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

Good morning, and welcome to the Cellectis Clinical Update. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Cellectis website following the conclusion of the event. I'd now like to turn the call over to Andre Choulika, Chief Executive Officer of Cellectis. Please go ahead, Andre.

Well, thank you very much, and welcome, everyone. Thank you very much for waking up early this morning to attend this webcast. We're really excited to present some update on our AMELI trial, UCART123, and our BALLI trial, UCART22, that will be presented by Mark after. Before this, I will give you a quick introduction of the company. If I can have the next slide, please. I would like you to read carefully. I'll give you a few minutes to read carefully the legal notice on the disclaimer. Thank you. So a quick overview of Cellectis. Cellectis at the glance gives you a quick idea of what we are at. Cellectis have 4 ongoing clinical trials with more than 40 patients that have been enrolled so far in those. We have also some global GMP facilities that are operational since 2021. And it's an end-to-end manufacturing, I'll go more deeply into this in a few slides at the end of the slide show, and I'll give you some idea of how this works. We have a number of near-term catalysts, some UCART clinical data update. We had one yesterday. We'll give you one today. And there will be numerous ones during year 2023 that will be distributed through the year. Cellectis has enough cash, which is expected to take us in a runway into 2024. And of course, Cellectis has a strong number of partnerships that are diversified with leaders in the industry with more than 200 patients that have been dosed so far and a potential revenue of over $4 billion in milestones plus royalties. We have 6 sponsored clinical trials with Cellectis as a license partner with Servier and Allogene, with Iovance and Cytovia. Can I have the next slide please? So what's all about the invention that's like to roll back the years, which is the off-the-shelf CAR-T concept. Off-the-shelf CAR-T is something that always excited us on our side because it's a frozen pharmaceutical product. You can have a manufacturing that can be scalable. It reduces cost with hundreds of doses that are done per batch when you do an allogeneic CAR-T. It's very robust. So our target in our manufacturing, our process development is robustness. The goal is to provide potency and consistency to each patient. Each patient gets the same chance when he gets a product. And one of the big achievements that we're extremely proud of is the robustness of our manufacturing through a very deep work over 10 years of work in process development for making allogeneic CAR-T. And then finally, of course, there is the market access potential for Cellectis which is it's a product that is off the shelf, so it's immediately available and eligible for patients. And this is something that makes a big change for a lot of patients, but also the access in a lot of different hospitals outside transplant centers. Further next slide, please. So that's the platform of Cellectis. It gives you an ID of every CAR-T that we've built is built on the same platform. Essentially, on the left side, you see the TALEN and knockouts that we do. So most of the product that's based on the same platform, which is the TCR track knockout with reduced risk of GvHD, there is the CD52 knockout, which gives you the CAR-T resistant to alemtuzumab. And most of the product that we developed are on this platform. There is one exception today in the clinic, which is CS1, where we knock out CS1 to prevent fratricide killing, but there is no CD52 knockout in the CS1 CAR-T. And then on the right side, you see what we add as [ CAR ] inside. So there is like, for example, going from bottom to the top, CS1 as a CAR-T, the CAR123, the CAR22 or last but not least, CAR20 plus CAR22, which is the first dual allogeneic CAR that is entering the clinic today. And now I would like to pass it to Mark Frattini, our CMO. Mark?

