Cellectis SA (CLLS) 2021 Q3 法說會逐字稿

Greetings, Welcome to the Cellectis Q3 2021 Earnings Call. (Operator Instructions) Please note, this conference is being recorded. I will now turn the conference over to your host, Eric Dutang, chief Financial Officer. Thank you. You may begin.

Thank you, and welcome, everyone, to Cellectis' Third Quarter 2021 Corporate Update and Financial Results Conference Call. Joining me on the call today with prepared remarks is Dr. Andre Choulika, our Chief Executive Officer; and Dr. Carrie Brownstein, our Chief Medical Officer.

Yesterday evening, Cellectis filed its interim report and press release reporting our financial results for the third quarter and 9-month period ending September 30, 2021. This report and press release are available on our website at cellectis.com.

As a reminder, we make forward-looking statements regarding Cellectis' financial outlook in addition to its manufacturing, regulatory and product development. These statements 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 for the year ending on December 31, 2020 and subsequent filing Cellectis makes with the SEC from time to time.

I would like now to hand the call over to Andre.

Thank you, Eric. Good morning, and thank you, everyone, for joining us today. Over the course of the third quarter and the last 9 months of 2021, Cellectis has achieved a series of key milestones and we are incredibly grateful and proud of all the hard work achieved by our team, our partners and our stakeholders. 2021 has been a productive year thus far for Cellectis. We have made significant progress on all fronts that we are thrilled to share with you over the next half hour.

Notably, yesterday, Cellectis announced that the release of 2 abstracts accepted for presentation at the third -- at the 63rd American Society of Hematology Annual Meeting. Cellectis will present additional preliminary clinical data from its BALLI-01 trial of UCART22 in patients with relapsed or refractory B cell acute lymphoblastic leukemia and presentation of our first preclinical data of TALGlobin01 for the treatment of sickle cell disease.

Additionally, with regard to our preclinical UCART pipeline focusing on solid tumors, we have made notable progress with UCARTMESO, our allogeneic CAR T-cell product candidate targeting the dopamine-expressing solid tumors. We are excited to share that the first preclinical data demonstrating in vitro and in vivo antitumor activity will be presented at the Society for Immunotherapy of Cancer Annual Meeting later this month.

In 2018, Cellectis made the transformative decision to internalize the manufacturing of its therapeutic products. This decision, we feel, the crucial competitive advantage in today's world. This investment in our GMP manufacturing facility provides Cellectis with independence and control over its gene and cell therapy processes from buffers to DNA, messenger RNA, vectors and, of course, our cell therapy such as our UCARTs. We create and own our processes, our development and our production. In the cell and gene therapy space, whoever owns the process owns the product.

Due to the success of completion of both of our GMP manufacturing facilities, we can move swiftly into an innovative ID at the R&D stage to clinical trials with potential to produce commercial-level supplies in the future. We're proud to be one of the only companies of our size that are capable of moving into innovating new IDs from R&D to clinical trial to manufacturing and delivery directly to the patient, all in-house. We believe that bringing manufacturing in-house could contribute to eliminating some of the barriers competitors are facing.

Our goal is to provide consistency and safety on our production, ensure lead times are met and adaptability as each disease targeted by our advanced therapies may require cutting-edge innovation at the level of our manufacturing capabilities. We need to fully master the process. Importantly, having our manufacturing in-house means that we can rapidly burden promising therapeutic candidate as we monitor clinical responses, leading to the best possible product at registrational filing.

Our parent GMP manufacturing facility is now fully operational for the production of starting material. On the other side of the pond, our Raleigh GMP manufacturing facility, qualification of the facility equipment and systems was completed successfully in Q3. Qualification of the second UCART production suite equipment remains on track to enable start of engineering grounds of the third UCART product in early 2022.

Now I would like to turn the call over to Dr. Carrie Brownstein, our Chief Medical Officer, to give an update of our 3 sponsored clinical trials and preclinical product pipeline. Carrie, please go ahead.

Thank you, Andre. Cellectis continues to progress our Phase I clinical trials, evaluating our 3 proprietary allogeneic CAR T-cell therapies in hematologic malignancies: BALLI-01 evaluating UCART22 in patients with relapsed or refractory B-cell acute lymphoblastic leukemia; AMELI-01 evaluating UCART123 in patients with relapsed or refractory acute myeloid leukemia; and MELANI-01 evaluating UCARTCS1 in patients with relapsed or refractory multiple myeloma.

