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

Thank you, everyone. Welcome to our next speakers from Cellectis. Today with me, we have André Choulika, the Chief Executive Officer; Carrie Brownstein, Chief Medical Officer; and also Simon Harnest, SVP of Corporate Strategy and Finance. With that, I hand over to André.

Well, thank you very much, Gena. I think that the thing that we're going to do is essentially share few slides to open for the Q&A, and spend most of the time answering your question and maybe browsing through the slides. I'd like to welcome everyone to this session. And give the work to Simon to make a quick introduction on the company.

Yes, perfect. Thank you so much, André. And giving a quick introduction on Cellectis. Please note we're publicly traded company. So there are some forward-looking statements and rules to take into consideration. So for Cellectis, and many of you know us already. So thank you again for joining us, and thank you, Gena, for hosting us. Cellectis is an allogeneic CAR T-cell company and gene editing company combined. And it's something that we've been doing for many years now. We started 20 years ago as the first company in the gene editing space, and we started in 2015 with dosing our first patients in ALL in acute lymphoblastic leukemia with our first gene-edited off-the-shelf CAR Ts. And we're very proud of that development because we spear had it a completely new space, which back in 2015, was still thought to be impossible. But today, we actually have a series of companies trying to do the same thing, and we're very proud to have these peers in our space and all trying to pursue the same goal. So what we basically do is we, instead of using patient-derived T-cells and engineering them and infusing them back into patients, we use donor T-cells and genetically engineer them so that these donor T-cells are non alloreactive and do not cause a side effect called GvHD or graft-versus-host disease. And that is done through our proprietary gene editing platform called TALEN. And that TALEN platform is a very highly precise gene editing platform that we developed in-house and with our partners at the University of Minnesota. And that platform is something that enables us to do a lot of different things. On the one hand, we can engineer these cells to be non-alloreactive. And on the other hand, we can also engineer these cells to be persistent in the environment of other antibodies that keep the immune system of patients low, and we can do other engineering steps, which we will get to later, that will help these cells basically pursue targets that were previously impossible to pursue without the use of gene editing. And so the other fact, apart from the scientific rationale, is that these T-cells can now be mass produced. We can do hundreds of batches or hundreds of doses for hundreds of different patients in 1 manufacturing run and 1 manufacturing run takes about 2 weeks. And that enables us to really have an economy of scale here where we can potentially provide these treatments at a much lower cost than what we currently see on the autologous CAR T-cell approach. So the mass production, pursuing novel targets and also having the ability to persist in the environment of immunosuppressive antibodies is what makes our allogeneic CAR T-cells so outstanding. We also have some world-class alliances that we built over the years. Most notably, the lead programs are partnered with Servier and Allogene, which, in the CAR T-cell space, 1 target is very well-known as the CD19 target, and that is interesting for patients in ALL and non-Hodgkin's lymphoma. So Allogene is pursuing non-Hodgkin's lymphoma, and Servier is pursuing ALL with the CD19-directed CAR T. And for Allogene, that program is called ALLO-501 to ALLO-501A and Servier called it UCART19. And what is very exciting that this program has shown very mature data so far that actually shows that the results with an allogeneic CAR T are on par with an autologous CAR T. And we'll again get to the clinical data a little bit later. But this is a very important alliance on the CD19-directed CAR. Cellectis is entitled to receive up to $410 million of outstanding milestone payments plus a low double-digit royalty on worldwide sales. And the split here is that Allogene owns the U.S. rights to the CD19-directed CARs and Servier the rest of world. Then we have 15 targets directly licensed to Allogene, and each one of those targets carries $185 million in potential milestone payments, plus a low -- high single-digit royalty on worldwide sales. So these 15 targets directly licensed to Allogene are largely still undisclosed, but the lead program here is the BCMA program, and that is followed by the CD70 targeted program, which is in pre-IND phase. But you'll see more of these targets getting put into the clinic by Allogene and they're doing fantastic progress, and you'll see also a presentation on the BCMA program upcoming at a scientific conference by the end of this year. The third alliance that we have is with Iovance Biotherapeutics, where Iovance is furthering their TIL platform through the use of our TALEN technology. And this is a very specific target that we engineer for them with our TALEN. It's not a broad platform deal, but it's a very interesting deal for us and for Iovance to further the TIL programs. And we have not disclosed the milestone payments for this yet, but these are very material, and we will talk about this as it gets closer to the clinic. Our pipeline really quick. At Cellectis, we