I'm going to begin with the updates for AMELI for UCART123. This was presented yesterday afternoon in an oral presentation at ASH. So AMELI-01, the preliminary results from a Phase 1 trial of UCART123, an anti-CD123 allogeneic CAR T cell product in adult patients with relapsed and refractory CD123-positive AML, and it was presented by Dr. David Sallman from Moffitt Cancer Center. So in terms of background and introduction, AML, it's estimated that there'll be over 20,000 new cases that occur in 2022. And sadly, over half of those cases, over 11,000 cases will result in death. The outcomes for patients with relapsed/refractory AM have remained poor for many, many years. Response rates in this state of disease is less than 30% and the expected long-term survival is dismal. So the AMELI study that's being presented is open-label dose escalation evaluating the safety, tolerability, expansion and preliminary activity of UCART123 given in escalating doses after lymphodepletion with either fludarabine and cyclophosphamide or fludarabine, cyclophosphamide and alemtuzumab in patients with relapsed/refractory 123-positive AML. And as Andre just showed you the schematic of the product is seen here. CD123 is a validated therapeutic target in AML. The product is genetically modified allogeneic T cell product that's manufactured from normal healthy donor cells with both TRAC and CD52 knocked out for reducing graft-versus-host disease and allowing for use of alemtuzumab in the lymphodepletion regimen, respectively. And on the bottom right, I just wanted to point out, it's a 4-1BB based construct. This was the study design for the data cutoff that was presented in October. The key inclusion criteria, relapsed/refractory disease, there had to be 5% or greater bone marrow blasts. These blasts had to express CD123, and the patients all had to have organ function with an ECOG performance status of 1 or less. The primary objective being safety, tolerability and to determine the MTD or RP2D of UCART123. Additional objectives being investigator-assessed response, UCART expansion and trafficking and persistence in the blood and bone marrow as well as immune reconstitution. On the bottom left of the slide are listed the lymphodepletion regimen. So for the FC regimen, standard doses of fludarabine at 30 milligrams per meter squared for 4 days, cyclophosphamide was used at 750 milligrams per meter squared for 3 days. And for the FCA regimen, alemtuzumab was added to this at 12 milligrams per day for 4 days for a total dose of 48 milligrams of alemtuzumab. On the right side of this slide outlines the study design. The study initiated in the FC arm at dose level 1, which was 2.5 x 10 to the 5th cells per kilogram. This was escalated through dose level 2, at which point at the end of cohort meeting for dose level 2 with recommendations from the DSMB and investigators, the FCA arm was opened at dose level 2, 6.25 x 10 to the 5th. The FC arm did continue enrollment up through 1 patient at dose level 3, and the FCA arm continued enrollment through 1 patient at dose level too high. In terms of the baseline characteristics, there were 18 patients enrolled on this study who received lymphodepletion, 17 of whom went on to receive UCART123. The median age was 57. The performance status ECOG of 1 for almost all of the patients, 94%. Importantly, this was a very heavily pretreated and very high-risk group of patients. So their ELN risk was adverse risk in 80% of the patients. The median bone marrow blast was 37% with a range up to 88%. The number of prior treatments, again, median was 4, but the range was 3 up to 9 prior lines of therapy. Importantly, 50% of these patients failed prior allogeneic stem cell transplant. And in addition to that, in terms of the high-risk outlining more of the high risk of these patients, there were multiple different molecular and cytogenetic high-risk abnormalities, including 33% with a TP53 mutation and almost 20% of the patients with a high-risk monosomal karyotype. In looking at the UCART123 related treatment emergent adverse events. This slide is outlined into the FC arm, the FCA arm and then a total arm on the far right. column in the far right. And what's outlined in red are the major UCART123 or cell therapy-related complications that we would look at and expect CRS, obviously, in this patient population, not only because of the target CD123 but also because of cell therapy is an expected TAE for this study, and it was seen in 100% of the patients, albeit that most of these were grade 1 and grade 2. There were 2 grade 4 events in the FC arm, and there were 2 grade 5 events in the FCA arm. In terms of ICANS, there was only one case of ICANS in each arm, 1 grade 3 in FC and a grade 2 in FCA. Looking at all the other related TAEs, you can see there were no major increases in any of those. It's the transaminases, again, an expected increase as a result of not only therapy, but as part of what's seen in CRS, and you can see these were all low grade and easily manageable. Looking at the UCART123 all-cause TAEs, again, with CRS and ICANS outlined as before. Importantly, on this slide, we're also looking at potential infectious and bleeding complications. And it shows the difference between FC and FCA that there really is no significant difference in terms of the addition of alemtuzumab in terms of infectious related complications in the patients seen on this study, and this also mirrors what we've seen in the UCART22 study in AML that at the addition of alemtuzumab at the doses used does not increase the infectious complications seen. And looking at the antileukemic activity, it was observed in 4 out of 17 patients, and we'll start with the FC arm up top. And what you can see was there was one patient that the black line that had a significant response in blast clearance by day 14, but subsequently had a rapid recovery of their leukemia, however, still below the level of when they were assessed at screening, and that's a stable disease. Another patient in brown had a morphologic leukemia-free state at day 28. On the FCA arm below, we see there were 2 patients that had significant responses, 1 patient that had a 90% blast reduction. So clearance by day 14 was at 5% blast at day 28. This patient subsequently went on to receive a stem cell boost from their prior allogeneic stem cell donor. And the other patient in black, the 226 patient at dose level 2. This patient cleared their disease by day 14 and at day 28 had a CRI, which was then followed by a day 56 analysis that showed MRD-negative CR, and then I'll speak more about this patient in a few slides. And looking at the addition of alemtuzumab and its effect on lymphodepletion. You can see on the left side, in the FC arm, there was a relatively rapid recovery of host lymphocytes as assessed on the Y-axis as the absolute lymphocyte count with a pretty rapid recovery between day 10 and day 28. However, with the use of alemtuzumab, the lymphodepletion was persistent throughout the DLT period, the 28-day DLT period and beyond with all patients with the exception of one, who was a patient who developed a rapid relapse. And as a result of that, we saw increased lymphocytes during the time of peripheral relapse of disease. This slide is looking at expansion of the UCART cells and showing that the addition of alemtuzumab results in increased UCART123 expansion. So looking at the top curve on the left in the FC arm, you can see that there are 3 patients that showed some level of UCART expansion. And if you look at the bottom panel in terms of FCA, you see essentially all of the patients, approximately 80% of the patients showed expansion of the UCART123 cells during the course of their treatment. And this was approximately 9-fold higher level of expansion than what was seen in the FC arm. And this is quantified statistically more on the right side where we're looking at the area under the curve with the VCN in terms of days. And with FC, the area under the curve, the mean was 10 days, where with FCA, it was 35 days, and this was statistically significant. Next, we're looking at the pattern of cytokine secretion and ferritin levels in terms of correlating it with UCART123 expansion. I'll point out that these were patients from the FCA arm and looking at the top panels from left to right, we see an IL-2 increase that happens very early on after cell infusion and is indicative of UCART123 expansion. And subsequently, the IL-6 gamma interferon and TNF alpha all represent that these curves very much mimic and mirror the curves for UCART expansion. So at the time of expansion, we'll see increases in the cytokine secretion and this is common throughout all the patients that we've seen expansion in and again, this is with the FCA arm. On the bottom, we're looking at ferritin versus VCN in select patients from the FCA arm. But importantly, the ferritin again mirrors the expansion seen by VCN of UCART123. And I'll just point out that the patient in the middle at the bottom, 226 is our long-term responder. And as you can see, there's the peak of VCN and the peak of ferritin coincide together, mirror each other. Now again, looking closer at patient 226, who achieved a durable MRD-negative CR. This is a 64-year-old female that had adverse risk AML, relapsed/refractory AML, AML with MDS related changes, high-risk cytogenic mutations with a minus 7 and molecular mutations of EZH2 and IDH1. She failed 5 prior lines of treatment, which included induction chemotherapy, high-dose cytarabine and mutation-directed therapy with IDH1 inhibitor and venetoclax-based regimens as well as an allogeneic stem cell transplant. On the bottom left is looking at the bone marrow analyses from the bone marrow biopsy. So starting with screening at day minus 14, which showed 51% blast. And at day 28, you can see there were less than 5% blast, but it was MRD positive, but consistent with the CRI. Subsequently, this became an MRD-negative CR at day 56. And this response continues now out past 1 year. She was seen the end of November for her 1-year visit and remains in an MRD-negative CR state now after 1 year, which is incredible, given that this patient had grade 4 cytopenias going into the study and had been refractory to these 5 lines of therapy, including an allo transplant. On the right, looks at the tumor burden reduction, which coincides with the UCART123 expansion as measured by VCN. So as you can see, the blue line is the tumor burden and by day 14, that's gone, and that coincides nicely with the peak of expansion that's seen with UCART123 by VCN. So as a result of what we've shown, and I'll just review briefly. So for the patients that in the FCA cohort that were treated at dose level 2, there were several that were seen to have disease reduction by day 14. However, there is a narrow peak of expansion of UCART cells over a period of a few days. And as a result, some of these patients were then seen to subsequently relapse by day 28. So indicating that there was the reduction in tumor burden, but it was not enough to sustain antileukemic activity for these patients. And so by bringing in a second window of activity, a second expansion peak via a second dose of cells would then allow for additional UCART123 expansion and further clinical activity after that 10- to 14-day period. And most importantly, this could be