1 as a target for allogeneic CAR T-cells in multiple myeloma. As UCARTCS1 expansion and persistence was observed and correlated with changes in relevant serum cytokines and with anti-myeloma activity. Cellectis is currently enrolling patients with dose level I with FC lymphodepletion.

Lastly, I will speak to UCART123, our CD123 directed TALEN gene-edited allogeneic CAR T-cell product candidate being evaluated in patients with relapsed or refractory acute myeloid leukemia. This trial addresses a patient population with severe unmet medical needs. Where a successful CAR T-cell product candidate would be a major breakthrough. We are currently enrolling in our Phase I dose escalation trial with FCA lymphodepletion, enrollment in dose level II is ongoing. We look forward to sharing data from this program when it becomes available. Building on the technology platform of our current proprietary clinical programs, I'm excited to report that we plan to submit an IND for UCART20x22, our first allogeneic dual CAR T-cell product candidate for patients with B-cell non-Hodgkin's lymphoma in the second half of 2022. CD20 and CD22 are both well-validated targets in B-cell malignancies and represent a therapeutic alternative to CD19-directed therapies.

Targeting two antigens has important advantages. Firstly, it has the potential to increase efficacy by strengthening the contact of the CAR T-cells with the tumor cells for more effective killing. Secondly, it increases the breadth of antigen targeting and therefore, may increase the addressable patient population. And lastly, it provides potential to overcome antigen escape.

Preclinical data supports moving UCART20x22 into the clinic, and I'm very excited to start the clinical trial for patients with relapsed refractory NHL.

With that, I would like to hand the call over to Bing Wang, Cellectis' Chief Financial Officer, for an overview of our financials. Bing, please go ahead.

Thank you, Carrie, and good morning, everyone. I'm pleased to be here and thank everyone for the warm welcome. I will provide a brief overview of our financials for the fourth quarter and full year of 2021. I would like to highlight that the cash, cash equivalents, current financial assets and restricted cash position of Cellectis, excluding Calyxt, as of December 31, 2021, was $177 million compared to $244 million as of December 31, 2020.

This difference mainly reflects $116 million of net cash flows used in operating, investing and lease financing activities, which were partially offset by $45 million of equity proceeds raised from the sales under the company's at-the-market program established in April 2021 and $10 million proceeds from stock option exercises. This cash position is expected to be sufficient to fund Cellectis stand-alone operations into early 2024. The net loss attributable to shareholders of Cellectis, excluding Calyxt, was $97 million in the full year of 2021 compared to a loss of $54 million in 2020. This $43 million increase in the net loss between 2021 and 2020 was primarily driven by a decrease in revenues and other income of $21 million and by an increase in operating expense of $40 million, partially offset by $18 million increase in net financial gain.

The consolidated net loss attributable to shareholders of Cellectis, including Calyxt, was $140 million or $2.55 per share in the full year of 2021 compared to a loss of $81 million or $1.91 per share in 2020. The consolidated adjusted net loss attributable to shareholders of Cellectis, excluding noncash stock-based compensation expense was $102 million, or $2.27 per share in the full year of 2021, compared to a loss of $67 million or $1.57 per share in 2020. In 2022, we are focused on spending our cash on developing our core programs. This allows us to extend our cash runway, excluding our subsidiary, Calyxt, Inc. into early 2024.

Thank you, Bing. To close this call, I would like to reiterate how excited and proud we are of what Cellectis has accomplished in 2021, and how this success propels us forward into 2022. More than 170 patients with relapsed or refractory malignancies have been administered with TALEN gene-edited allogeneic CAR-T cell product candidate built on Cellectis technologies in trials sponsored by Cellectis and its license partner with a promising safety profile making the largest and the most robust disclosed clinical data set of any gene editing technology in the world. Our products in clinical development with the diversity of targets and indications as well as our allogeneic UCART platform business is at the forefront of developing novel CAR-T therapeutics that ushers in the next generation of cancer therapy.

We continue to leverage our expertise in gene editing and clinical development to transform the lives of patients with cancer and rare genetic diseases. And we look forward to accelerating this momentum in 2022 and beyond. At Cellectis, we strongly believe that our product candidates, our 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.