have selected targets that are very novel to the CAR T-cell space, but we think will bring tremendous value. For the first target here, you see UCART123, which is our CD123 target in AML. We are currently recruiting in a Phase I dose escalation study with AML relapsed/refractory patients. That study is ongoing, and we're very excited to share updates on this soon. The UCART22 program is currently ongoing. It's a CD22 targeted CAR T that is an alternative target to the CD19 target and for that, we will be sharing data at ASH. And we announced an abstract that out of 5 patients, we already have 3 responses with 2 CR CRis and 1 partial response, which is very interesting, given that this is at the 2 lowest dose levels of this trial and still with a sub-optimal lymphodepletion strategy. The third program, UCART CS1 is our multiple myeloma program, where CS1 is an alternative target to BCMA. We think this program particularly holds a lot of promise. Unfortunately, we are still on a clinical halt, and that was issued after a patient death, but we should be resuming this trial very soon. And we think we have a very straightforward path to get this program back on track, and hopefully show some data on this program next year. And then just to round up. So what I mentioned previously, our partnered programs here in orange, UCART19 and ALLO-501A are basically the same construct, but the ALLO-501A program is lacking an off switch that is still built into UCART19 that is activated by rituximab. And the rationale here is that patients with non-Hodgkin's lymphoma are sometimes treated with rituximab, and we don't want the product to be deactivated to that. So ALLO-501A does not have this off switch. But both of these programs are driven forward by Servier and Allogene, and we're super excited about the data that is coming out of these programs, which so far look pretty much on par with the autologous CAR T-cell programs. And these programs are moving forward in clinical development into potentially a Phase II next year. And last but not least, the ALLO-715 program, the multiple myeloma program, BCMA-targeted, is going to have a data update at ASH this year by our partner, Allogene. Really quick, our manufacturing process here. And sorry, this is our dose escalation process in our Phase I dose escalation. This is very important for us to find the correct dose of the CAR Ts that we're giving. And this is the most crucial step for us to find out exactly at what dose do we have the most optimal response and also with what kind of lymphodepletion strategy. So very different to a lot of other type of antibody trials or biospecific antibody, cell therapies. In CAR T, really, this dose escalation is the most crucial step. Because ideally, you do see response after 28 days, which is an endpoint for us after the injection of CAR T-cells. And so figuring out at what dose of cells per kilogram and at what lymphodepletion is the optimal strategy. It's one of the most important gating factors for these trials to move into Phase II. And so this is ongoing right now with our 3 proprietary programs and partner programs. Just to say on a high level, really quick before I open it up to Q&A. I'm just going to summarize the clinical data that we've seen so far. ALLO-501 is the program that was presented by Allogene at ASCO this summer. Showed a 63% overall response rate or if you take out the patients that have been treated with other CAR Ts before, you have a 75% overall response rate with a 44% complete response rate in non-Hodgkin's lymphoma patients. And this is amazing for us because this is out of a Phase I, again, that's a pool of data with doses that are suboptimal and other lymphodepletion strategies that are suboptimal, but the response rate already looks very, very promising. For UCART22, this is the newest data that was just released early November. These are very few patients that we have shown on UCART22, given that the program just started recruiting patients in January this year and the cutoff for this data was in July. We are presenting here data on 5 patients where at the lowest dose cohort of just 100,000 cells per kilogram, we already have 2 out of 3 patients in CR or CRi at day 28. And that is very promising for us because we frankly didn't expect to see any responses at that low of a dose, but we do see it already here and keep in mind that this lymphodepletion strategy is the cyclophosphamide to for depletion and does not include the alemtuzumab, which is an addition that we engineered and hold the patent on, and patients are currently being recruited with the addition of alemtuzumab to the flu Cy (sic) [ Cy/Flu ] lymphodepletion regimen. So that's very important for us as a step to move forward with this program. And we're very excited to recruit more patients and give a full data update on the arm with alemtuzumab next year. So this is just starting right now. And very important to note that some of these patients are treated prior with a CD19 CAR and have relapsed and are coming then into our study. So we're excited to show proof-of-concept with this program that we can actually treat patients other than in another CD19 CAR T therapy here with a 22 CAR-T therapy, we can treat patients that have relapsed after a CD19-directed CAR T before. And we'll give more color on that data at our presentation at ASH. And then going into next year, we will give rolling updates on this program and on our other programs. Gena, I'll try to keep it short. But with this, we can already open it up for questions.