As Andre mentioned, 2021 has been a busy and productive year for Cellectis with our proprietary clinical and preclinical programs making substantial progress, and we are excited to share additional preliminary clinical data from our BALLI-01 trial at the American Society of Hematology 63rd Annual Meeting next month. The abstract includes updated preliminary results from the Phase I open-label, dose escalation BALLI-01 study in patients with relapsed/refractory B-ALL from the first cohort of patients who received UCART22 after fludarabine cyclophosphamide and alemtuzumab lymphodepletion. The addition of alemtuzumab to FC was well tolerated, deepened host T-cell depletion and promoted CAR T-cell expansion and persistence. The data presented support the safety and activity of UCART22 after FDA lymphodepletion in patients with relapsed/refractory B-ALL and the additional data will be presented at the Congress. Enrollment in the study is ongoing.

Additionally, preclinical data from the TALGlobin01, an autologous gene therapy product candidate designed to repair the mutated beta-globin gene and subsequently restore production of hemoglobin A in patients with sickle cell disease, was awarded a poster presentation at ASH. The data that will be presented are the first demonstration that TALEN-based engineering could be used to correct the mutation in the beta-globin gene of homozygous sickle cell anemia patient-derived hematopoietic stem and progenitor cells.

The data showed high level of hemoglobin A expression, reversion of sickling phenotype, the capacity of TALGlobin01 edited cells to engraft in vivo and a low level of off-target cleavage. Collectively, the data demonstrate high efficiency and safety of TALEN treatment in HSPCs and positioned it as the best-in-class gene-editing technology for gene therapy product development.

We are also pleased to share that our partner, Allogene, will present data from our licensed allogeneic CAR T programs at ASH, data from both the Phase I ALPHA2 study evaluating ALLO-501A in patients with relapsed/refractory non-Hodgkin's lymphoma and the Phase I UNIVERSAL study evaluating ALLO-715 in patients with relapsed/refractory multiple myeloma will be shared in oral presentations. Allogene will also present a poster on data from their Phase I ALPHA study, evaluating ALLO-501 in patients with relapsed/refractory non-Hodgkin's lymphoma.

During the second quarter of 2021, we presented preliminary translational data from the first group of patients enrolled in the MELANI-01 trial of UCARTCS1 at the virtual 24th Annual Meeting of the American Society of Gene and Cell Therapy. The early preliminary data presented validate CS1 as a target for allogeneic CAR T-cells in multiple myeloma. UCARTCS1 expansion and persistence was observed and correlated with changes in relevant serum cytokines and anti-myeloma activity.

Cellectis is advancing one of the most robust allogeneic CAR T pipelines, and we anticipate filing 2 additional new drug applications for 2 novel UCART product candidates in 2022: UCART20x22 and UCARTMESO. UCART20x22 is the first allogeneic dual CAR T-cell product candidate, which is being developed for patients with B-cell non-Hodgkin's lymphoma.

UCARTMESO is an allogeneic CAR T-cell product candidate targeting mesothelin, a tumor-associated antigen that is highly consistently expressed in mesothelioma and pancreatic cancer and is also overexpressed in a subset of other solid tumors. In addition to expressing mesothelin-directed CAR, UCARTMESO also leverages TALEN gene editing to overcome immune suppression mediated by TGF beta. UCARTMESO is being developed for patients with mesothelin-expressing solid tumors. Cellectis will present initial preclinical data that support antitumor activity of UCARTMESO in a poster presentation at the Society for Immunotherapy of Cancer's 36th Annual Meeting in Washington, D.C. and virtually on November 10 to 14, 2021.

With that, I'd like to hand the call back over to Eric Dutang, Cellectis' Chief Financial Officer, for an overview of our financials for the quarter. Eric, please go ahead.

Thank you, Carrie. I will provide a brief overview of our financials for the third quarter and first 9 months 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 September 30, 2021, was $201 million compared to $244 million as of December 31, 2020. This difference mainly reflects $92 million of net cash flows used in operating, investing and lease financing activities, which were partially offset by $45 million of net equity proceeds raised from the company's ATM program in April 2021 and $10 million proceeds from the stock option exercise. This cash position is expected to be sufficient to fund Cellectis' stand-alone operations into early 2022.

The consolidated cash, cash equivalents, current financial assets and restricted cash position of Cellectis, including tariff, was $260 million as of September 30, 2021 compared to $274 million as of December 31, 2020. The net cash flows used in operating capital expenditures and lease financing activities were $92 million at Cellectis and $15 million at Calyxt in the first 9 months of 2021. The net loss attributable to shareholders of Cellectis, excluding Calyxt, was $75 million in the first 9 months of 2021 compared to $21 million in 2020. This $54 million decrease in the net loss between 2021 and 2020 was primarily driven by a decrease in revenues and other income of $30 million and an increase in R&D expenses of $32 million, which was partially offset by an increase in net financial gains by $8 million.

