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

Good morning, everyone. Welcome to 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 also Arthur Stril, our Chief Business Officer. Arthur, maybe I will hand over to you to give a intro for the company.

Thank you, Gena, and good morning, everyone. I will just do a brief like 5 minutes overview of where we are and what's to be expected for this year, in particular, to let ample time for Gena to ask questions. So we're primarily, as you know, a gene editing company, with a strong focus on allogeneic CAR T cells. We have currently 3 ongoing clinical trials in hematological malignancies with more than 30 patients dosed in our wholly-controlled programs as well as 5 additional trials with our licensed partners, Servier, Allogene, and very recently, Iovance, with more than 140 patients dosed. We have decided a couple of years ago to internalize manufacturing, all the entire allogeneic value chain from buffers, DNA, mRNA coding for our gene editing tools, vectors, all the way to the final allogeneic CAR T cells. This effort is now complete, and we're proud to say that we have 2 GMP facilities operational to cover all the manufacturing of our products. We're well financed with about a little bit under $200 million, which brings us -- with a cash runway which brings us into 2024. And we're expecting meaningful milestones, both clinical and new IND over the next 12 months. So this is a snapshot of our pipeline segmented into sections, our wholly-controlled assets on the top and our partnered programs at the bottom. So starting with the wholly-controlled asset, we have currently 3 in the clinic: UCART22, targeting CD22 in acute lymphoblastic leukemia. This is a program in Phase I dose escalation, and we're currently at the final dose level, dose level 3, with a preconditioning, including fludarabine, cyclophosphamide as well as alemtuzumab. As you know, our approach is to knock out the CD52 gene to render the allogeneic cells insensitive to alemtuzumab preconditioning. Importantly, with UCART22, this product is also currently being manufactured at our Raleigh facility. And we will start dosing with in-house product this year. Second program is UCART123 in acute myeloid leukemia. This program is currently at dose level 2, and we expect to go to dose level 2 and dose level 2 intermediate, also with FC and alemtuzumab preconditioning also Phase I dose escalation, and we believe being close to a recommended Phase II dose. And finally, UCARTCS1 in multiple myeloma targeting CS1 or SLAMF7. We're currently at dose level 1. This doesn't have alemtuzumab preconditioning or CD52 knock out because CS1 being expressed at the surface of immune cells, it's a self-lymphodepleting CAR T. And finally, we're excited to announce that we will file an IND this year for the first dual targeting allogeneic CAR T UCART20x22, targeting 2 recognized antigen in B-cell malignancies, CD20, the target of rituximab, and CD22. We will position it initially in non-Hodgkin's lymphoma. And this product will be manufactured straight out of our internal facility, so it will be an interesting showcase of the end-to-end production from discovery, product development, GMP manufacturing and clinical development, everything under the same roof. Finally, we're excited about the progress of our partners, Servier and Allogene. Importantly, Allogene has guided that mid this year, mid-2022, they will begin a registrational trial for ALLO-501A, a CD19-directed AlloCAR T in non-Hodgkin's lymphoma. This is not only -- this will not only be likely the first allogeneic CAR-T to enter a registrational trial, but also will provide a meaningful milestone to us. With Allogene, there's additional programs, 715 and 605 targeting BCMA in multiple myeloma as well as more recently, 316, the first in solid tumors targeting CD70 in renal cell carcinoma. All these partnerships with Servier and Allogene are bringing us up to $3.2 billion in development and sales milestones as well as high single digits to low double-digit royalties on net sales, so that's why we're very excited about the progress of these programs. We've also signed gene editing partnerships to leverage our TALEN gene editing in additional cell types with Iovance in tumor-infiltrating lymphocytes and Cytovia in iPS derived NK and CAR-NK cells. And 2 days ago, we were very proud to announce together with Iovance that 2 years after the partnership with them, Iovance filed the first IND for TALEN edited tumor-infiltrating lymphocytes in solid tumors, which showcases our ability to provide TALEN as a meaningful gene editing solution of choice in cell therapy applications beyond the allogeneic CAR-T space. So moving forward, just briefly on the clinical results. We have presented a clinical proof of concept of UCART22 in acute lymphoblastic leukemia at ASH last December. We have shown from a safety perspective that even at the higher dose level, there is a very tolerable safety profile with no dose-limiting toxicities, neurotoxicities and mild-to-moderate CRS. There was one case of GvHD, but it was proven to be in the context of reactivation of a prior allogeneic bone marrow donor and not linked to the CAR T cells themselves. From an efficacy standpoint, we have shown that the -- bringing alemtuzumab and the CD52 knock out compared to not doing it provides very impressive host lymphocyte suppression, which allows for CAR T expansion, which correlates very nicely with the patients that responded. So we did see CAR T expansion, and we did see a meaningful response in the patients that expanded with blast reduction from close to 0% in a very heavily relapsed and refractory population. So moving forward briefly, we have now 3 sites that's in the U.S. and Europe that fully integrate the entirety of the allogeneic CAR T value chain from discovery, product development, cGMP manufacturing of the starting materials and of the final cell therapy product, all the way to clinical development, showing that as of last year, Cellectis has become a true end-to-end one-stop shop for allogeneic CAR T applications. And we're very excited about that, what this will bring in terms of speed of execution, but also potential partnerships. Finally, on the expected milestones for this year, with UCART22, we'll enroll the final dose level and switch to our internal manufacturing facility. This is the plan for all programs moving forward as we would want to reach registrational study and then BLA down the line with our internal facility and drop our reliance on contract manufacturing organizations, which have historically been a source of complications in the later trials and registration. With UCART123, we'll enroll at dose level 2 and dose level 2 intermediate, and UCARTCS1 at dose level 1. We believe that for all these 3 programs, we could be reaching therapeutic levels and being close, pending data, to a recommended Phase II dose. We will file an IND for UCART20x22 in non-Hodgkin's lymphoma, and we'll have the UCART22 and 20x22 manufactured internally. Finally, as mentioned, we will have updates from our licensed partner, Servier, Allogene. We had the IND from Iovance 2 days ago, and we expect importantly the initiation of the registrational trial from Allogene. So all in all, we believe Cellectis has a very exciting year to come, with a fully integrated allogeneic CAR T platform that has already been clinically validated in a number of indications and with the potential for 4 shots on goal, 123, 22, CS1 and 20x22; an end-to-end manufacturing, and we know as we heard from the previous presentation that the product -- the process is the product. So owning the manufacturing internally is owning the product; a best-in-class gene editing platform, which we believe is a solution of choice for cell therapy applications, as we have now shown with Iovance in addition to the work we've done with our partners in allogeneic CAR T; and strong partnerships, which provide clinical validation as well as financial upside to the company. Thank you for your attention. And Gena, back to you.