given without the use of additional lymphodepletion secondary to more lymphodepletion would just put the patients at an extended risk for extended myelosuppression and infectious or bleeding complications. So by doing it this way, we're able to give 2 doses of cells, get 2 peaks of activity with one lymphodepletion regimen. And ideally, the second peak of expansion in the setting of that reduced disease burden after day 14 should continue to be safe and allow for clearance of that residual disease to help increase the response rate. And as a result of this, the 2-dose regimen will initiate at dose level 2, and this is a dose at 6.25 x 10 to the 5th cells per kilo. That has already been administered to 8 patients in the FCA cohort, has been cleared by the DSMB as a single dose. And in addition to that, to help mitigate any potential severity in CRS, we are also incorporating a dose of prophylactic tocilizumab prior to each dose of cells that's given during the treatment period. So now the amended protocol with the 2-dose regimen is outlined on this slide. So because of the fact that we did not see adequate lymphodepletion nor UCART123 expansion as a result of that during the DLT period for patients that received FC, that arm has been closed. And the 2-dose regimen arm is now open at DL2 x2 doses, that's 6.25 x 10 to the 5th. So in conclusion, for the UCART123, adding alemtuzumab to the FC regimen was associated with improved lymphodepletion and higher UCART123 cell expansion that correlated both with improved clinical activity as well as cytokine secretion profiles. There is 1 patient at dose level 2 in the FC arm that achieved a meaningful and significant blast reduction over 90% at day 28, allowing her to proceed to a stem cell boost from a prior allogeneic stem cell donor. And the 1 patient, the long-term responder, which we discussed in detail, which is who has a long-term MRD-negative CR now past 12 months. Overall, the data support further study for 123 after FCA lymphodepletion in patients with relapsed/refractory AML. And based on what we've shown in terms of the expansion patterns, the cytokine profiles and the responses, the study is now enrolling in the FCA 2-dose regimen arm. And again, we're employing a prophylactic tocilizumab dose prior to each cell infusion. I'll move now to the BALLI-01 study, UCART22. And just so that, as a reminder, this is our Phase I/IIa open-label dose escalation and dose expansion study to evaluate the safety, expansion, persistence and clinical activity of UCART22 in patients with relapsed or refractory CD22 positive B-cell ALL. And across the bottom, in terms of objectives, the primary and secondary objectives of safety, tolerability, RP2D/MTD determination as well as investigator-assessed response with the exploratory objectives of UCART22 expansion, VCN and the whole blood and the peripheral blood and bone marrow. In the middle box outlining the eligibility criteria, these are patients in the escalation part. So eligibility is 15 to 70 years with adequate organ function, good performance status, a blast expression greater than 70% and relapsed refractory disease. Today, I'll first review what was presented at ASH last year and EHA this year in terms of patients enrolled through dose level 2 and 2I. And then I will go into the recent results and new results to share with you of the patients that received dose level 3 at 5 million cells per kilo, where we've dosed 5 patients, and we'll discuss the results of those patients. Importantly, the lymphodepletion regimens are listed here as well with the FC being 30 milligrams per meter squared per day, cyclophosphamide a gram per meter, and with alemtuzumab, the cyclophosphamide dosing was reduced to 500 milligrams per meter squared with the addition of alemtuzumab 20 milligrams a day for 3 days for a total dose of 60 milligrams of alemtuzumab. Additionally, I'd like to point out that this product that was used for this part of the escalation is what we call our P1 product, which was made by the CMO. And so we'll proceed with a review of the data that was originally presented at ASH last year. So this was looking at up to 12 patients that were dosed with UCART22. And this showed a very promising safety profile. Again, the median age 30 with a high risk, again, patients that were very refractory. So 60% with BALL with recurrent genetic abnormalities and 1/3 of the patients with the Ph-like mutation CRFL 2. In terms of median lines of therapy, were 3, but up to 6 were seen and these patients, the majority, almost 3/4 failed prior blinatumomab, almost half failed inotuzumab. We saw almost 30% that failed prior CD19 autologous CAR T cell therapy and about 25% that failed prior allogeneic stem cell transplant. Importantly, several of these patients also failed multiple of these lines of therapies from 2 to 4. Looking at the safety, there were no DLTs seen to date, no ICANS seen to date. There were no UCART22 severe related TAEs. 3 patients had CRS, but these were mild cases of CRS with 2 being grade 1 and 1 being grade 2, and they're responding quickly and resolving with either no therapy or in the case of grade 2, a dose of tocilizumab. Finally, there was 1 patient that did have an investigator assessed a graft versus host disease in the skin. Importantly, several things, this was not confirmed by biopsy, but however, this patient did receive and failed a prior allogeneic stem cell transplant. And what was shown both in the peripheral blood, in the bone marrow is that after clearance of the patient's leukemia by the UCART22 cells, there was reactivation of the prior allogeneic stem cell donor stem cells, which were then detected in the blood, in the marrow and likely mediated graft versus host disease that was seen. So now I'm going to show you the patients that responded, that were treated with dose level 3. This was 5 million cells per kilogram. We dosed 5 patients with FCA lymphodepletion, and these are the responders. So patient 1 was a 34-year-old male. As you can see, heavily pretreated, intensive chemotherapy induction, followed by intensive chemotherapy salvage, the patient also went on to receive an allogeneic stem cell transplant, which they relapsed from, went on to receive venetoclax-based regimen followed by autologous CD19 CAR T cells, which they relapsed from and then went on to receive additional venetoclax for which they were not responsive to. As you can see, the cytogenetics were very high-risk and complex with greater than 5 abnormalities and a high-risk molecular mutation with IKZF1. In terms of safety for this patient's treatment course, they had a few days of grade 1 CRS that was easily manageable. There was no ICANS that was seen. There was no HLH that was seen. The patient achieved an MRD-negative CRI, and they are currently month 7. So long-term MRD negative CRI, they have gone on to receive a DLI from their prior allo transplant donor. And as I said, remain in MRD-negative CRI, with plans to proceed to a second allogeneic stem cell transplant given that they are still in a MRD-negative state at this point in time after 7 months. Patient 2, a young female, 24, again, very high risk, failed, as you can see by the cytogenetics with in version 3 and version 11, other additional cytogenetic abnormalities, received high-dose chemotherapy for induction and which they relapsed from, subsequently went on to receive autologous CD19 CAR T cell therapy, which she relapsed from and went on to receive venetoclax-based regimen as well as a allogeneic stem cell transplant, which she relapsed from as well, so failing both in allotransplant and CD19 autologous CAR T cells. This patient experienced no CRS. There were no ICANS. There was no HLH seen in this patient. Their best response was an MRD-negative MLFS that began at day 28 and continued until day 84. On the recent bone marrow evaluation, they were found to be MRD positive, but still in a morphologic leukemia-free state, and they are currently out over at day 117 today in an MLFS without receiving further therapy at this time. And the third responder out of the 5 patients was a 57-year-old male who again received multiple prior lines of therapy. And this patient's prior therapy included blinatumomab, an allogeneic stem cell transplant, autologous CD19 CAR T cells and inotuzumab with [indiscernible], the CD22 targeted ADC. So this patient failed all 4 of those in addition to chemotherapy, had 1 day of grade 1 CRS at day 8 for which they received a dose of tocilizumab. Otherwise, no ICANS, no HLH, and this patient has achieved a full MRD-negative CR, and they are currently at day 71 and continue without having any interval therapy after the UCART22 cells. So a summary of the UCART22 DL3 data that I've shown you, there were 5 subjects that were dosed at dose level 3 with the P1 product at 5 x 10 to the 6 cells per kilo. Again, this was the product that was made by the CMO and this was using FCA lymphodepletion. No safety issues, no grade 2 or higher CRS in any of these 5 patients that were treated. Out of the 5, we had a 3 out of 5 clinical responses for a 60% overall response rate in this very heavily pretreated, high-risk patient population, all of these patients again failed both an allogeneic stem cell transplant and autologous CD19 CAR T cells. And we saw 1 MRD-negative CR and MRD-negative CRI and in MLFS. So in terms of next steps for BALLI-01, dosing has now started with our UCART process 2 or P2 product. This is a product that is made wholly from end to end at Cellectis and is currently in the clinic. Due to the fact that this P2 product has shown significantly higher potency in vitro than P1, we are beginning at dose level 2 at 1 million cells per kilogram with the first patient that's receiving P2. We expect the next data set with P2 to be shared in 2023. And just to summarize the 2 studies today. So for what I've shown you for AMELI-01 or UCART123, adding alemtuzumab to the FC lymphodepletion regimen was associated with improved lymphodepletion throughout the DLT period, which allowed for a significantly higher UCART123 cell expansion, and this correlated with improved clinical activity with 1 patient, obviously, a long-term MRD-negative CR now out past 1 year. The study is in currently enrolling patients in the FCA lymphodepletion, we're using FCA lymphodepletion in the 2-dose regimen arm beginning at 6.25 x 10 to the 5th cells per kilo per dose. In addition, we're also using prophylactic tocilizumab prior to each cell dosing to help mitigate any severity of the potential CRS. For BALLI-01 or UCART22, I've shared with you the new data from the 5 patients that were treated at DL3, 3 of which had a clinical response for a 60% overall response rate. And those clinical responses in this heavily pretreated, high-risk patients that again failed both allotransplant and prior CD19 auto CAR, all 3 of them with one of them also failing additional blinatumomab and inotuzumab for a full MRD-negative CR, MRD-negative CRI and in MLFS, and these have been long-term responses, as you can see. And finally, that we are bringing UCART22 process 2 or P2, which wholly made at Cellectis is now being used in the clinical study, which we're beginning at using it at dose level 2 or 1 million cells per kilogram. At this point, I'll turn it back over to Andre to talk about the manufacturing.