The consolidated net loss attributable to shareholders of Cellectis, including Calyxt, was $89 million or $2 per share in the first 9 months of 2021 compared to $42 million or $0.98 per share in 2020. The consolidated adjusted net loss attributable to shareholders of Cellectis, excluding noncash stock-based compensation expenses, was $80 million or $1.79 per share in the first 9 months of 2021 compared to $30 million or $0.72 per share in 2020.

We are laser-focused to spend our cash on 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. On the other hand, our focus on maintaining an efficient corporate infrastructure should enable more limited growth in G&A spend.

With that, I would like to hand the call back over to Andre for concluding remarks. Andre, please go ahead.

Thank you, Eric. (foreign language) Our allogeneic UCART platform position us at the forefront of developing novel CAR T therapeutics that usher in the next generation of cancer therapies. 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 continuing this effort in Q4 2021 into 2022 and beyond. At Cellectis, we continue to leverage our groundbreaking gene editing platform to develop novel preparatory medicine to transform the lives of patients with serious diseases.

Our current preparatory clinical stage programs are focused on patients with advanced hematological malignancies, and we continue to expand our robust pipeline into the clinic to tackle additional oncology settings, including solid tumors, and to address the unmet medical needs of patients with severe genetic disease.

With that, I would like to open the call for questions and answers.

(Operator Instructions) Our first question comes from the line of Yigal Nochomovitz with Citigroup.

I had a question on UCART22 and the ASH data. Could you provide a bit more detail with respect to the collected data that we'll see at the presentation? And what is your internal bar that would qualify as an initially successful data set?

Well, thank you so much for this question. I think the most appropriate person to answer the question is probably Carrie. Carrie, do you like to take this question?

Sure, absolutely. Yigal, nice to hear from you. So what we're planning on showing is the first handful of patients that were treated with the fludarabine cyclophosphamide and alemtuzumab lymphodepletion regimen. So in the abstract is the first group that we had ready to prepare for the abstract, but we will have additional data at the meeting. And just know we're -- as you know, we're still in the dose escalation phase of the study. So we're not quite where we need to be for what we consider a bar for an approval, so to speak, for that.

As you know, we are in a very relapsed/refractory group of patients. We will have patients who have previous CD19-directed therapy. So for acute leukemia, I'm not expecting as we move through our clinical development plan for our first shot on goal, so to speak, with this product. I would not expect the bar to be tremendously high.

Got it. Okay. And then I just had a question on the UCARTMESO for the data to be presented at SITC. To the extent that you can comment, could you give us any preview of that data set? And what are the key features of that preclinical data set that are supporting the clinical development?

Carrie, do you want to also describe -- maybe (inaudible) how do you want -- okay.

Andre, I think you're in a better position to do that. Yes. Thanks.

Yes. So like MESO has been developed, I think it's like the first off-the-shelf CAR T without like all the complication that you see in other type of sourcing for allogeneic CAR T-targeting meso. And one of the features is extremely interesting that would be shown at ASH on this is like the knockout of the TGF beta receptor on the cell. TGF beta receptor is always -- is a potential down regulator for T cells in the tumor micro environment. And one of the big challenges Cellectis is battling to all the CAR T we're developing for solid tumors is trying to tackle the tumor in like macro environment, the TME, such as SAP, for example, that is something that's supposed to blow the -- like it seems like an article, but definitely SAP is the product that will take hold into the solid tumor protection.

And meso is essentially a CAR that's not going to be shut down by the negative feedback loop that you have with TGF beta-2 that is present in the macro environment. And this is the type of data that we have. We show also that this type of CAR will probably work in combo and that would probably give very interesting features, not only for mesothelioma, but potentially for a lot of different type of cancers.

[The idea] was selected also with all the attribute that this CAR has, which is like a CDC. It's the same platform as all the other CAR we developed, which is a CD52 knockout, so it will work on alemtuzumab and TCR alpha, plus it's a triple knockout. I think it's the first of its kind triple knockout CAR T. We're currently preparing this CAR to go into clinic. And I think the data are compelling and definitely encourages us in vitro as well as in vivo preclinical data gives like the compelling results for the tackling series of solid tumors.

Our next question comes from the line of Gena Wang with Barclays.

I have a few regarding more the big picture questions. So the first one, maybe for Andre, wondering the -- your partner Allogene had the clinical hold. And I think at their earnings call, they comment -- well, they did not disclose too much, but they comment there's some concern about translocation. So just wondering how the readthrough to your programs? And then also regarding your drug product, how much do you test regarding each step with the chromosome translocation events and how do you detect that?

And then my second question is regarding the allogenic CAR T approach in general. We did see several companies and also your partner, Allogene, will share some data on consolidation approach. And we did see improved complete response data -- complete response rate, and we don't know about the durability. But any thoughts from this approach like applied to your programs.