Thank you, Arthur. So maybe I would just start with the manufacturing, like you already completed both in the U.S. sites and the France. So maybe -- and we do see like, of course, in your cases, allogenic CAR T, you don't have a time restraint there. For others, autologous CAR T, the manufacturing capacity is very important. So maybe from your end, can you give us a little bit of sense in terms of, say, viral vector manufacturing capability and capacity and also the sales part.

So we have all the capacity to manufacture viral vectors. So currently, we're manufacturing through recombinant lentiviral vectors in our Paris facility. The capacity is not that big because we don't need huge capacities. What we need is quick reaction. Today, there is so much demand worldwide for viral vectors in general, would it be AAV, would it be recombinant lentiviral vectors or other type of vectors also is huge. And so the time for signing agreement and finding a slot takes you approximately with the delay of a year. But before this, you of course, have to manufacture the plasmid DNA to produce the lentiviral vector. So it takes a lot of time. So the delay is something that we shortened very much. We can immediately right away, when we want lentiviral vector, get it. With the same thing, we produce also AAV6 vectors. So lentiviral vectors are essentially provided to introduce the CAR in the cell and AAV vectors to do homologous recombination as a matrix to do homologous recombination in T cells or other type of cells also. And we have also, as Arthur said during the presentation, messenger RNA manufacturing, cGMP in Paris and also plasmid DNA manufacturing in Paris. We do also have buffers, have cell libraries, everything, everything internally. And this is essentially meant to be quickly reactive, not dependent. And when we enter into a pivotal trial, then you're definitely married to the CMO for the rest of the life of the product. If you want to switch, it induces a lot of complexity. We've seen with UCART22 that has been manufactured formerly at CellforCure that has been acquired by Novartis that we're dosing currently with DL3, we're switching second half or third half this year -- for like third quarter this year, second half of this year, third quarter, around third quarter with internally manufactured product. The quality of the product -- process is slightly different and the quality of the product is very different, higher potency, higher expansion, higher killing activity, et cetera. So we'll have it probably to bridge. And we're expecting so we will be working for a year now with the FDA. And the FDA has a comparability plan and study that we are conducting currently. And we're expecting potentially to deescalate. So you cannot switch easily. And especially when you're in the registrational trial, you cannot say, "Oh, well, this CMO, I'll go and switch with another," because like the prices are growing, et cetera. It's not possible. So once you start a pivotal trial, you're totally locked. That's why we decided to internalize everything, and we're extremely excited about that.

So Andre, did I hear you correctly? So this your internal manufacturing is not just for clinical, but also for commercial or...