(Operator Instructions) Our first question comes from Yigal Nochomovitz with Citibank.

On UCART22, you're moving from the CRO product to the in-house product in the second half of the year. Could you just talk a little bit about the comparability between those two products whether the FDA has signed off on the comparability and presumably, you will need an IND amendment to start the studies with the in-house version?

Thank you, Yigal. Andre or Dave, this is Arthur. Andre or David, do you want to take this one?

Yes, I will. Thank you, Arthur. So we have already started the conversation with the agency as for how we will compare the P2 product, the one made in Raleigh and the one that we've been using so far that was originally made at our CMO CellforCure. So this is an ongoing conversation, and we're very confident we'll come to the definition of an appropriate means to do that swiftly.

Okay. And then regarding the 3 Phase I data sets that you're working on, are you -- at this point, are you able to give any more granularity on which of those we might see data for in 2022?

So we're definitely in the process as announced by Carrie, this is Arthur, to go through the various escalation data sets of these trials. We're not committing in particular to giving data on one specific program as we would want to get a meaningful data set, a meaningful clinical data set prior to sharing at a conference as we have done for UCART22 at ASH last year. But what is safe to say is that we would definitely provide an update on at least one of these programs in the course of the year, if not more, depending on how data matures over the course of the year.

Okay. And last question. Obviously, the CD20x22 is a very, very interesting product. Can you talk at all about what other combo cars you might be contemplating beyond 2022?

No. Actually, if someone wants to answer it. This is Andre answering the question. So listen, it's -- I think the strategy that Cellectis is in today, I think it's going to have like -- go into a very interesting payoff. Probably people are -- have been criticizing us on the fact that we want to unvalidate the target. If we don't consider that these targets are unvalidated such as 22, 123, CS1 or 20x22, but we have a very interesting positioning to develop and commercialize these products. The are not 19, they are not BCMA. This is a great positioning because we don't have to face, for example, products such as BCMA products competition or 19 competition that is already commercial, and we have a different type of angle. So disclosing the next product we're going to develop is probably going to tip our competition, and this is not something I think would be wise on our side to disclose.

I would like to have all your attention on 2022 and the data releases that was going to happen this year, as Arthur has said, because we believe that we're in a very good place concerning the development of these type of products so far. So this is the thing that excites us, but disclosing what's going to happen in the future for dual target that we believe is a very interesting approach for numbers of reasons. First, for potentially lots of targets, but also for enhancing the tumor acetated antigen density and the formation of (inaudible) to have a better killing of these products is something that would be crucial and potentially also increase the safety and the performance of these products in general.

Our next question is from Gena Wang with Barclays.

I have two. The first one is regarding UCART22 in-house manufacturing. Can you lay out the steps you need to complete in order to start dosing in-house product? My second question is regarding UCART20x22. Just wondering, any updated thoughts on initial doses based on the UCART22 data?

Thank you so much, Gena. I think the first question may be for Steve. And the second question for Carrie.

Sure. This is Steve at Raleigh, in terms of the UCART22 produced in-house here in Raleigh. We've already done so the clinical materials have been produced and analytical testing is ongoing as well as preparations for an IND amendment. So we're well on track to be using that material in the second half of the year.

Yes. Sorry. And what's the second question again? Was the doses for 20x22?

That's correct. Any update or thoughts on initial doses?

Yes. I'm not going to provide details on what the clinical trial design is going to look like when we start the trial and it's in clinicaltrials.gov, you'll see, but we have lots of data from both internal and external data to help support where we start. And hopefully, given that it's a very well-understood patient population and space in terms of CAR T-cells with NHL. We have a lot of data to help support where our starting dose will be and potentially could help expedite the trial.

Our next question is from Kelly Shi with Jefferies.

This is Dave on for Kelly Shi at Jefferies. My first question is on CART20x22. Just wondering, in your clinical trial design, are you thinking of enrolling both CD19 naive and relapsed patients?

Yes, I can take that. So we're thinking about enrolling a broad patient population to start because that always helps expedite clinical trials. And then based on what we see, we would make decisions that we would expedite moving things forward in one or more specific subsets.

Got it. And another one is on your solid tumor program. Do we expect any update during the course of this year?