Well, thank you, Gena, so much for the questions. First of all, I think I'm going to let the Allogene management team comment on the clinical hold because I think it's like we're definitely very supportive and very confident on the handling of the situation by the Allogene team that's making fantastic work on their side. We're extremely excited by the data they're showing on UCART19 or ALLO-501A actually. And I think this is definitely a transformative data on the allogeneic CAR, especially with the consolidation. I'll come back to this.

But to speak about the impact on Cellectis. There is like -- of course, we're monitoring the situation very closely. We're helping as much as we can, do whatever we can, we'll definitely help Allogene to go through this period. And we have like a strong confidence in the product and the outcome. And we believe that this is -- like this trial is going to resume definitely.

Nevertheless, chromosomal aberration are quite frequent in nonhuman population. And would it be certain chromosomes have more aberration because they are subject to DNA recombination due to the state where they are. So like a lot of our immune cells, B and T cells, undergo DNA recombination at this stage -- at a certain stage. And sometimes these DNA recombination can lead to some chromosomal changes in there.

However, a few things that should be said. First, the prologue is not in danger right now like they see that there are like series of patients that have been dosed with the same platform. So we're confident on Cellectis' global platform and are -- not only gene editing, but also the global platform where we develop our allogeneic CAR T to be very stable.

The second thing is that T cell -- adult T cells -- you don't need -- there is no cell line on adult T cells in general. And then finally, the cancer is like -- an allogeneic cell term cancer, this is all the beauty about an allogeneic approach. Different types of cancer, especially T-cell cancer, T-cell cancer from like an allogeneic donor, this is not going to happen. Actually it's never happened in the history, and it's something that could be quite far.

So we're quite confident with this, and we believe that the platform on the contrary will come stronger from the space and also with a lot of confidence that what we have. So we have no concerns today on the potential risk on what Cellectis and our partners are doing. And we believe that this is like on an intermediate phase in there.

On the contrary, we're very focused and very positive on the outcome of the data that not only our partners are having, but also Cellectis keeps producing. And these all are IDs and products and targets that Cellectis has been incepting. And I think for the size of the company in driving so many life-saving products, something that's definitely transformative and will remain with the same type of technologies that we have.

Now on the consolidation study, it's something that I think always a very strong advocate. But I think it could be interesting to have Carrie's view because I've been speaking about like a consolidation study since years and we discussed this together, Gena. And -- but Carrie have like a pressure eye than myself and more medical doctor than I. So Carrie, if you want to say a few words about this.

Gena, nice to hear from you as well. So I'm really excited about the presentation that includes all the consolidation treatment. I think that I've been saying this since I joined Cellectis now 1.5 years ago. I mean it's one of the main beauties and key points that I think is going to make to allogeneic CAR T-cell therapies successful is the fact that you can give additional doses. And that's one of the huge drawbacks of the autologous setting.

We all know that these additional treatment, whether we're using chemotherapy, whether you're using antibody therapies, whether you're using small molecules, whatever it is in the history of treating any of these diseases has to do with being able to get the cancer cells to a state that not only you don't see them anymore, but that you can't measure them anymore. And the deeper the remission that you can bring a patient to, the longer their duration as well as their -- longer their survival and potential for cure.

So giving additional treatment is always the right way to go when you can. And therefore, it's really exciting to finally being able to see larger data sets of patients who received more than one therapy in the allogeneic setting and showing that it's able to really make a difference in treatment for these patients.

Our next question comes from the line of Michael Schmidt with Guggenheim.

This is Kelsey on for Michael. I've got 2 quick ones. First, could you just provide some color on where you're at with the other ongoing CAR T program, so UCART123 and CS1? And then with respect to the TALGlobin program, could you just remind us kind of the key areas of differentiation versus existing competitors in the field and how you kind of think about that?

Carrie, do you want to give an update on 123 and CS1? I can give an update for TALGlobin.

Yes, sure. That's perfect. Sorry, I was on mute for a second. Yes. So for UCART123 for relapsed/refractory AML and for the -- I'll start with that one first. So that study, as we've said, has been moving through dose escalation. I think, as you know, AML is a tough space with patients who are quite sick and tend to be a little more fragile than you would see with acute lymphoblastic leukemia or with lymphoma. So it is taking a bit longer, but we're moving through dose escalation, and we're hoping to have additional data at some point next year, we'll see, to share with everyone.