Thank you very much, Mark. So a very quick overview of how the company functions. So we have a New York facility that are essentially labs, where we have all our TALEN gene editing platform. That's where the things start where we have all our discovery, where the new [ CAR Ts ] are imagined and built. Once they're built, they're sent to Paris and they function, of course, like to be tested in New York. They are sent to Paris, where we have our process development, analytical development, where we'll scale them up to industrial processes. And once the process is stabilized and we have all the analytics around the process because you have to measure the product, then we make the raw materials, the buffer, the plasmid DNA, the messenger RNA, we do AAVs, we do ROVs. And all these raw materials are sent to New York to Raleigh, our Raleigh facility, where we do all the manufacturing of our final product which are the cell therapies, the CAR-T vials, where we have a warehouse on cryogenic storage and this facility is ready, of course, for clinical supplies, making all these IMPs such as P2 or 20/22. But also we have all the logistics to send them that is currently set at Raleigh. Once this is done, that it's looked up back to New York, where we have our clinical development team that conducts of course, all the clinical operations and clinical science entire for the trials. On the next slide. This slide is really important, and I'd like you to focus on this a bit because it would definitely give the rhythm for year 2023. We have 4 trials and a rich year ahead of us. As you've seen like the end of 2022 is already quite rich with UCART22 that Mark presented, but we're extremely excited to show you next year the data for P2, which is the in-house manufactured product. Also, we're extremely excited to show you next year the data of the 2-dose regimen for UCART123 at 6.5 x 10 to the 5th cells per kg, we're also excited for the dose level 1 for UCARTCS1 in multiple myeloma. And then last but not least, we'll start in enrollment for UCART20/22 with the first dual allogeneic CAR-T. It's a non-CD9T CAR-T, non-CD19 CAR-T for not Hodgkin lymphoma and the first in human data for this CAR-T that has been totally make inside Cellectis. So top quality, of course. And we're looking forward to present to you such a rich year for 2023 will be written by all these 4 clinical trials. Next slide, please. With that, I would like to hand it over for the Q&A. Thank you very much for your attention.

