Cellectis S.A. (ALCLS) Earnings Call Transcript & Summary

Good afternoon. My name is Gena Wang. I'm a senior biotech analyst at Barclays. Thank you for joining Barclays' Global Healthcare Conference. It is my great pleasure to introduce our next presenting company, Cellectis. With us today, we have Andre Choulika, Chief Executive Officer and a Board Director. Andre, maybe before I dive into specific questions, do you want to give a brief overview of the company?

Of course. Yes, sure. Quickly, because I think that you probably have a list of questions. For the one that doesn't know us, Cellectis is a cell and gene therapy company that has been founded a long time ago on the concept of gene editing. I think we're the first gene editing company in the world. But currently, we're focusing essentially on allogeneic CAR-T. We have a series of assets in the clinic today, one called UCART22 in acute lymphoblastic leukemia in a trial called AMELI -- BALLI-01. But we're going to go in details into this. The second one is called UCART123, is in acute myeloid leukemia called AMELI-01. The third one is UCARTCS1, targeting multiple myeloma in a trial called MELANI-01. And last but not least, a new one that we're -- is currently starting, which is a dual allogeneic CAR-T targeting CD22 and CD20. I think it's the first dual targeting allogeneic CAR-T for non-Hodgkin lymphoma and NatHaLi-01. Beside this, we have a series of other assets, solid tumors and gene therapy product using our TALEN gene editing technology. We're very excited about these products. They're still on the shelf, and we're waiting a bit up to the time -- the global market maybe recovers a bit of the current situation before we can push the next product into the clinic. Besides this, we have a series of collaboration. We have 2 collaborations with allogeneic CAR-T. The first one was with Servier on UCART19 or CD19 CAR-T, that has licensed their U.S. rights to Allogene that is currently conducting the trial for ALLO-501A. But this has the sublicensing rights from the agreement that we have with Servier initially. The other, of course, is a direct licensing with Allogene on series of assets such as [ anti-BCMA and anti-CD70 ]. Then we have also a very interesting exciting collaboration with Iovance Biotherapeutics with the first TIL tumor infiltrating lymphocyte that has been gene edited by TALEN that is currently dosed in patient. And last but not least -- not last actually. Before to last, it's the collaboration with Cytovia and NK -- iPSC-derived gene-edited NK CAR-T cells. And last but not least, this time for truth, it is a venture that started with Hibiscus, which is a venture fund that is developing TALEN for mitochondrial diseases. TALEN is one of the only-technology working currently in mitochondria. For numerous reasons, I'm not going to detail here. And we're very excited to do this collaboration with them through this new company that has been found called Primera with also together with Mayo Clinic. And I think it's going to be the start of a very nice runway for this company that is revolutionizing mitochondrial diseases. In nutshell, that's it, and maybe we can fire up for questions.

Sounds good. Andre, so you mentioned that you are the basically first company conducting gene editing technology high level. Why you in the end choose TALEN? I know you drive many different genetic tools. And how you see your current platform could be differentiated or benefit for the indication you are going after?

Well, yes, we're not a technology-focused company. We're not a CRISPR company or a TALEN company. We're a gene editing company, are totally technology-agnostic. And have been long enough in the space of DNA recombination and gene editing in general to have the experience to know that technology gets obsolete or has some limitation at a time and marrying yourself with a technology that's becoming potentially limited or obsolete. And when I'm talking about experience, I've started working for -- with the first gene editor, the grandfather of the old editing technology called isu-1, which is homing endonuclease back in 1988. So -- I'm serious, it's 1988. And I think I filed my first genetic back in 1992. People can track that on USPTO or I check it on my name. And you see that technology. Well, so it started with homing endonuclease, meganucleases, [indiscernible], whatever you want. And then finally found out TALEN that have interesting DNA recombination features. I was discussing this with a person. I think that the field has totally lost the fundamental idea, is that when you click DNA on itself with [Technical Difficulty], there are physical things that happen behind this. And the whole DNA recombination space has been lost nucleates themselves. And the real secret, the secret sauce is how the DNA [indiscernible] recombine afterwards once [indiscernible]. We, of course, tested CRISPR. And I think the first patent we filed on CRISPR was in March 2013. Not a single one in this room has heard the term CRISPR in March 2013. Maybe some of you, but raise your hand. No one. Okay. March 2013. That was like 3 months after the publication of Doudna and [ Jacques Francoise ]. And we didn't think that it made really difference. It's easy access. But for gene editors like us, especially for gene engineers like us we preferred TALEN for numerous reasons. I don't know if you want to get into this. But one of the main things that you should focus your attention on is the way this nuclei dissociates from DNA. The speed of dissociation from the 2 strains after cleavage is extremely important and leads to different type of recombination, I think, is at the roots of numerous problems in the DNA recombination. The more it's balanced to release -- for example, the 2 taus have 16 bases there on each side. They're released quite easily. If the nuclease doesn't release at the same speed from this side -- for example, the grandfather, like this icu-1 I started working on back in the ages in like the '80s released faster on one side than the other. So the DNA recombination is not balanced on both sides of the DNA. And that's why we like this technology. It's extremely precise, can place the cut almost at the base there. It's very efficient, of course, very safe. We've seen like multiple trials in patients. And then finally, also, there is a concentration of the IP there like safety, et cetera. So we really like it for now up to the time there is a new technology that would come and we like more than this one and we'll switch.