As far as the myeloma study for UCARTCS1, that, too, as you know, we had been on clinical hold. We reopened after changing the protocol, adding some additional safety pieces for guidance for treatment of adverse events as well as some other rules that the FDA was requiring to ensure safety as we move forward. So we've been moving through dose escalation, and that, too, has been moving along nicely. There's lots of interest from all of our investigators. And again, this is another program that we hope to be able to show additional data later next year.

As you know, earlier this year, we did present the original translational data from that source data set before the hold, which did show some interesting translational data that included the expansion of the cells. It shows all the cytokines that we expect to see, and we did see some response. So we're super excited about this program continuing to move forward and are looking forward to share data when the time is right.

Thank you, Carrie. On the TALGlobin side, the big differentiation that we have -- most of the current trials that you see for tackling the beta globin or beta thalassemia or sickle cell disease is based on the knockout of 1 repressor to reactivate a different type of hemoglobin, which is a sickle hemoglobin. So you keep the sickle hemoglobin in the cells. You destroy another gene. So there is 1 gene that is disrupted with mutation in the sickle in the cells. With the slowing of the gene that is a repressor and finally, we activate the gene that is not supposed to be expressed that can restore kind of the phenotype, which works actually (inaudible) the results that have been produced so far.

What people imagine on what could be the gene editing is if there is a point mutation that induces the sickling in the hemoglobin gene, people imagine -- figure out that editing the mutation would be fixing back the mutation, which is not happening in most of these trials. So the approach Cellectis is taking is repairing the mutation in the hemoglobin B gene and fixing this mutation and restoring the adult hemoglobin in the cells without leaving any scars or new scars in the DNA. So you put back the gene to the sequence it was supposed to be. This is an approach.

We're not -- of course, there are -- there is competition in this field, but we believe that Cellectis approach with the technologies we're developing such as TALEN and the approach we have with our -- with certain technology, which is gene engine and the Cyto Pulse technology brings it to a very high level of repaired adult modeling to like cells that are totally fixed with a very reduced side effects around and a very high on-target, with a very accurate repair of the hemoglobin at the end. So that's what differentiates us for most of the approach that you see currently in the clinic. And we believe that this is what patients want, their hemoglobin to be fixed.

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

This is [Dave] on for Kelly. Just a quick question on the readthrough. Is it possible that other things like CD52 lymphodepletion regimen could be the reason for this unexpected outcome? And another question is the -- for ASH data, can you provide some details whether it will include patients who had prior CD19 CAR T treatment?

Well, thank you very much for the question. Well, you mean -- like just to ask a precision on. Do you mean that like the CD52 monoclonal antibody could induce an inversion or like a chromosomal aberration somewhere?

Yes, that was the question.

Well, personally, I might not have all the information about this, but it seems to me complex, especially for non-internalizing antibodies such as like alemtuzumab to -- or like a by generic alemtuzumab to induce such type of chromosomal aberrations that are quite classical in general. It's not something that has not been observed and is observed quite often in a lot of not only patients but potentially the global population. It's not (inaudible) that is susceptible to chromosomal changes in there. So it's extreme, it's possible, but extremely unlikely on the mechanistic side. Excuse me, the second part of the question, I just tapped out.

The second part of the question is if you can provide any color on ASH update. Do you -- will you have any data on patients with prior CD19 CAR T treatment?

Carrie, do you want to take that?

I can answer that. So -- sure. I mean, to make a long story short, the ASH abstract will include the next group of patients treated on the study. All of their prior therapies, whether it was CD19 or otherwise, will be included in their past medical history, past prior treatment data set. So that data will be included, but I'm not going to speak to today what proportion of those patients. We do allow patients in the trial who have had prior CD19-directed therapy. And I think we have already disclosed in terms of our study design for the expansion, we're going to focus on those group of patients. But for the dose escalation, we're not limiting to only those types of patients.

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

Just got a couple of quick questions. I wanted to follow up on the CD19 project. Some of those patients that are on CD19-directed therapies also have an antigen loss. I don't know if that is all of the patients that relapse or if it's CD19-directed therapy, that's a subset. And if it is a subset, could that be a biomarker, for example, in dose expansion for an accelerated sort of like approval, assuming you see good responses? So that's number one.

And then number two, in terms of your solid tumors you'll be revealing, it's really interesting. We're looking forward to this data among the first, I believe, in solid tumors that would -- preclinically with allogeneic CAR T. But Andre, you've spoken to this earlier, but can you talk specifically how a clinical development plan in Phase I and Phase II could work? I mean the PD-1s and PDL -- the initial PD-1s were approved in 3 to 4 years as immunotherapy in various cancers. And solid tumors seem to be you can move faster. Any thoughts there just in terms of what a development program could look like, assuming you see success early on with the (inaudible)?