[Operator Instructions] So our first question comes from Shawn Tan from Jefferies.

This is Shawn Tan on for Kelly Shi. I have a 2-part question for UCART123. Firstly, did you see a kind of correlation between cell expansion and antileukemic activity? My second question is which 2 of the patients had the grade 5 CRS and can you remind us of the onset and duration of the event?

Thank you so much for the questions. I think both would be for Mark.

Thank you, and thanks for the question. So in terms of the grade 5 events, I'll answer that one first, the grade 5 events, the patients passed away from the CRS event. And so they were 1 patient at dose level 2 in FCA, 1 patient at dose level too high in FCA. And I'm sorry, I forgot the first part of the question again. Can you repeat that?

Sure. Did you see a trend of correlation between cell expansion and antileukemic activity?

Yes. So as you can see in the FCA arm, we saw a significant higher expansion, about a tenfold higher expansion than FCA. And so this is where we saw our most significant responders was in the FCA arm. And we did see obviously also some blast reduction to day 14 in other patients in FC. But as we pointed out and from the curve, there were some that also had early relapse, and this is why, based on all this data, why we are bringing forward the 2-dose regimen to give us an extra later boost of clinical expansion and clinical activity to help with the response.

So our next question comes from Ben [indiscernible] from Baird.

We have 2. First off, I would love to hear any additional information you could provide on the dose of alemtuzumab that was used in the study as part of the FCA?

Thank you, Ben. Mark, over to you.

Yes. For the AML study, the dose was selected just based on the fact that with AML is different from the lymphoid studies. We didn't think we needed as much alemtuzumab for the myeloid disease for several reasons, but the one being that there is no CD52 expression on myeloid leukemia. So all of the alemtuzumab would be active against the host T cells and K cells. Secondly, that in terms of we wanted to keep the cyclophosphamide dose higher because of the antileukemic activity of cyclophosphamide in AML, and therefore, we wanted to help minimize the potential infectious complication if there would be any infectious complications from adding alemtuzumab to the regimen. So we wanted to use enough that we could sustain lymphodepletion throughout the DLT period but not too much that would cause more problems.

Understood. And then if you look ahead and plan to do the consolidation dosing, how did you decide on the 10- to 14-day window for the second dose? There's others out there that I believe used 28 days in 3 doses. So what drove you to use a shorter window? And is there any risk for toxicity surrounding 2 doses of CAR-T in such rapid succession.

So yes. So the reason why we're doing this is importantly that by doing this within the DLT period. So we know that we can get lymphodepletion out past 28 days. And that return of the host lymphocytes is what will prevent our UCART123 expansion as obviously was shown in the FC patients, where we saw rapid recovery between day 10 and day 20 in terms of the lymphocytes. So it enabled us to bring this window in 10 to 14 days, what we've seen is most of the CRS or those complications are actually resolved or resolving in that by day 14 window, number one, so that they wouldn't really overlap toxicities because what would be seen from the first cell dosing would not be seen when the second cell dose is administered. The second reason and probably more important is the fact that by doing this within the DLT period, we do not need to use additional lymphodepletion. And as you know, after day 28, it's everyone that does this uses additional lymphodepletion. This is one of the things that the investigators also were very keen on because of the fact that by adding this additional lymphodepletion prior to the second dose, it would potentially exacerbate or cause more infectious or bleeding complications in this patient population. And so those are the reasons for doing it in that window. The last reason is also that by giving that second window there, we're actually going after a residual disease component that was reduced by day 14 with the first cell dose. And therefore, by putting the second expansion in there, we're allowing for much further disease reduction and hopefully increasing our response rates and not causing putting the patients at risk for further complications due to a potential second dose of lymphodepletion.

Our next question comes from Ashiq Mubarack from Citi.