That's good. I think looking at the time, we will not go to details. That we will save another time and elaborate all the time to participate. I'm very excited...

But I'm ready to answer the questions if you want more details about this in the future.

Yes. And then -- so maybe another important part for you is also the manufacturing. So you do have the in-house manufacturing plant. You need to sort of modernize the capacity and the capability with this new manufacturing site.

Well, Gena, I don't know if we wouldn't have taken the decision to internalize manufacturing today how we would do it. And I don't know how others do it today. It's such a difficulty to manufacture with CMO. I think it would have killed the company if we had done this. Of course, for example, we manufacture our TALEN back with BioNTech. BioNTech have other ambitions today than being the CMO of Cellectis. How do you find manufacturing? So we decided back in 2018 to integrate all the manufacturing from A to Z. Even now the supply chain for the hospitals and shipping our vials to different hospitals is being internalized. So we do buffers. We do sell libraries. We do plasmic DNA. We do messenger RNA that is the way we code our TALEN. We do our vectors, lentis, AAVs, do our CAR-T, everything, even electroporation technology. The company that we purchased in Maryland back in 2010, [indiscernible]. And that's what helped us in executing really nicely. This is for me a crucial point in the cell and gene manufacturing space. If you don't manufacture yourself -- and the real owner of the product is the one that manufactures the product, especially when you start filing a BLA. It's not kind of client-vendor relationship. It's a marriage. A lot -- a few of the times, but it's not an easy part. We see [Technical Difficulty] with the manufacturing model. We switched our entire products. You have to do comparability studies. You have a lot of different things that gets to be done. It's not the same products if it's manufactured at different places even if you have developed all the processes, right? And we are the owners of the process. Today, Cellectis is the best company in the world to manufacture allogeneic CAR-T.

You have this implant, and I know you have like now that would be a good lead for '22. Now you have a P2 manufacturing internal capability. And you do see the improvement of the quality of sales or efficacy compared to the first gen P1. So like maybe thoughts on using this technology, did the future plan applied to all the programs and now stepwise, how do you see this play out regarding the application and then commercial profile?

Well, first of all, we have no choice, actually. When we started manufacturing UCART22 in self-focus, which was the CMO south of Paris. And they produced all the vials that were injecting up to the end of the BAL. Then sulfur 2 was applied by Novartis. And I think the work is working out from soon. And we have the choice, either we manufacture internally and that was done at trial. We had to wait a bit or we decided to work at another CMO. So we decided to make it in-house. And the quality of their product after all the testing that you do, gives you a product that has a potency. And what's the potency, it's pretty simple to understand. How many kills in a road can do? And what is the number of cell division that cell can do put injection? So boom, boom, book, serial killing and number of cell divisions. The less it can do cell divisions more unless it can do serial killing the less potent the cost. And the way we do manufacturing internally keeps the cell with a huge potency of cell expect and that keep killing. The good news is that UCART22, we had 0 safety issues in the patient during the cell escalation. The dose escalation with the product that has been manufactured at self-occur. So we were pretty reassured that came back to the internal product that has a huge potency, we think about the product. The only thing that was the concern is essentially not to inject too much products and potentially not to bring another issue that was not present in the first dose escalation. So we decided to deescalate from PLN50 perk to 1 milligram DL3 to DL2. And currently, we're dosing at the GL2. That could potentially be the RP2D and we'll disclose the data this year. So we're excited about that. First roll-up for manufacture that is in the patients.