Yes, yes. It's totally set for commercial. The Raleigh facility has been like actually, we had a visit there. We were talking about autologous manufacturing, it's interesting. When you visit an autologous manufacturing setting, you usually have lines under -- with different type of colors that are set everywhere even on the floor in order not to mix between [ batch ]. And you don't want the leukapheresis of one patient to be screwed up and mixed up with another leukapheresis of another patient given that can induce GvHD. So all the complexity is behind this. And the logistics is so complex that even with all these complex settings, sometimes these events happen. So one person who was visiting, was saying, where is all the cargos et cetera. No, cargos here. It's an off the shelf. It's simple. And so you store the things, put them in like a liquid nitrogen tanks, and you can ship all UCART22 or CS1 or 20x22 vial to hospitals, every patient can have this. And this position that we have in our facility in Raleigh is totally set for commercial use, distribution, logistics, et cetera. It's all being thought from day 0 in 2018 and to date in the projection of being able to commercialize this program.

So then if you can give, like, say, just using simple way of how many patients you can supply, the patient doses you can supply. Of course, it all depends on the dose, but roughly, let's say, assuming if general dose level 2 or 3, that range, how many patients you think, rough estimate like the capability -- the capacity once you reach...

We believe today that the capacity -- okay, we're not giving numbers because it's very competitive. And I know roughly the numbers. We know that for the 4 indications that we have with the market penetration that has been calculated internally, we could be able to supply the entire world demand with only the Raleigh facility, with the exception potentially of certain countries where you need to build up a plant there, so that has been discounted. But theoretically, we are not limited for full world capacity in Raleigh. It's a 82,000 square feet facility that allowed to do this. We'd be building -- there's one suite that is working currently, but we have the capacity to build 4 more suites, and the second [ tail ] that is also being ready to do all the raw materials to do this. But it has been [ thought ] and the capacity with the staggering the batches allow us to supply the whole world.

Okay. So just want to be specific. You said 4 programs. So if I look through, it's ALL indication, AML, multiple myeloma, non-Hodgkin lymphoma. And then at least the -- are we thinking about the total patient if we're just adding this together? Or would be the addressable patient suitable for the allo CAR that you think you can supply for the whole world of these 4 different diseases?

It's addressable patients. Addressable patients not by, for example, the non-Hodgkin lymphoma population in the United States approximately 120,000, 130,000 roughly, probably I know the number. But then I -- we get that probably there is a certain market penetration that the product that we have will allow us to do over the next 5 years post marketing, and then we'll see after this what we'll have to do. Nevertheless, this is for the 4 products we have, but we have more products that are shelfed currently, UCARTFAP UCARTMESO, UCARTMUC for not like triple-negative breast cancer, mesothelioma or like a wide array of solid tumors have to be calculated to see how we can integrate these in the future. But at least, it's a role model plant that we have that can be cloned somewhere else as the architecture is really interesting.

Okay. Good. So now we dive into specific programs. So maybe just one on the UCART22, you presented at ASH last year and it was improved Flu/Cy alemtuzumab approach, right? So we did see like the T cell really peaked quite a lot. But on the other hand, we did see the variability there and also the persistence. So any thoughts there, what you -- any additional improvement you could do in order to say like a -- first question is maybe how important is the persistence of the cells? At what point you think it's minimal -- at what time frame you wanted to see the persistence of the cell that could translate to the clinical benefit? And then the second one is what you could do to make them more -- from patient to patient more or less variability?

Well, it's a good question. First of all, all patients are really different. And immune system of every patient reacts differently. So we see variation between one patient to another facing the preconditioning regimen that we give, Cy/Flu plus alemtuzumab. And that also induces sometimes responses that can be different. So sometimes you could see the same peaks and drops out. And sometimes it peaks and stays because the immune system is better controlled by the preconditioning regimen. So yes, there will be a variation. We think that this can be tunable in the future. And we're already working on the pivotal expansion trial, where we'll have a different type of dosing strategy and also preconditioning strategy. What we're trying to determine now is, of course, the dose for the expansion. And well, for '22, it's interesting because the product that we've been injecting so far is going to disappear from Cellectis in the second half of this year and be replaced by Cellectis product, and that's going to be the real deal at the end. So we don't know exactly what the dose will be, but we have kind of an idea of what we saw [indiscernible] start responding on DL2, DL2i now with DL3. So if we have a deescalation, we don't want to inject too much of doses in order to improve the cost of goods. So it's better to -- we know approximately to what kind of the range will be at this time. Don't expect us to do exactly the same type of injection during the expansion because the preconditioning at start will be the same, that's not going to change. But potentially, we'll do like a repeat dosing, so it will be consolidation type of injection. And for me, it's not the persistence that much importance. The deepness of the response, how much the T cells are going or the CAR-T cells are going to expand at the first injection that is determining the response, not that much of time of the cells staying in the patient. I hope this year, we'll be able to show you some data maybe from other clinical trial where it's not the length of the duration, but more of the deepness of the response of cells.