Thanks, Hartaj, for the great questions. I'm going to split it in two. So the first part of the question -- your question, maybe Carrie can answer this because she knows a lot of it. The second part of the question, she can also answer. Gee, I guess she can answer all the questions.

Or maybe I won't answer them (inaudible) that will give you (inaudible).

If you wanted to, we can do both but I hope I can work -- sorry go ahead, please, Carrie.

Yes, sure. So the first part of the question about CD19, so I think that's a good point. But no, not everyone who relapses and/or doesn't respond to a CD19-directed therapy has the antigen loss. I think the numbers, if I'm not mistaken, is somewhere between 20% and 30%. That said, I wouldn't necessarily call that a biomarker, but I'll get to that in a second. So there's not a tremendous amount of data in leukemia, obviously, after a CD19-directed therapy. We have the panitumumab data, and there's some of the UCART19 data from Servier, but there's no -- it's not as vast of a data set as you would -- as you've seen for lymphoma. So it's hard to compare what we know from one data set to another.

But that said, in terms of the development plan and we've been very open about this from the get-go. My plan for this program is to try to get it into patients as quickly as possible and have a therapy that can go to a BLA. And as you know, that is exactly the group of patients that, while it's a super small niche indication, it is a place where the bar would be extremely low for the amount of data as well as the response rate to see something.

And so absolutely, that is a group of patients that we're focused on. It's in our clinical trial design for our expansion to focus on that group because we know that group really needs therapy and needs it quickly and could help us bring a product to market quick. That said, the reason it's such an interesting piece is that it gives -- depending on how good the data is. So even if it works in patients who have failed and maybe they have CD19 loss, it also may show dramatic activity even in patients who haven't failed. So it gives us an opportunity to kind of move into multiple spaces in the treatment paradigm for these patients, and I think it's super, super important. So yes. And it's yes and yes, but also no, if that makes sense.

Yes. And just on the solid tumor question, just broadly, what are your thoughts there once you get into the clinic? Any potential for accelerated approval in the mesothelin overexpecting (inaudible)?

Yes. I mean I think that the mesothelin program is really interesting and exciting. I do think, however, it really will be the first program targeting mesothelin from an allogeneic setting. And while, yes, can we have a chance for an accelerated approval, it's all going to depend on the data we see. And until we get into the clinic and see what we see, it's going to be hard to make that calculation.

But obviously in my plans and when I look into how do we do clinical development, I'm always looking for multiple different avenues to take so we can have staggered approaches and whether there's an accelerated approval path for a specific high -- like mesothelioma, for example, highly specific cancer where there's clear, consistent overexpression, where you would likely see your proof of concept and where there isn't a ton of options, I would be looking for one option to go quickly and fast. And that could be one. I'd also be looking for broader ways of getting larger indications and a bigger market share and things like that. So all of that will be looked into, and we would be putting together comprehensive programs so we can find ways of doing that quickly and efficiently.

Hartaj, what is interesting is that the monoclonal antibody like a PD-1 enters -- or PD-L1 blockers enter into the solid tumors. So they can get into there. The problem is that immune cells are protected by the cancer-associated fibroblast. In 70% of solid tumors, they do not respond because of the difficulty of the immune system to access the tumor itself that can continue to grow protected by the CAFs. So the concept of blowing up the CAFs with a [fat] CAR can be transformative in unique type of combos. And the approach to this is, I think, what Carrie's describing is a very wide type of approach that can definitely expand the potential that is today not really -- we cannot really have a grasp on it. It could be transformative.

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

I just have one brief one. And I know we're going to avoid commenting on Allogene's specific instances here. But I was wondering if you could provide any update with regard to ongoing regulatory interactions you have with the FDA? And have regulators had any requests for additional product specifications or anything of that nature as we move past this hold with Allogene?

Jack, thank you so much for the question. It's a hard question to answer fully for the simple reason that a lot of these interaction we have on a regular basis with the FDA are confidential and under -- I don't want to share particularly because it's also a competitive advantage Cellectis has on its side. But so far, we haven't seen any significant change into this. I guess that things are going -- so there's some -- these exchanges are very fluid today and doesn't change anything. So I think that it's important to monitor the situation on a daily basis. But Cellectis is so far on a very good track with their ongoing development trials. Excuse me, but like it's difficult to share more than this.

Our next question comes from the line of Raju Prasad with William Blair.

In the ASH abstract aspect for BALLI, it said that the 3 patients in the FCA DL2 discontinued. I was just wondering why. And as we think about the 20x22 next-gen candidate, can you maybe put that into the context of UCART22 development?

Carrie?