Before I move to specific questions in regard to '22, maybe ask you how much do you view envision in the internal manufacturing? That's good. Before I move to specific question on UCART22, maybe ask you, how much do you have invested and how much like rough estimate on there?

Well, we invested a lot in there, I don't know exactly the details about this, but the same like we're seriously very proud of this. But I would definitely have a huge payout for the company. I think in a short period of time, if this market recovers, but we don't need to invest more. Actually, we can move forward is actually and to be BLA ready to start the expansion UCAR-T23 that I hope will start soon. That expansion can take place. But currently, it's working as it is.

And then capacity, if you can describe it.

We can produce all the 4 products that we have worldwide production currently. We can do 2 suites that we have enabled. We can build 2 more suites currently. There's like the Shell 2 more. We don't really need this, but also we are very cautious on the cash spending. But currently, the production is rolling there and the company with a home eventually, if we bring more parking in the clinic, poly tumor CAR-T or potentially with partnership, et cetera, were not don't want to become like the business model is definitely not being a CMO. But that would enable potentially the 2 other suites. So we're bringing this up to 4. What is interesting that we have a second part for the building that we can build in the future if we need more acquisition, but that's not in the plan.

Okay. And then when you say that's also the clinical supply rent. No, no, for the commercial supply. Of course by far, clinical supply like every batch when yields hundreds of vials. So just on, okay. Sorry about that. Okay. Now you got to reduce the nowhere the dose and the 1 million cells. Give us a little bit more color why you chose that dose? And what do you think that dose in the RP2?

Certainly, GL-12, like, of course, we do a lot of QC. And the data do we get some potent metric that we have compared to DL 01 like the P1, P1 versus P2P. One may won that battle. The comparison between 2 and the quality testing that we do showed even at DL 03, higher potency than GL02. So we decided to deescalate DL2, if the safety is there. So we hope at the end of this testing to compare the data if we have the similar data as we had with DL3, which is 60% CR DL3, well, that makes it an approval of products. We can move for the expansion and get the registration with that type of data. It's enough for trial. Just as a reminder, it's the only allogeneic CAR-T for acute lymphoblastic leukemia currently developed. There is no alternative. If you fail blinatumumab, if you fail an older CAR-T, whatever they then the only alternative for an Allogeneic CAR-T is your CAR-T 2022 and we're excited about that.

So the 60% I wanted to confirm from CR or IR?

It's overall response.

Okay. So if the 60% ORR. So what kind of duration of the response you'll be looking for that you think it will be sufficient?

Well, we'll see that actually. Today, it's difficult to answer that question.

Okay. So maybe just from a big picture mechanism with you. And then we understand Allogeneic different from oncology team. So autologous CAR-T you saw that 6-month duration of translate to long-term benefits. So here, like mostly about in terms of CPV.

Well, it's pretty similar to what you have with autologous CAR-T. It's very comparable. It's not better, eventually, especially ALLO, not talking about non-Hodgkin lymphoma. But because lymphoblastic leukemia, of course, like first when we fail to fill all lines of treatment and potentially cost bone marrow transplant, which is not part of the product. But we'll give you an update on the patient and in for Q1 on the upcoming conferences and telling you what the duration of what we had at DL3 in the past. And so that would definitely give you some color on what you should expect for P2 on that matter.

That's good. Okay. So that would be very good. And then now switch to UCART123 and you do have a 2-dose there. Yes. So I wanted you maybe elaborate the reason why 2 doses and also the timing, when we look at the timing of that, we do see across the field and someone choose different doses, but if you want maybe, several -- this question, why it is 2 doses, I think the rest question.

Okay, it's quite simple. So DL2, we had kind of like 25% of ORR, which is kind of limit. So when we escalate to DL3, we had a bit of higher CRS and then DL2 was kind of bug. DL2 seems to be a very safe and quite potent dose. So we had, for example, one patient that went into MRD negativity and like in complete remission for in a year. And that's a very exciting event for DL2. We had some patients that had like 60% to 70% flat in the bone marrow that was reduced to 5%. You have the feeling that you have a very meaningful blast reduction. But with -- if you can hammer what's left like the real MRD positivity or the 5% black that you can climb up this from 25% to over 30%, 40% and that makes us approval product without altering the safety of the DL2. So it's a kind of a splitting perk twice. And why we do it at D0 and D15 because of the peak of the expansion is gone at day 14. While the info depletion is maintained. So without really sort of quick depiction, you have all the peaks and ferritins and expansion of the RT is gone, then you can move on, on the second dose without applying AT and we can totally wipe out what's remaining. So the first one is a packed dose and the consolidation dose for the second one, without changing the LD.

