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

Good morning, everyone. My name is Gena Wang. I'm a SMID cap biotech analyst at Barclays. Welcome to our second virtual Global Healthcare Conference. First, I wish everyone stayed healthy. And I would like to thank all the participants, investors, companies and especially our event team and corporate access team who made this virtual health care conference possible. With that, I would like to introduce our next speaker, Simon Harnest, Senior VP of Corporate Strategy and Finance from Cellectis. Simon, I hand over to you.

Thank you so much, Gena. I'm actually going to share my screen, so just let me know if you see this. And thank you so much for hosting me today. And I'm always very excited to present at Barclays, really one of the leading research teams in the world, and especially covering gene editing. So Gena, thank you so much for having us. I would like to give an introduction on Cellectis and a quick update on our clinical pipeline and also, finally, what milestones to expect from us and from our partners this year. So please note there are forward-looking statements in this presentation. I will skip a couple of slides because we don't have so much time, so bear with me while I flip through this presentation. And obviously, these slides are also available on our website at cellectis.com. But just as a quick introduction, Cellectis is a gene editing company. And Cellectis has been in the gene editing space for actually over 21 years. And especially, the founder and CEO of the company, André Choulika, is one of the first gene editing inventors in the world, where in the '80s and early '90s, André Choulika discovered a technology called meganucleases. We have since progressed through a series of different technologies, starting with meganucleases. We looked at zinc finger nucleases. We now use a technology called TALEN, which is also in the nuclease family, and we have a series of patents on the CRISPR technology. And we are technology agnostic, and we think there's a lot of new developments coming in the gene editing space, and we're at the tip of this. And we're constantly evolving our gene editing precision efficiencies. And currently, we found TALEN to be the most precise technology in the gene editing space for our applications, which is specifically off-the-shelf gene-edited CAR T-cells, and I will explain what that means. So when you think about the CAR T-cell space, it all started with the fantastic development of individualized medicine, where it was discovered that you can actually extract T cells from the patients and modify them by introducing a chimeric antigen receptor or CAR for short. And this CAR enables this T-cell to find a tumor-specific antigen with very high-precision and kill cancer cells in a phenomenal way that we've previously never seen before. There were trailblazers at the University of Pennsylvania and actually out of Israel that developed this technology in the very early days in 2005, and this resulted in the first product approval in 2017 by Novartis and Kite Pharmaceuticals (sic) [ Kite Pharma ] at the time. And this is what we call autologous CAR T-cell development, where, again, you take the cells from a patient and you modify them and you reintroduce them into this patient. That is a very lengthy process, and it's also unsure to know how good these cells are going to perform at the patient at the end. And most of these cancer patients are critically ill that they don't have the time to wait, and they cannot take this uncertainty to wait for a product made from their own blood. What is much more desirable, which is the era we're entering now, is off-the-shelf or allogeneic CAR T-cell development, where you actually source T-cells from healthy donors in advance of treating a patient. So this is manufactured off the belt to result in a gene-edited, off-the-shelf CAR T-cell product. So starting with the raw material from healthy donor T-cells, which is an abundant material out there, we have actually, at Cellectis, invented this concept of making through gene editing this approach possible. And that is a very important step to open up this therapy to millions of patients worldwide and not just focus them on very specific institutions to also have a cost-effective manufacturing process, which means we can produce with economies of scale. Where we can make what previously was one manufacturing run for one patient, now we can have one manufacturing run for hundreds of patients. So at Cellectis, we really perfected the cell yield and the quality of our cells out of this production process, which is now fully internalized at Cellectis as a stand-alone manufacturing capacity within Cellectis. And this also saves a lot of time because once the patient comes to a hospital or is in treatment, you just open a freezer and take out a vial of off-the-shelf CAR T-cells, and you can unfreeze them and inject them right away into these patients. So the market access, the cost efficiencies and the time saving are a few of these benefits. But also the power of the product being sourced from healthy donor T-cells, now we see that this makes actually a big difference that these T-cells are very fit versus what we see in autologous CAR T-cell development. And we do a series of engineering steps that are based on our gene editing platform that gives us really a world of opportunities with these off-the-shelf CAR T-cells because we can make smart CAR T-cells. We can gene engineer CAR T-cells to be specifically targeting certain tumor-associated antigens but also create their own lymphodepletion, which I can explain later. We can make our CAR T-cells stealth to different chemotherapies or, for example, enhance their activity through PD-1 knockout. So there's unlimited combination therapies and innovation potential for these off-the-shelf gene-engineered CAR T-cells. And as I said, we use a technology called TALEN, which is a very precise gene editing tool, and the reason why this is so precise is that we are able -- with a construct of 2 pairs of 16 base pair recognition sites, we can dial in the precision of this cutting efficiency at up to 6 base pairs precise. This is outstanding in the gene editing space, and it really gives us the benefit and the differentiation to have the most accurate gene edits and the highest cell yields in our manufacturing process. So we usually get routinely in GMP close to 100% knockout efficiencies now. And that is just the start. And what you see on the bottom of the slide is that we're