Sure. Andre, yes, I can take this one. So our abstract includes the first 3 patients. We will have the other patients -- additional patients in the abstract presentation at the meeting. And all of that data will be in there. So I don't want to get into reasons for discontinuation [back into the] data set, and I don't think I can share that due to embargo rules since it's part of the data set. But again, suffice it to say that we're still in dose escalation, and we haven't reached our recommended Phase II dose yet. So there'll be different reasons for why patients came to the study.

And as far as 20x22, I mean, I think the big difference is, and why this is important is, as you well know, the UCART22, which was our first -- one of our first programs, has the RQR8 CD20 [monitored] on it, so it would be potentially deactivated and killed with rituximab on board. And as you know, in lymphoma, we can't really use that as well since most patients will have rituximab on board. And rituximab has been shown to be floating around in patient bodies for up to 6 months or longer, and therefore, it would potentially diminish the activity of our cells. So we wouldn't want to do that for lymphoma.

So we're positioning UCART22 for ALL for leukemia because of that, and rituximab is rarely used in ALL. But 20x22, which not only is fantastic because it has the dual CAR and really has an opportunity to really differentiate itself from what's out there, but therefore, would not cause an issue with rituximab.

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

I have 2 questions. First, I just wanted to get some clarification on the UCART22 ASH abstract data, where you said 1 patient has blast reduction consistent with CRI. Could you provide some additional color on this reduction? Is that a confirmed CRI?

And then second question is that you're also presenting really encouraging preclinical data for TALGlobin at ASH, and your approach is very differentiating from competitors. But could you comment on how do you see a preclinical data compare to the competitive programs from CRISPR and blue's? And also, is the IND still on track for next year?

Yes. So I can start with the first part of the question about UCART22. Now I'm trying to remember exactly what the question was there was just so many questions. So...

Sorry. So the question is just the reduction consistent with CRI (inaudible) from CRI or...

Yes. Well, the thing is with leukemia, it all depends on -- it's not the same as -- there's no such thing that's confirmed or not confirmed in terms of the response criteria. So it's sort of -- it depends on the -- which response criteria are being used, whether you can count it as an actual CRI or not. So -- and you'll see in the data set when we present the data what the patient had and what their blast reduction was. It was quite impressive, let's say and -- however, depending on which response criteria you use in leukemia, and there's a few.

So the one is the NCCN, which is what we were using. There's also the modified [chasing], which was what was used for inotuzumab and just each one of them has different dependence on how long you can measure it for. But unfortunately, unlike with other -- with like (inaudible), for example, we're not checking the leukemia status in the bone marrow every day. So it's really hard to know exactly whether or not it meets certain criteria. So that's why we were kind of careful and cagey with our answer there. But I think it's extremely interesting and it's extremely encouraging data at a lower dose level in our first group of patients treated with FCA, which is pretty amazing in my opinion. And then I don't know, Andre, if you want to speak to TALGlobin?

Yes. The TALGlobin is currently being manufactured, but once we finish the manufacturing, we have to go through all the requirement to -- with the GMP material to start preparing the IND package. And this is something -- the work will start probably next year once the product will be released. And this is all done internally, so it's something that's quite exciting. And I'm not giving any guidance for the IND filing today, but it's definitely a product that will go in the clinic.

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

First question just going back to the ASH abstract in what data will be presented. So have you cleared the 2.5 mg per kg dose? If not, when do you think you'll do that? And is the next step 5 million per ml -- sorry, per kilo? And I have a follow-on.

Sure. I mean, again, I really -- given the embargo rules for ASH, I don't want to get into exactly what we're going to be presenting and which cohorts and which data sets unless it was already in the abstract that's been released. But the -- as you pointed out, the dose level 2 is the 1 million and the [2I] is the 2.5 million and the next stage would be 5 million, yes.

And then just on the absolute lymph count profile. There are no range bars on the data that's in the abstract, but it shows only a 50% reduction 9 days after infusion of the CAR, bottoms out at 11. Is that the profile you want? It's -- I would have expected ALC to have bottomed out pretty before infusion or at the time of infusion.

I have to pull up exactly what you're looking at because maybe it's not accurate, the way it's being interpreted. But what I can tell you is the patients all went to 0 with the lymphodepletion and the alemtuzumab. So you may be looking at the other line, which is the UCART expansion (inaudible).

I'm looking at the blue line which says absolute lymphocyte count. So...

So I have to pull it up then. I know in one of the patients (inaudible) the data was shown -- yes, I have to look at it. I don't have it open in front of me. But what I do know is that -- we can get back to you in an e-mail that would explain it, but what I can tell you is it depends on which -- where it was being measured from. So in some cases, we're measuring the actual UCART cells and the absolute lymphocyte count. So that could be what you're looking at. But I'll look at it and can send you an e-mail with the clarification.