This is Ashiq Mubarack on for Yigal Nochomovitz at Citi. We had just 2. We wanted to ask about how much further you believe you can push the dose for both 123 and 22? And maybe how close you are to what you consider the sort of maximum range? And then the second part of my question is that I think many of us are familiar with CRS with cell therapies in areas like lymphoma, multiple myeloma, but maybe less so with AML. And I know, of course, by definition, these patients are very aggressive and very sick. So we're just wondering if you can comment generally on the capacity for these patients to even tolerate maybe a low bridge CRS relative to those other tumor types?

Thank you, Ashiq. These are both great questions, and I'll pass it to Mark to answer both.

Okay. Yes. Thank you for the questions. I think we'll start with the first one in terms of the dose. I think where we're at right now with 123, as we said, we are beginning a new treatment regimen. So we're just starting with first patient with a 2-dose regimen with UCART123. So we are beginning at 6.25 x 10 to the 5th. And as you saw, I mean, this was a dose that was shown to be effective. We have the long-term responder out over 1 year in an MRD-negative state from this. So we know it can be an effective regimen. So we have to see how this 2-dose regimen is tolerated and look at what we're seeing in efficacy, but there is a potential to dose escalate after that. But I think we are operating in an area where it is, we're at a good dose right now. But again, we need to see what happens as we move forward if we escalate or not. For 22, I think the same issue, I think we [indiscernible] there's no further escalation planned for the P1 product. You saw the patients at dose level 3 with a 60% overall response rate. As we're bringing the P2 product or wholly made Cellectis product in to the clinic now because of the data that was seen in vitro in terms of showing that being significantly more potent, we did drop that down to 1 million cells per kilogram at dose level 2. And again, to your question, I mean, it requires to see what happens as we dose these patients. Again, 1 million cells per kilo has been shown to be an effective dose in the autologous 22 trials that are out there. So we could very well be at a good dose with the P2 product as well. So it remains to be seen, but we're operating in areas where we have seen responses at equivalent dose levels. In terms of your second question, in terms of CRS. So AML patients are incredibly more fragile than some of the NHL patients and even some of the ALL patients that have been treated with CAR-T therapies. To that point, though, they do tolerate mild to moderate CRS usually without pretty very well. I mean we aggressively treat the situation. The investigators are all aggressively treating with tocilizumab. There's bringing in early use of dexamethasone, if needed, et cetera. But there have been, like I said, 100% of the patients in the 123 study did have some level of CRS and the ones with grade 1, grade 2 CRS tolerated very well.

Our next question comes from Shrunatra Mishra from Goldman Sachs.

Congratulations on the data. I am Shrunatra on for Salveen. I have 2 questions. The first is on UCART22. Is there a subset of patients that are responding better to UCART22 compared to the rest? And the second on 123, were there any specific features about the one patient that was MRD-negative that contributed to response?

Thank you, Shrunatra, for your questions. And I think these would be both addressed by Mark.

Yes. Thanks for the question. So to address the 22, so in terms of moving forward, I think the UCART22 will be the first allogeneic CAR-T cell product to be used in ALL as we move forward. And so I believe there is a role for that in terms of obviously treating patients that can't receive autologous product either because they either can't get a spot or can't be mobilized, et cetera. So I think that will play in. I think to your point in terms of responders that how we could assess them, these patients that we're showing you for dose level 3, they really have failed everything. The responders all failed allogeneic stem cell transplant. They all failed autologous CD19, 2 of them failed venetoclax-based regimens. And one of them failed blinatumomab as well as inotuzumab, and they all had significant long-term responses. So I think this is broadly applicable in terms of these patients have failed everything. So in terms of responding. And I'm sorry, the second follow-up regarding the of the 123 patient. So in assessing the 123 patient, long-term responder, the fact that there's really, we're looking into potential other reasons at sort of the molecular and protein level, if there's anything we can identify. I don't have that information to share. But looking at either what they received prior or certain genetic mutations or anything, there's really nothing that we can call out about that patient that was different than the others. I'm sorry can you guys still hear me?

I hear you, Mark.

Our next question comes from Luisa Morgado from Kempen. Luisa, you might be on mute. So we'll just go to the next question while Luisa figures out her audio. Our next question comes from David Dai from SMBC.

I have about 2 questions, actually. One is just around the CRS events, the grade 5 CRS events we've seen. Could you talk a little more about the 2 deaths. What are their cytogenetic profiles? And were there any kind of blast reductions before their death?

Thank you, David. Mark, over to you as well.

Yes. Thank you for the question. In terms of the grade 5 CRS is, unfortunately, I don't have the data with me about the cytogenetics for those patients, but we can certainly get that to you. In terms of blast reduction, again, there was the effect of the lymphodepletion in terms of reducing the disease burden and blast reduction. The CRS events in these patients, as you know, happen very early in the treatment period within the first week. And so that was before they had their day 14 bone marrow. So in terms of getting any kind of extensive bone marrow analysis that was not able to be done for these 2 patients. But peripherally, their disease burden was minimized by the lymphodepletion regimen and was followed peripherally. So I hope, does that answer your question?

Yes. Thanks, Mark. So next question just around your overall view of the manufacturing process for UCART123 and S1, is the long-term plan to bring those both UCART123 and S1 in-house?

So maybe, David, I think this one would be best answered by Andre.

Well, yes, thank you. So of course, the plan of Cellectis is to build everything in-house. And for numerous reasons, first of all, the control of the cost of goods. Second, when you start filing BLA, which we intend to do with these products is that like when you get started with a CMO, then you're locked to the CMO for the rest of the lifecycle management of the product plus you know that definition of a product for manufacturing, essentially defined by the process. So who owns the process owns a product. So we intend to own the product ourselves and we have everything internal, and it's extremely cost-effective. But beyond this, what we realized that the quality that is produced internally with Cellectis staff that is extremely motivated that knows very well the product and have been owning this process for more than 10 years now, gives product with uncomparable quality at the end and robustness that we hope to show you next year through UCART22 trial that is internally manufactured and UCART22. UCART123 will probably follow for this course because it's already programmed.