So I can start that. This is Arthur. So basically, what we've announced this year is a focus on...

Actually, it's a good question as we announced it given the hyper focus of the company today on our three clinical trials and 20x22, IND and start of the development. There will be probably some scientific conferences with the development of certain solid tumor products that are currently still in R&D and shelf, but the fact is that the strategy of the company is trying to push as hard as we can to get these products rapidly into expansion, pivotal trial, the 4 products that we're considering, and we'll see how the market evolves and the global situation evolves. The pressure that we have, that external pressure on the international situation and the market conditions for cell and gene therapy space before we can reconsider pushing these type of products into the clinical -- into clinical trial.

We're extremely excited by these candidate products that we have. Very, very excited, but we have to choose our fights. And we think that the most mature product that we have -- have all of them, huge potential. And I think it's in the interest of our shareholders and the company and of course, the patients to put all our power into developing these hem-onc products that we have.

Our next question is from Raju Prasad with William Blair.

Just had a quick question on the CD52 condition regimen. I know Allogene has to run a trial to show the impact of CD52 on engraftment. Is that something that you anticipate having to do? Have you had any discussions with the agency on any commissioning trials that you have to run?

Sorry, I could start, if anyone else wants to chime in. I think that -- oh, okay. Sorry, it looks like the folks in Paris got disconnected. I could take this. So it's a little bit different. I think I'm not going to speculate here what we may or may not need to do for our BLA filings. But remember, the Allogene program is using a different anti-CD52 antibody, which is their own proprietary, ALLO-647, which is not a product that's ever had a marketing authorization anywhere. So it's a little bit of a different situation. But obviously, as we move forward with development, we'd have these discussions and see what we would need -- but I think what we're doing right now is we've already looked at -- in all of our trials with that we're using the alemtuzumab in with and without the antibody. And I think there's -- as we showed at ASH in December, there's strong data to support that we're not seeing expansion and persistent without it. And personally, I would find it unethical to continue dosing without it, but that would be something we'd have to discuss as we move forward with our development plans.

Great. And just curious, as you get data from the 20x22 product, kind of in concert with the 22 product, how are you thinking about making decisions on pivotal trial and how to move forward? Are you planning right now to kind of move both products forward? Or would there be kind of a decision point at some point maybe next year or the following year?

Yes. I think that's a really interesting question because, obviously, given what we're talking about with 20x22, it could potentially also be on work in not just NHL, but in, for example, ALL. But I think as it is right now, given we have UCART22, and we're moving it forward in ALL, we would likely continue to move that forward for this niche patient population that has a high unmet medical need as a separate product. But again, those are conversations and discussions we would have as we move forward with both programs.

Our next question is from Jack Allen with Baird.

I have two quick ones here. I guess first, on the clinical side of things. I was hoping that you could provide a bit more color around your progress with the CS1 candidate. It sounds like you've moved into dose level I, but I'm curious as to how many patients may be you've dosed in dose level I and I guess, maybe any color you can provide around the totality of that cohort and your plans to move on to dose level II. And then on the financial side, I was hoping you could just lay out a little bit around the timing of potential milestone payments that we could see in the coming year. I think ALLO-615 just moved into the clinic, and then they do have that ambition to initiate a pivotal study in the middle of next year. So I'd love to hear any color on those milestone payments. And then any comments on milestone payments from other collaborators as well Iovance and Cytovia?

Carrie here. I could start with the questions about the CS1 program. So we are moving ahead with the UCARTCS1 program in myeloma, and we have disclosed that we're in dose level I. I'm not going to speak to how many patients and when we're going to be planning on getting into the next sets of data. I think suffice it to say, we have extremely excited investigators. There's still high unmet medical need. As you know, we did come off of clinical hold, and we had previously disclosed that there's some long waiting periods in between patients and things that were required by FDA. And so we are moving through it as lean expeditiously and safely as we can and hope to provide a data set external -- for external disclosure when there's -- when we have a reasonable data set worth sharing and probably at a pivot point for when we would potentially be starting to move more quickly, like in an expansion of some sort.

And I will now pass it on to Arthur and Bing for these financial questions.