Okay. Maybe last one. Obviously, it's a very heavily pretreated population, as you've said. I think median is 5 in the abstract versus 3 at ASH last year. As you think about expansion, is this the kind of population side median priors of CAR T failure? And if so, is that a population you think you can successfully complete the trial? I mean we already have a patient here who has apparently no benefit from the CAR T, but it still has no lymphocytes because they had the alemtuzumab and lymphodepletion. So it's -- that patient is obviously in a very challenging place.

Yes, yes. It's a really good question. I think the answer, though, is yes. I mean -- and I think it's in our -- if you go to clinicaltrials.gov, it has the information on our expansion cohort, I believe. But I think that this goes to what I said before, it's really important to have a comprehensive multiple shot on goal plan for development of any product. And I think particularly given our size and wanting to be able to bring a product to BLA and approval, this is definitely something that we can do.

And I think that while in leukemia, even -- with you've had multiple, multiple therapies, it is a disease that's typically with a younger, healthier people. So it's not like acute myeloid leukemia where most people -- the vast majority of patients are over 65, even over 75 for that matter and are super frail, had multiple therapies, their organs don't work well. Generally speaking, leukemia patients are younger.

It's the most common cancer in children. It is the most common cancer for young adults. And we're going to be, as one of our arms, so to speak, of development for this program is to really focus on these patients who are otherwise in super good shape. Maybe they've had multiple therapies, but they're in super good shape and can keep taking more and bring them to hopefully to a cure somewhere where they can continue to have a long life. And I think that's -- it's super important.

So I think in ALL, in particular, it's a little bit of a different story than when you're talking about myeloid leukemia or some of these other diseases that you see in older people. So I think in our expansion and where we would want to potentially have a faster market strategy would be in these younger CD19-directed failures. So they still need a therapy and are still otherwise -- otherwise, with the exception of their leukemia, really well and need to be able -- need to be treated and need something that they can move forward and potentially have a life.

So that said, though, there are -- it's a small niche indication and therefore, other strategies and other development plans are in place for us in terms of where else we can go and how we would go about doing that. So we can bring it to a larger group and, to your point, potentially not necessarily people who failed 5 therapies and have also failed CAR T already. But that will (inaudible) the program obviously.

Our final question comes from the line of Ingrid Gafanhão with Kempen.

I'll keep it a bit brief then. The second -- I just want to check with you once again what are your plans with Calyxt and your shareholdership. I think you mentioned you're planning to maintain it. But would you begin to monetize this? Any -- let's say in the short to midterm?

Ingrid, excuse me, I missed the beginning of your question. Actually, it was not super clear. It's about what?

Yes, sure. I just want to check with you what is your current thinking on Calyxt and your shareholdership.

Yes. Actually, currently, we think Calyxt just announced a leadership change with the arrival of Michael Carr and also a change in strategy that has been induced not only by the new leadership, but also by the Board of Directors under the chairmanship of Yves Ribeill, and we believe that this change is about to transform the company in a very meaningful manner. And Cellectis has a significant stake into Calyxt. I think that we're positive on the fact that this is going to bring a lot of value, and you see that since then it has been quite well received by the market. As I said, like Cellectis has -- definitely has a vested interest in the success of Calyxt and waiting up to this. And it's something that we believe is going to be very valuable in the future for us as shareholders of Calyxt.

So we have to wait up to the time this change in strategy is implemented. And we believe that the current company has all the pieces to be extremely successful in the implementation of this new strategy very rapidly and very swiftly, which should be to our advantage.

Andre, that's clear. And if I may, I have just one more question for Eric. Just looking ahead into next year. Considering that you're planning to move some programs' INDs forward, are you providing any guidance on your cash burn?

We don't provide any guidance on our cash flow. What we said the cash runway is early 2023 on Cellectis. And we don't disclose milestone payments. We have a partnership with Servier where we can get up to [$210 million] from the 19 programs and also the partnership with Celgene where we can get up to $3 million on 15 targets.

And also with Iovance and with Cyto, a series of milestones to be paid. But currently, the cash burn into 2023 is unchanged.

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

Well, thank you very much, everyone, for this Q&A. We're extremely excited to have all these questions. I'm excited about our trials and our partners' trials. There's a lot of things ongoing at Cellectis. I think that Cellectis has hit seriously a leading point, a turning point for the company with internalizing all the manufacturing. And what comes next in the coming months and years is the transformative Cellectis that is becoming a true bonafide biopharmaceutical company, making things from A to Z and like one-stop shop with gene editing, CAR T, oncology, gene therapy and of course, with a careful strategy in the clinic we've been sharing with Carrie. And I think that this is going to change. So please watch closely and come to our meetings and posters at ASH. We're waiting for you. Thank you very much.

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