Our next question comes from Silvan Tuerkcan from JMP Securities.

Congratulations on all the data. I just have 2 quick questions. First, is there any effect of, I mean, you've talked about this initial cell dose on the efficacy UCART23 that you can already point to? Did you calculate, for example, the factor to target ratio of CAR-Ts per reduction in the small patient population? And then my second question is, if you could please talk to the exact commercial setting that you're envisioning here for UCART22, it seems like you are working towards a regimen here, conversation of speeding that up. So it would be great to hear your description about the future here.

Great. Thank you so much, Silvan, 2 interesting questions. I think let's start with Mark for the clinical question and then maybe Andre for the commercial question.

Okay. Great. Thank you for the question. Unfortunately, these are data that you're talking about that we are looking into. It's a great question, but I don't have the answer to give you definitively right now, but we can follow up with you later.

And for the commercial setting, yes, Cellectis is planning very soon to start some of the expansion that can be penetrable. So it depends on the patient population. For example, ALL is small population. It's also a niche because like there's a scarcity of patient, we're talking about like 6,000 to like 8,000 patients, either in like for in the U.S. and in Europe. It's something that could be definitely addressed by Cellectis. I think there is like a strong medical need in this field for ALL because all the approaches are essentially autologous therapies or what we showed, for example, the venetoclax or bispecific antibodies such as inotuzumab. And there's absolutely no allogeneic CAR-T. So if you want to treat these patients with allogeneic approach, then it's blank. And the only option could be potentially UCART22. So we're very excited by this product, and we think that an organization such as Cellectis, improving in the future could definitely implement this. For non-Hodgkin's lymphoma, and we think, for example, that UCART20/22, which is an exciting product also could potentially be done through a partnership because the population instead of like being 120,000 for the U.S., for example, that requires probably more logistics and preparation to launch a commercial product such as non-Hodgkin lymphoma, so that would make sense more in a partnership and finally, UCART123 sits between the 2, it's like between like the 10 to like 22,000, 25,000 patients either in the U.S. or in Europe. And there is also a strong unmet medical need. There is not that many allogeneic CAR-T, there is none out of allogeneic CAR T that are developed in the field of AML. And we believe that potentially, it's like if the company improves well to be able to launch this type of product either in the U.S. and in Europe or, for example, to make a partnership and try to make a deal that would be co-development or territorial development. So everything is still on the table today. We're thinking about the strategy for commercial. And of course, the pivotal trial can come very quickly in this space and we're excited about the future.

Our next question comes from Tiffany Marchell from William Blair.

Congrats on the data. I was wondering if you could comment at all on the durability of responses with UCART22. And if you guys saw any sort of loss of target expression in patients that relapsed or maybe low baseline expression in those that didn't respond.

Thank you, Tiffany, for the questions. I think both would be directed to Mark.

I guess I'll address the second part first. I mean as part of the inclusion criteria for the study, there has to be 70% expression of 22 in the patients prior to beginning lymphodepletion. What I can tell you is that at least, again, small numbers, but what has been seen so far is that there has not been a loss in CD22 expression. And then for your second question, the durability of response. So for these patients at dose level 3, again, these are, like we pointed out, I mean, the worst of the worst, they failed allo transplant, they failed prior autologous 19 and to achieve a 60% response rate in these patients that has been very durable. As you can see, 71 days, 117 days, et cetera, this is fantastic. So it's allowing them to some patients decide not to proceed with the second transplant, obviously. And so a durable response like this is amazing, given what they failed. So I think the durability that we've been seeing is quite good. It's very good. So I don't know if that answers your question.

Our next question comes from Yanan Zhu from Wells Fargo.

A couple on UCART123. How confident are you that the prophylactic tocilizumab could potentially help avoid grade 5 CRS? And then the second dose of UCART123, even in the absence of lymphodepletion do contribute to the occurrence of CRS or the severity of CRS?

Thank you, Yanan. These are 2 very interesting questions that are definitely for Mark.

Yes. Thank you. So in terms of the first question, using prophylactic tocilizumab. So yes, we believe based on the data that's out there in at least where it's been used in the NHL space. The use of prophylactic tocilizumab on the day of infusion has resulted in a decrease in the severity of CRS that was seen in those patients treated. In addition, they did show also that it did not affect the efficacy of the cell infusion. So we think that by incorporating the prophylactic tocilizumab that will have a positive effect on helping us control the CRS severity in these patients moving forward. In terms of your second question, the second dose of cells, one of the reasons to actually give it earlier on around day 14 or so is to give it in a setting where the disease burden is actually minimized. So these would be in a setting where the disease would be very, very low or just beginning to relapse after day 14. And so by giving that in that setting with minimal disease burden, we would expect to see also a decrease in the severity of potential CRS in that situation, particularly based on what's been seen in the literature for the other autologous CAR field particularly in ALL, where it was shown that the disease burden and CRS severity can correlate. So we expect to see much less severe CRS in the setting of a minimal disease burden.

Got it. That's very helpful. And then on UCART22, I was wondering if I can follow up with one of the prior questions about durability and perhaps to frame your question this way, but what kind of durability of response will support a viable product profile in this very refractory patient setting? And will this be mainly a bridge to transplant strategy?