Yes. So Jack, for the milestone payments. So basically, first of all, on the Servier Allogene collaboration on CD19, we're definitely eligible for a milestone payment upon the initiation of the pivotal trial, which Allogene has guided for mid this year. And we haven't disclosed the size of the milestone payment, but there will definitely be one. To the other partnerships, again, we haven't disclosed either the terms of the Iovance collaboration. But for Cytovia, this is going to be with the recent amendment up to $805 million of milestones, and we're also getting an equity stake of $20 million into Cytovia stock. And so we expect that as Cytovia progresses these products in the coming months, we will start seeing some economics.

Our next question is from Hartaj Singh with Oppenheimer & Company.

Great. Two questions, and thanks for all the updates. Just a quick question on the manufacturing. Just going back to that I think you had highlighted previously, you might have to do an IND for 22 from the Raleigh facility. Was that been set to sort of as you go to clinical trial, hopefully, get ready to file a BLA. Will you be set sort of on the clinical manufacturing side of the potential BLA at that point after doing this IND? And then secondly, in that same vein, would you have to -- assuming you convert CS1 and 123 and get materials from Raleigh manufacturing facilities, might you have to do future IND there if you were to convert using the Raleigh manufacturing facility? And I just got a quick follow-up.

Steve, do you want to take this one? .

Sure. In terms of UCART22 being produced for Raleigh, that's going to be an amendment to the existing IND because it's considered a major change in the manufacturing when you move from one location, namely a CDMO to new. So they're to internal manufacturing. So there will be an IND amendment. And BLA as a future state, of course, dependent upon where we are in the clinical trials and how well they progress. But yes, we are very hopeful this would progress us at some point to a BLA. But for 22 at the moment, the focus is on submitting an IND amendment to enroll Raleigh as the manufacturing site.

And then just on CS1 and 123, would you ever consider moving those producing them in the Raleigh facility?

Hartaj, yes, we're planning to do this, of course.

Great. And then just last question.

Your next in line...

Okay. Great. And your dual targeting CARs. Do you see those in the future with 20x22 and then others kind of sort of being more competitive against the current CAR T, so that would be sort of a second generation kind of approach with CAR T, the dual CAR T? Or do you see it as sort of moving a little up further along and going up against the bispecifics, which some people believe might be a bridge to CAR T. I mean I know a potential play up, but just any thoughts there.

Hartaj from a development perspective, I'm happy to take it. I mean I think that, again, a lot of where we're going to end up positioning these programs and these products in the market space is going to be dependent on the data. I think what's extremely important to recognize when we're talking about allogeneic CAR T-cells versus the current autologous space, is that -- I don't know, competition is the right word. But again, given their easy accessibility, the fact that they're in the clinical ready, they're in the freezer, you don't need to wait for manufacturing between patients, it changes the entire paradigm of treatment for CAR T versus the autologous space. So while the autologous space has been great and has been more of a kind of a second line or after, as you said, the bispecifics, I think provided data are strong enough. I think that we don't need the specialized centers and, and, and even this data isn't as strong, let's say, as which I think it will be, but let's say it's not as strong as autologous 19 or something. I don't think that's going to matter.

I think that the fact that physicians can get their hands on it and give it to patients quickly is going to be huge and really change how the treatment paradigm is set up from standard of care purposes, so to speak, from all of the key players who are treating patients. So I think, again, it will depend on the data. If the data obviously aren't as strong then maybe it would come after. But I think our positioning is going to be as strong as possible based on the data.

And then you have to also remember when we're looking at data and comparing it's actually more helpful to almost compare against bispecifics versus the CAR Ts because remember, when you look at the data in the labels for all of these autologous therapies that have been approved, their denominators are based only on patients who've received cells and they throw out all of the patients who, either they had a manufacturing failure or it was an (inaudible) product or that the patient progressed prior to getting treated. And so if you actually redo a lot of those numbers, the response rates and PFS and everything is just much, much, much lower than what's in the label. And so we need to be extremely careful when we're comparing. And that's part of the reason those CAR T-cell therapies looks so much better than bispecifics as well. So yes, so I think we could be clearly in any position, which is what makes this so exciting.

Carrie, thanks for all the updates and the wood that you're chopping on the manufacturing side.

(Operator Instructions)

Our next question is from David Dai with SMBC.