actually very efficiently knocking in completely new types of genes. So something that you cannot do, for example, with base editing is actually adding a whole cassette of genome, of a piece of DNA efficiently, which we can do with this TALEN technology, which actually enables us to target new treatments and also new diseases that are only targetable through actually efficiently repairing a genome versus just doing a knockout or gene inactivation. However, for our CAR T-cells, this is the first step. We just knock out what makes these cells nonalloreactive, which is called the TCR, and then we do different knocks out -- knockouts in those T-cells. This is the manufacturing process. I briefly alluded to this. We start with raw material from donors. So this is basically leftovers of blood donations. And then we really manufacture the highest quality of T-cells out of this raw material that we start with. We introduce the CAR with a lentiviral vector. We go through this process of electroporation to bring our gene editing tool into the cells. We perform the gene edit. We have a mild cell expansion, purification step. And at the end, we end up with hundreds of doses for hundreds of patients in one of these manufacturing runs, which takes about 2 weeks to manufacture hundreds of doses of CAR T-cells. So this is really the key to the scalability of this process. So now coming to our clinical partnership programs. We have a very interesting partnership alliance with a company called Allogene and Servier. Allogene is a company that's publicly traded. Servier is a private company in Europe. Allogene and Servier have the rights to our first product, which is a CD19, off-the-shelf CAR T, which is called ALLO-501, which was previously called UCART19. And that program is the most advanced one in Phase I expansion, and we're expecting more data on this Phase I in the middle of this year. And Allogene and Servier have announced that potentially by the end of this year, they're entering a Phase II potential registration study for the CD19 product. And for us, this is super exciting because we not only have over $400 million in outstanding milestone payments for this product, but this would also potentially be the first off-the-shelf CAR T product that is on its track towards an approval in the next couple of years. So super exciting for us and for patients to have really the first time a path towards an approval with an off-the-shelf CAR T- cell development. Apart from the CD19 target, we have also licensed out 15 other CAR T targets directly to Allogene, and we're entitled to receive $185 million for each target under this alliance. And these targets include also BCMA and CD70, which Allogene is moving forward this year. So very exciting for us to have this partnership. We recently actually entered into an alliance with Cytovia, which is not on the slide yet, which is a very new alliance we just announced in our year-end earnings call last week. And that alliance is very exciting for Cellectis because it enters for us into the iPSC-derived NK cell space. We have 5 targets partnered with Cytovia. And with Iovance, we have a partnership in the TIL space, the tumor-infiltrating lymphocyte space. And all these partnerships are based on our gene editing technology and give us at Cellectis very interesting access to targets in these new modalities, like NK cells and TILs, while at the same time, it allows us to focus on our powerful CAR T-cell development. From a clinical perspective, we are in an exciting phase now because this year, we actually have 7 clinical programs in Phase I ongoing that will, one after the other, read out clinical data. So I will start with Cellectis' proprietary pipeline. And the interesting thing about our proprietary targets is that we picked those targets for a very specific reason, meaning that we pick targets that are differentiated in their targets and are differentiated in the space. So when you think about our targets with UCART123, it's a completely new target for CAR T in AML, acute myeloid leukemia. If this works, then you have the first off-the-shelf CAR T in AML, which could be an amazing breakthrough for relapsed/refractory AML patients, where there's currently no other treatment option and the life expectancy is very limited, something about 20% overall survival after 2 years. Then coming to UCART22, which is a CD22-targeted CAR T as an alternative to CD19. That's a very interesting product because we think it's largely derisked because the concept is very similar to our most advanced product in development with Allogene, UCART19 or ALLO-501, and UCART22 is a copy of that but with a different target. And we're treating patients that are actually relapsing or haven't responded to CD19-targeted therapies. For UCARTCS1, it's similar. The interesting thing about UCARTCS1 is that it is targeting CS1, which is very highly expressed on multiple myeloma cells. But previously, it was not targetable with a CAR T-cell because CS1 is also expressed on the T-cell themselves. So you have to gene edit out CS1 before fusing a CAR going after CS1 onto this T-cell. And we have achieved this step, and therefore, we think CS1 is a very competitive target to BCMA. And we're excited about the progress in the clinic. Quickly about our upcoming clinical milestones. UCARTCS1 will have data in the second quarter this year on patients we treated last year in the MELANI-01 clinical trial. UCART22 is now in a Phase I dose escalation trial with a so-called FCA preconditioning, which includes alemtuzumab, or the anti-CD52 antibody that we have in this product, to prolong the window of persistence for this product in patients. And we expect data by the end of the year on this Phase I dose escalation with UCART22 and FCA preconditioning. And finally, UCART123 is also in Phase I dose escalation with an FCA preconditioning, and we are working on our dose escalation with UCART123. And we will decide by the middle of this year when we will announce data for this product, which is showing some very interesting early signals, and we want to conclude this Phase I dose escalation. Our partnered programs, as I said, UCART19, are in Phase I expansion -- or ALLO-501. We will expect data on this in the first half of this year. And then finally, for UCARTBCMA, which is our -- or ALLO-715, which is the licensed target for BCMA to Allogene, we also expect data by the end of this year. And maybe here, I'll open it up for Q&A for Gena because we can go through the Q&A easier with clinical data updates, et cetera.