Okay. So that translates to the peak expansion of the cells is more important than the persistence of the T cells.

Yes. That's why we also internalize manufacturing because the quality of the product and the expansion of the product, so like the fitness of the product itself is determinant of the response. We need to master this.

So then regarding the deepening response, what if you do not say 100% of the tumor cells, you left 3 or 5 cells and then your CAR T-cell is gone because you don't have a persistence. So if those 3 cells amplify and then how would you be able to -- like how would that translate to durable response?

Cy/Flu alemtuzumab [ T0 ] injection wait up to a certain number of days that we're calculating. So I'm not saying this. And then you hammer them in other time it was not the injection. And the 3% that will restart expanding will disappear as [ alternate ] treated antigen that are present in the patient with a potentially second injection of preconditioning that could be alemtuzumab potentially. And then you can wipe out everything because you have enough duration and you can inject with second -- like second injection with a very powerful program that totally pristine of any expansion.

Okay. So then very interesting, you did not say the -- what is the timing for the second one?

[indiscernible]

So like when we saw, like say, Allogene's approach, [indiscernible] approach, they are one month, first dose. And then one month and then depends second conditioning regimen, depends on the standard 1 or only alemtuzumab or like CD52, like do you think that one month is enough or you think you need to -- like is one month...

Is it too much or...

Like too soon or...

Too late?

Yes. Maybe not too late because your T cells [ to wipe down ].

It's not bad. I think it's good. The thing is that given the second dose, it's not chemotherapy. So injecting cells is fine. It's not going to harm the patient if there's no tumor acetated antigen. The thing that could happen is essentially, the cells are going to die if they're not stimulated by the tumor acetated antigen. So if there's no more CD22 or CD123 injected cells, then the cells will go there, they will not expand nothing will happen. So giving a second dose is something that I think would become a standard and not waiting up till the time we start or we start expanding again, at least, whether or not you're going to inject the cell. And usually, the cells start packing into the bone marrow and start expressing again. And that's what we would like to [indiscernible] so we have a slightly different type of protocol.

And I think that the beauty of the lymphodepletion that is tunable. So when during the second dose, you can pretty much tell up or down because of the CD52 and alemtuzumab approach. So unlike other approaches, which are not tunable like [ UCART22 ] or others, I think especially in the context of redosing, it's great to have that kind of switch to the -- and tune the lymphodepletion. That's something we'll be also exploring.

So do you think the CD52 is more important or the chemo is more important for the second?

CD52. Alemtuzumab for sure.

Because it differentiates between the CAR-T and the patients who is [ immune ].

It's not chemo.

Okay. And when will we see the data from -- maybe I know you have...

This year, you'll probably see data from the dose escalation that will be really interesting, the expansion will be probably for next year.

Okay. So I know we don't have too much time left. We do have -- Arthur did highlight all the programs. So maybe just like later this year, I know it is data-driven. So at what point do you consider the data will be mature and from what program we will start to see the data in 2022? And then same question for 2023?

Well, we presented data for our UCART22 for ALL at ASH. I think it's going to be different this year because it all will be a different type of program. So 20x22 too early because we're going to start dosing patients second half this year. Process 2 for UCART22, we're going to start dosing second half this year, so it's going to be too early. So it's going to be between CS1 and 123. And I think that's going to be interesting. So yes, we're extremely excited about what we're going to present here. It's going to be -- it has been painful to go through the early doses and trying to find the right preconditioning regimen. But we think that we're on a great momentum currently for the 3 -- especially like with UCART123 and UCARTCS1 is potentially I think that we could potentially present.

Okay. That will be this year?

This year.

Okay. Okay. Good. And then which means next year likely will be the 20x22...

Yes. So you will see in P2 -- the process 2 for UCART22, 20x22, so non-Hodgkin's lymphoma data. I think this dual CAR T is extremely interesting because it's not the [ 19 ] CAR T for NHL and you see a lot of relapses in NHL and you see also relapses in ALL. So it's like a real great 2 products. And we're glad also by CS1 because CS1 is not the BCMA CAR T. And finally, when you see that the PFS is well like to -- the overall responsible situation, approximately 2 years to me. Yes, it's like a lot of interesting things will happen with us because we cannot redose with the BCMA. So the fact that we are a very [ linear ] and very differentiated type of target and similar indication as competition makes us -- puts us in a position to come afterwards, after the first wave.

Okay. Well, looking forward to the data.

We're excited too. Absolutely. Thank you, Gena.

Thank you. Thank you, everyone.

Thank you, Gena.