Okay. And then the first dose, and second dose will be the same dose, right? So second one is compared to CD CAR-T22 versus CDCAR123, why UCART22, what dose will be sufficient and why you have 123 immediate returns, you have different target, the different tumor types or...

That's exactly a different target. And you see UCART22, you can do one like for -- family and sell without any safety issues. So you can definitely inject more and more without having any safety troubles, while it was 150, that's like kind of the dose is a bit difficult to enough. And I think we're in the right window of deal too. While if we could have escalated to like 5 on cells per kg, maybe it would have been one dose. But I think that we don't want to risk to grow up the product and just won't get high doses as we soon complete the issues at higher doses.

Okay. And then the second question is, we did see other, but that's CD19 target. And they have a dose 1 not at the day 1 and then dose 2 at day 28. So thoughts about that, but some will have 2 different conditions twice with the patients, some at your partner were elotuzumab second times and additional condition regimens. So any thoughts on your approach versus theirs regarding the 2 doses? And then also, what is the focus of all trying different 2 doses and a different time point? Is that trying to get the peak slower penetration or try to get as long as possible extension of that duration?

No, it's not -- I don't think like there is many papers that came out that showed the cell duration in the patient is not the factor of the persistence of the -- or the persistence of the cells is the duration of the therapy itself. It is more like the deepness of the expansion and the onetime response that makes the duration of the therapy itself. So I don't think it makes a difference seriously between doing the second dose at day 14 or day 28. The only thing that makes the difference is that they have to give a second dose of something, whatever some elotuzumab is something else. We thought that it might be more of a comfort for the patient to have like the 2 doses on the shorter window. While the effect would be the same, it's just trying to convert that to be a small MRD positivity to turn this into negatively afterwards without having to really to deplete the patient.

Okay. So the timing, we would expect later, right?

Double dose is something that it's actually could be presented the therapy too also done for UCART22. It's going to be a rich year I hope in data.

Quickly on UCAR20 and 22. So maybe your rationale for FCA additional regimen in a single dose?

Yes. So the single dose is 20 by 22 is similar to 22, it's like just add like 20. And by the way, it's the first non-dual CAR-T. There is no other allogeneic deal CAR-T. And most of the dual CAR-T that are autologous always start with 19. I think this is not great because usually, if you come especially with the product, it's better not to be 19 because a lot of the physicians are saying there is an overcharge of the '19 target with blinatumumab CD19 CAR-T or the CD19 plus something a CAR-T. So if you come with something that's totally pristine of any '19 targeting, you have the potential to get this CAR-T into larger than of patients, especially the CAR-T is very potent itself. And it's too validated target CD19, no CD20 and CD22. And the second thing that is very important, it has been manufactured internally with quality at '22. And I know that there's a lot of excitement among the physicians community that '19 CAR with a potential very high potency at the end. And that's what might change also the interest and this CAR and the potential commercialization of this CAR because it has a specific window to appropriate, so excited about this. But we're starting dosing patients this year. And we'll have probably data at least for the DL01, DL02, we'll see where we are at.

Okay. So it'll be likely 2024?

Yes.

Okay. Good. I know we are running out of time just quickly on the cash. I know you have cash runway into 2024. Any thoughts how you cut or prioritize the development, the program or any thoughts?

So we're focusing on the CAR-T that are a real driver to 123, 22, 2022. S1 is slow. The cash flow, of course, like the cash that you see does not integrate the capital rate that we've done in the first quarter and of course like the EIB loan of EUR 40 million that has not been integrated in what was published so far, nothing. A lot of people thought that the first EUR 20 million has been -- has been exercised, but not really, not cast for now. So yes, we currently think that we are very prioritized so far. So if we could, we could have launched probably behind this year. I don't think that it's reasonably the trend company and we're very excited contracture.

I look forward to a lot of data update later this year, right?

Thank you.