Okay. And yes, the durability that's seen here is with these 3 patients at dose level 3 is we think is really is amazing in this patient population, given the fact of what these patients failed and how quickly they relapsed from their prior therapies. And it's certainly the durability is enough to allow for any further treatment decisions for the patient as they progress. And I will also point out that given what was presented yesterday at ASH in terms of the autologous 22, the durability for the allogeneic data here from BALLI is significantly longer than what was shown for the autologous product yesterday. Again, small numbers in apples and oranges, but still it's out there. So I think the durability is very impressive. It will allow for further clinical decisions. And I think, to your point, when patients are as highly as refractory as these patients were failing transplant, failing prior auto 19 with essentially no other treatment options, yes, transitioning as a bridge to a second transplant is always an option. And it's obviously, it's a patient decision or a personal decision and the patient whether they undergo a second transplant. But yes, it could be this, the durability could clearly allow for that to happen, yes.

And to look up on your question of, if we think that this rate of response is enough to get a product into expansion [indiscernible] we think that like hitting a 60% today was like with P1, so like the first manufactured product is definitely a good threshold to push the product further into a potential BLA. But the second thing is that if we have to wait to the data of P2, I just definitely like to invite you for the next update on BALLI-01 for P2 because if we get a recommended Phase 2 dose for the product that has been manufactured in-house that would definitely push us into an expansion and a registrational trial if the response rate remained similar or if not better because the product is the higher quality, we believe. And that is a product that we believe is already within the range of something that could definitely hit the market. It's the only allogeneic CAR-T that is currently developed for ALL.

Our next question comes from Luisa Morgado from Kempen. Luisa, you might be on mute. Right, so we'll go to the next question. Our next question is from Ingrid Gafanhao from Bryan Garnier.

I have a couple of similar questions to what we had before, but this time for UCART123. So if I understand correctly, AML can be a little bit elusive in terms of targeting. So for UCART123, was the expression anyhow related to the expression of CD123 at baseline? And just a follow-up on that. Have you had a chance to look at what happened to CD123 after you gave the patients of first dose?

Thank you, Ingrid, for the questions. And Mark, over to you.

Yes. Thank you for those. So actually for the entry criteria into the study, they just have to be CD123 positive by their local flow cytometry laboratory assessment at the sites. At the current time, we're not indicating a particular percentage cutoff for enrollment into the study. And to that point, we're also in the process of determining and looking at some of the data to see if there is a correlation or not. So I don't have an answer for you right now, but it is something that we are working on. And I'm sorry, I missed the second part of your question.

Yes. I was curious. I will change that a little bit. So I was curious to hear, are you going to look at the expression of CD123 again before you give them the second dose?

So there won't be a decision point based on 123 because biologically, it's probably unlikely that the expression pattern will change in a period of 7 to 10 days. But the peripheral blood is obviously being followed for disease, which will also encompass 123 by flow cytometry when we're looking at their peripheral blood. So there will be some measurement of that, yes.

Thank you, Ingrid. This concludes the verbal portion of our Q&A session. I'll now turn it over to Arthur Stril of Cellectis to read the remainder of the questions.

Thank you, Tara. And I think given time, we'll have time to read one more question from the chat. So we have a 2-part question from Gena Wang from Barclays. So congrats on the progress. For UCART123, do you have a cutoff for your CD123 expression at baseline for enrollment? What could be the reason for lack of response in patients 115 233 and 104 218 despite having roughly 2x duration of cell expansion and the patient with complete response. And I think that's definitely a question for Mark.

Okay. Thanks, Gena, for the questions. I think for the first question to answer your question, there is no cutoff for expression level that we have currently in the study for 123. They just have to be 123 positive by the site's local hematopathology flow analysis. And Arthur, I'm sorry, the second question again for the patients.

Yes. So about the 2 patients, 115 233 and 104 218 that had a lack of response despite having 2x duration of cell expansion versus a patient with complete response, if there's a rationale for that.

I have to look at that more closely, but I know for patient 115 233, they had a very hyperproliferative leukemia. And so while there was some level of detection of blast reduction, it was just very hyperproliferative and relapsed very, very quickly. And in fact, that patient was the one patient in the FCA cohort that recovered their lymphocytes before day 28 secondary to a very proliferative relapse in their disease very quickly. The other patient we'll have to look at and get back to you.

And the second question from Gena is what would be equivalent doses of the 1 million cells per kg P2 product and P1 product based on preclinical characterization. So maybe I'll take that question. I think it's always difficult to fully translate what is going to happen in the clinic. But basically, we have designed the P2 part of the BALLI-01 study at DL2, given the improved potency that we're seeing with the internal manufactured products. And I think to fully get the answer to that, we welcome you to come to our 2023 update where we will present data with the P2 products. So I think this concludes the written part of the Q&A and in the interest of time, and I will hand it over to Andre for concluding remarks.

Well, thank you very much, Arthur. And special thanks to everyone that connected to this webcast this morning. We were extremely excited and happy to share this data with you this morning. And 2022 has been a very productive year for Cellectis on all fronts in the front of manufacturing and in the front of the clinical side. There is plenty of things that are happening currently in the company. And we believe that 2023 is going to be very event-rich year for Cellectis. Of course, we've [indiscernible] like 4 trials that are moving forward. We're excited to share with you data of P2 for UCART22 because the internally made process is definitely very differentiated. Same thing for 20/22 that has been manufactured internally. It's something that's very exciting for us, non-Hodgkin lymphoma, non-CD19 product and we started like, of course, we're starting enrollment. And finally, there is also very much of excitement for the company for UCART123, double dose and that we believe is something that is going to change the trend in the AML for AML. And of course, like UCARTCS1 that's enrolling currently at DL1. And so 2023, you will be very regularly updated on Cellectis clinical trials, but also on the older progress of the company, the company is entering into a very interesting phase. And definitely, thank you very much for following Cellectis. Thank you.