Great. Simon, thank you. 2021 will be very important year for Cellectis. We will see lots of data. So maybe we just go through each program, like what kind of expectation we have on like the numbers of patient or data. So maybe we'll start with UCART123. So if you can walk through the -- I don't know how much additional color you can share with us regarding the doses because you said you may conclude the dose escalation phase. If you can give a little bit more color on how many doses you already dosed. In the past, you proposed 4 different doses. And by the -- later this year, when you present the data, how many patients? And how many doses? And what kind of data you'll be sharing with us?

Yes, absolutely. UCART123, I think, personally, I've always loved this product because I've been with the company now since 2015, and I've seen the early development and the entrance into the clinic with this product. And I think this target is one of the best targets in AML. It's very highly expressed on AML cells. It's also expressed widely on the bone marrow cells and cells that are actually reproducing blood, which in AML, that's the source of the disease, these progenitor cells. So targeting CD123 is both an opportunity and a challenge because the idea is basically to wipe out the bone marrow of these patients to allow them to have a complete reset button and not relapse again with AML cells. And so we are currently at dose level 2, which is at about 625,000 cells per kilogram, and we're going into dose level 3 at just over 1 million cells per kilogram. So we always give per kilogram of body mass because this is important for us when treating patients in different age groups, for example. But at dose level 2, going into dose level 3, I think, is where we start to see some clinical activity, and we want to put into perspective with our next data update what this means for this space. These patients come after multiple lines of therapy. They have not responded to anything else out there, including bispecific treatment or any ADC development or any other CD123-targeted therapies. And then they come into our trial, and we see responses. So measuring those responses and doing this in a safe manner in this dose escalation is the first goal of this dose escalation. We have to derisk the target from a safety perspective. We have to make sure that we have no serious adverse events that are outliers out of the usual CRS-related adverse events in CAR T trials. So we have to validate this target from a safety perspective, and then we can start looking into responses. How long do we see, for example, the amplification of CAR T-cells? Do we see a reduction in blasts? If yes, how strongly do we see a reduction of blasts? So this is data we're actually collecting as we speak. And I'm very, very excited to show data on this product very, very soon. The question is like in what format, at what scientific conference. There's always kind of debates at which conference you're going to present this, where it makes most sense. And we're right now in this kind of data gathering phase. So I will be able to give a more clear answer on how many patients and what we're trying -- and when we're trying to present maybe in a few weeks' time once we are over this Phase II -- the dose level 2 in the Phase I dose escalation, and then we'll give clearer guidance on the data readout.

Okay. Great. So regarding study trial design, how many patients will be -- are supposed to be enrolled for each cohort?

Yes, we have the opportunity to dose between 3 and 5 patients for each dose level. And any dose where we, for example, see no response, we move right to the next dose, which sometimes is the case, moving from dose level 1 to dose level 2 because dose level 1s are usually picked to not expect any efficacy data out of this but just to kind of see if it safe because you don't really do a safety study in healthy volunteers. Here, these are all patients so you start at a very low dose level. So usually, dose level 2, 3 -- and in the case of UCART123, we actually have 4 dose levels. So towards the higher dose levels, we expect to enroll more patients. So I would assume smaller amounts of patients in lower dose levels and higher numbers of patients in the higher dose cohorts.

Okay. That's very helpful. And then since the -- I think, early days, you reported some cases of capillary leak syndrome cases. Any more or any -- what other safety -- would you say safety looks good? The -- any -- can you give a little bit more color there?