Congrats on the progress. I have a question on UCART123. We know that UCART123 is an updated product with the new construct and new manufacturing process. Could you just share some additional color on the changes on the construct also the manufacturing process? I also have a follow-up after that.

So maybe I can start.

David is taking it. Arthur, David is taking it.

This is David. So we did evolve UCART123 to incorporate the CD52 knockout, and that allows us to explore lymphodepletion including alemtuzumab, which is what we have disclosed, and that was a major change in terms of molecular constructs. We also evolved the process itself, taking into account all the teachings that we had gained from working with UCART22 and UCARTCS1. And, well, in a nutshell, we are basically producing a much better product, and we think it's much more robust and reproducible so far. So I won't get into the details of the process evolution. But those are the elements that we can share at this stage.

Got it. That's really helpful. Just as a follow-up. And then could you provide some quick update on the in-vivo programs maybe share some additional color on the timing of potential IND filings for those in-vivo programs?

I'm not sure what you think about in vivo programs because we definitely have plans in the space, but I'm going to reiterate the fact that in the current situation and the road map, that we have currently, we're putting 100% of our focus on the 4 as we have your UCART22, UCART123, UCARTCS1, and UCART20x22 that we believe have a huge traction, are exciting and mature product. We are extremely excited and interested also in in-vivo approaches using TALEN or TALEN-based editors also potentially for different type of applications, because we have a fantastic technology concern on base editing because it's a split activity between the two arms of TALEN that have a very high accuracy and we're excited about that. But today, in the current situation and the current market conditions, et cetera, all the focus of the company is on these four trials. When the situation will improve, resume, et cetera, -- of course, we'll put the pedal on the metal on the in-vivo programs. And today, they're essentially developed at the R&D stage that is perfecting and polishing and finessing all of these programs.

Our final question is from Silvan Tuerkcan with JMP Securities.

And welcome, Bing, to the team. I just had two quick questions. I don't know if you can comment on this, but on UCART123, I believe the last comment was that you were looking to enroll in dose level III -- II, could you just give us some color on where you're at in terms of dosing on that program? And then I have a quick follow-up?

Sure, it's Carrie. I can speak to that. I mean we're not -- again, we are not disclosing exactly where we are in terms of number of patients in which dose levels other than that at the beginning of this year, we've been starting at dose level II. We've been working on flowing out that cohort, and we'll continue to move forward as the year -- time goes on. And as we -- when we have a reasonable data set to share and we're ready for the next stage, we'll be sharing data.

Great. And on UCART22, I think there was going to be an additional data cut this year. And is there any chance that this could have some of the new material from the Raleigh facility in the data? Or do you think that's premature at this point?

Yes. So we have not -- as Arthur spoke to earlier in the call, we actually haven't disclosed per se exactly which data set we would be sharing this year. We will share data on at least one of the programs. So we did not specifically speak to it being 22 or not. As I've said with all of the programs, I think it's really important that we share and disclose data sets when there's a meaningful data set that's giving us the support to move to the next stage and not just be giving dribs and drabs over time because we fill the cohort. So that's not something that I want to do. So we will be figuring out which will make the most sense based on where we are and what the meaningfulness is of the set at the time.

We have reached the end of our question-and-answer session. I would like to turn the call back over to management for closing comments.

Well, thank you very much. And thank you for all the attendees for our earnings call this year. We're extremely excited. We're excited by 2021, which was a very productive year for Cellectis because we've been pushing on our three clinical trials, and also one thing that is transformative for the company. It's a different company in '22. We're now producing our own IMPs from A to Z. And this is convertible to producing pivotal product and convertible commercial in the future. And this is a huge change for Cellectis. You know the history of the company, how much difficulties we had in the past with certain products that were produced at CMOs. But today, it's a different type of Cellectis that you have. We're entering into a very interesting phase into all our clinical trials. And 2022, I cannot be more excited about what's going on in the company. And for this year, I hope that we will be sharing very exciting and interesting data in the coming future. And passing the step, Cellectis is unstoppable. With that, I would like you -- to thank you all and wish you a great day.

Thank you. This does conclude today's conference. You may disconnect your lines at this time, and thank you for your participation.