Can you hear me?

Yes.

Okay. Perfect. Okay. So maybe I will just start with big picture question. And we did see quite a few encouraging data, including your partner Allogene's data as well as the CRISPR data, and they all have a different approach. And then you also have a different approach regarding host-versus-graft issue and that you have CD52 media -- lymphodepletion in some of your programs and some you don't, it depends on the targets. So any maybe first question, more for André. Like your thoughts regarding the approach, your approach versus others? And how you can learn from others for the next step? And then more important, any thoughts on the beta-2 m knockout or modify for the future program?

Well, thank you very much, Gena and for this great question. Actually, we don't think that our approach is different than other approaches. Because we started all this concept of allogenic CAR T with various approaches. And for example, the knockout of beta-2 microglobulin by gene editing is something we thought very early stage in, for example, the concept of [ allogeneic ] beta-2 microglobulin with a TALEN or with a CRISPR is slightest [indiscernible]. So we do cover this aspect since years now, and we obtained plenty of IP on this side, and we've already done this. But not in the clinic yet. So our approach is a step-wise approach. Initially, when we find our first IND on UCART19, which is ALLO-501, was to go full-fledged [ with or without ] alemtuzumab. And now we think that it's better to know exactly how to [ correlate ] without our alemtuzumab to be able to dose properly alemtuzumab. And when you look at the data, for example, for UCART22, what Simon just present, we dosed 100,000 cells per kg, which is approximately 100 like 80 million cells for an adult. So less than 100 million cells for an adult. This is not like even the start dose for competitive studies you're talking with where there is absolutely no results with the CD19 target. So it gives an idea of the quality of the production of the T-cell that Cellectis is able to do. So comparing a CAR that is been designed by our manufacturing versus competition, when you look at the level of dose, we're start seeing signs of responses that are 100x above the size of our DL1 for UCART22, but on a target that it's supposed to be a better target than 19. It's very difficult to compare. Now we think that we have to go step forward, start with signed like -- without anything just playing and there are certain trials that go playing that are interesting. Then you add alemtuzumab, and eventually, you do beta-2 microglobulin, we replaced beta-2 microglobulin by HLE to block [NK tag ] et cetera. So you have a full array of all the different type of approaches and try to keep the persistence of the CAR in the patient. What's going to be interesting also to see is subsequent to depleting CAR Ts such as UCART CS1, I know it's on halt currently. But it's also a different type of approach than the other approaches where the CAR induces its own engraftment and persistence in there by embedding its own self-lymphodepleting agent, which is CS1. So all of this is part of the tools that we can use and that has been sold off years ago, before even anyone thought about going in allogeneic CAR T that Cellectis is deploying now.

Great. Very helpful. So maybe diving to your UCART22 program. So a few questions there. First is, it seems like you required the enrollment criteria for patients, you need at least 90% CD22 expression. Just wondering, using that criteria, what percentage of ALL patient will fall into that criteria and a similar apply to the non-Hodgkin's lymphoma population.

Carrie, do you want to answer this question?

Sure. Thank you, Gena. So for ALL, just to be clear, we started the enrollment in the dose escalation with a high proportion of CD22 expression, because it's a dose escalation study, and you really want to be able to choose the patients that are most likely going to show some benefits. So you can make some decisions. We don't know now, for example, yet if lower expression necessarily means that it will work. And that's something that we're going to continue to be monitoring and looking at in the trial. That said, CD22 is one of the ubiquitous B-cell expressing antigens in NHL and ALL. There's a small proportion of patients with ALL that don't express it as frequently. These are typically the ones that have an MLL rearrangement, which is often seen in infant ALL. But for the most part, I'd say the vast majority of patients would still have approximately 90% or a very high proportion of CD22 expression. It's very similar to CD19, actually.

Okay. And how about the non-Hodgkin lymphoma population?

No. I think it's pretty similar as well. Yes. It's again, it's 1 of the early progenitor B-cell malignant B-cell antigens, and it's typically seen similarly to CD19.

Okay. And then for the ASH abstract, I think you also mentioned that the host T-cell recover during day 17 to 28. Do you think at that time window is sufficient for CAR T to drive response? Do you know the end of the quarter improvement?