Yes. Not to my knowledge any more capillary leak syndrome. What we actually discovered is that capillary leak is something that is now kind of expected in high-CRS cases because you also give these patients perfusions and you basically keep their blood pressure high artificially. And that, in some cases, especially in elderly patients, can lead to capillary leak, which is not specific to Cellectis' programs but CAR T overall. We've seen cases of that in Novartis trials, in Kite's trials and Juno's trials. So it's something that is now much more understood versus a few years ago when we were in the very early stages.

Okay. That's good. And then move to the UCART22. So we did see some data recently. And I know it is a small number of patients. We did not see a clear dose response. And then the number of cells was actually lower than the Kymriah recommended dose, the one that showed response. Any thoughts you have regarding the data?

Very good question. So for UCART22, we actually started with a dose level where we see actually responses. That was about 10 to 30x lower than comparable CAR T-cell doses. And we started these low doses to validate the target first, but we were so excited with UCART22 because we checked a number of boxes. We actually had a lymphodepletion regimen that did not include alemtuzumab, so a flu/cy-only lymphodepletion, which is crucial to kind of dial in the window persistence of these CARs. So we didn't precondition patients to dial in a longer window of persistence, but we just started with kind of the first step. And here at dose level 1, we already saw 2 out of 3 patients with a CR. And these are patients that have not responded to any other therapy or relapse after, and they have not had the opportunity to be treated with the CD19-directed therapy. So we validated the target, 22, as a new target. We also have shown that we can bring patients into CR that previously relapsed or failed a CD19-directed therapy. And third, we got patients into CR that were not pretreated with alemtuzumab. And now we are pretreating with alemtuzumab to increase the window of persistence of our products to actually prolong this response and to have a deeper response. So that's really the data we look forward to, to bring this into a dose expansion study. And that again is expected by the end of this year. And here, I think the dose response is still too difficult to figure out when you're only talking about 2 or 3 patients in each dose. So I think you need somewhere between 5 to 10 patients for a dose in that expansion to confirm your activity. So I wouldn't take the dose response too much as a signal right now, more about like the actual number of patients we're treating and then also with a longer window of persistence of these CAR T-cells with the preconditioning with alemtuzumab.

Okay. Very helpful. And then quickly touch on CS1. So you will report data first half this year. So any -- maybe any additional color you can give, how the [ clinical hold was being moved ] and also how many patients we'll be expecting to see?

Yes, absolutely. So the product is a completely new construct in the CAR T-cell space, and we started last year with a first dose of 1 million cells per kilogram, which again is 10x higher than our usual starting dose. And we, on the one hand, made this as an informed decision by thinking we have to have a higher dose because UCARTCS1 is targeting both multiple myeloma cells and immune system cells to create its own lymphodepletion. And that was a good rationale to think about it this way, but what we found out is that the product actually activates rather quickly because, probably, there's more antigen presence. So maybe we need less of a starting dose to start this dose escalation. So this is the consideration we're going into now with the new enrollment this year. The data we're showing from last year is from dose level 1. And the first patient on dose level 2, which, unfortunately, that patient passed away in the observation period. So it's not unusual that patients, of course, in these studies still pass away after being treated with more than 13 lines of treatment, and they have a very progressed stage of a disease. But we think the data that we want to show shows a significant step forward, first of all, from a targeting perspective, targeting CS1 for multiple myeloma, and also what this means for this product in terms of an antitumor response. So look out for this presentation. I think it's a very interesting proof-of-concept with some antileukemic activity of UCARTCS1.

Okay. So Simon, does that mean, the new patient enroll, you will lower the dose? Like, what would be the dose? That first dose, I remember, was 1 million doses. And so what would be the current dose now?

Yes. We haven't disclosed the dose of the new dose escalation starting dose. But again, these dose escalations always go through different doses. That's the nature of a dose escalation. And we will start somewhere between 100,000 and 1 million cells per kilogram, so in the middle of what we usually do in a regular dose escalation for [ our drug trials ].

Okay. So if I look at your UCART123, your first dose was actually the 250,000. And the second dose is 625,000. So it will be similar around that range, right, for the...

Yes, in the middle of that range.

Okay, in the middle. Okay. Perfect. Okay. That's very good. And we are running out of time, but this was a very productive discussion. And I think in 2021 will be a very exciting year for Cellectis. So we'll keep our fingers crossed, and hopefully, we can see quite a lot of proof-of-concept and important data this year.

[ Yes, we'll give you the data once we get it, for sure. ]

Thank you, Simon. Okay. Okay. Bye-bye.

Thank you, Gena. [ Thank you so much. ] Talk to you soon.

Talk to you soon.