Good morning, welcome to the Cellectis Clinical Update. At this time, all attendees are in a listen only mode. A question and answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player, or by emailing your questions to questions@lifesciadvisors.com. 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 André Choulika, Chief Executive Officer of Cellectis. Please go ahead, André.
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 updates on our AMELI-01 trial, UCART123, including and our BALLI-01 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 and the disclaimer. Thank you. A quick overview of Cellectis. Cellectis at a glance gives you a quick idea of what we are at.
Cellectis have four 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. It's an end-to-end manufacturing. I'll go more and deeply into this in a few slides at the end of the slideshow, and I'll give you some idea of how this works. We have number of near-term catalyst, 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 to which is expected to take us in a runway into 2024.
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? What's all about the invention that Cellectis rolled 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 costs with hundreds of doses that are done per batch when you do an allogeneic CAR T.
It's very robust, our target in our manufacturing, our process development is robustness. The goal is to provide potency and consistency to each patient. Each patient get the same chance when he gets a product. One of the big achievement 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. Finally, of course, there is the market access potential for Cellectis, which is the, it's a product that is off-the-shelf, so it's immediately available and eligible for patients. 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. For the next slide, please. That's the platform of Cellectis.
It gives you an idea 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. Most of the product is based on the same platform, which is a TRAC knockout, with reduced risk of GvHD. There is a CD52 knockout, which gives the CAR T a resistance to alemtuzumab. Most of the products 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. There is no CD52 knockout in the CS1 CAR T. Then on the right side, you see what we add as CAR inside.
There is like, for example, going from bottom to the top, UCARTCS1, as a CAR T, UCART123, UCART22, last but not least, CAR-20 plus CAR-22, which is the first dual allogeneic CAR that is entering the clinic today. Now I would like to pass it to Mark Frattini, our CSO. Our CMO, sorry. Mark?
Hi, André. Thanks very much. I'm gonna begin with the updates for AMELI-01 for UCART123.
This was presented yesterday afternoon in an oral presentation at ASH. 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. AML, it's estimated that there'll be up to over 20,000 new cases that occur in 2022. Sadly, over half of those cases, over 11,000 cases will result in death. The outcomes for patients with relapsed refractory AML 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.
The AMELI-01 study that's being presented is an 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. As André just showed you the schematic of the product that's seen here. CD123 is a validated therapeutic target in AML. Genetically, 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. 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, relapse refractory disease. There had to be Grade 5% or greater bone marrow blast. 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. For the FC regimen, standard doses of fludarabine at 330 milligrams per meter squared for four days. Cyclophosphamide was used at 750 milligrams per meter squared for three days.
For the FCA regimen, alemtuzumab was added to this at 12 milligrams per day for four 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 times 10^5 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 times 10^5. The FC arm did continue enrollment up through one patient at Dose Level 3. The FCA arm continued enrollment through 1 patient at Dose Level 2 .
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 one for almost all of the patients, 94%. Importantly, this was a very heavily pretreated and very high risk group of patients. The 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 four, but the range was three, up to nine prior lines of therapy. Importantly, 50% of these patients failed prior allogeneic stem cell transplant.
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, the slide is outlined into the FC arm, the FCA arm, and then a total arm on the far right, column in the far right. 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, in 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 two Grade 4 events in the FC arm, and there were two Grade 5 events in the FCA arm. In terms of ICANS, there was only one case of ICANS in each arm, one Grade 3 in FC and 1 Grade 2 in FCA. In 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. 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. It shows that 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. 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.
In looking at the anti-leukemic activity, it was observed in four out of 17 patients. We'll start with the FC arm up top. 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 thus 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 two patients that had significant responses. One patient, they had a 90% blast reduction. Clearance by day 14, and 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. 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 an MRD negative CR. I'll speak more about this patient in a few slides. In 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.
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. 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. Looking at the top curve on the left, in the FC arm, you can see that there are about three patients that showed some level of UCART expansion.
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. This was approximately nine-fold higher level of expansion than what was seen in the FCA, in the FC arm. 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. With FC, the area under the curve was, 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. 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, IFN-gamma, and TNF-alpha all represent that these curves very much mimic and mirror the curves for UCART expansion. At the time of expansion, we'll see increases in the cytokine secretion. This is common throughout all the patients that we've seen expansion in and there, 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. Importantly, the ferritin again mirrors the expansion seen by VCN of UCART123.
I'll just point out that the patient in the middle, at the bottom, 226, is our long-term responder. As you can see, there's a very, the peak of VCN and the peak of ferritin, coincide, are together, mirror each other. Now, again, looking closer at patient 226 who achieved a durable MRD negative CR. This was a 64-year-old female that had adverse risk AML, relapse refractory AML with MDS-related changes, high risk cytogenetic mutations with a - 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 biopsies. Starting with screening at day -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 a CRI. Subsequently, this became an MRD negative CR at day 56, and this response continues now out past one year. She was seen the end of November for her one-year visit and remains in an MRD negative CR state now after one year, which is incredible given that this patient had Grade 4 cytopenias going into the study and had been refractory to these five 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. 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 the UCART123 by VCN. As a result of what we've shown, and I, and I'll just review briefly. 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 was a narrow peak of expansion of UCART cells over a period of a few days. As a result, some of these patients were then seen to subsequently re-relapse by day 28.
Indicating that there is a, there was the reduction in tumor burden, but it was not enough to sustain anti-leukemic activity for these patients. By bringing in a 2nd 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 10-14 day period. 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. By doing it this way, we're able to give two doses of cells, get two peaks of activity with one lymphodepletion regimen.
Ideally, this 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. As a result of this, the two-dose regimen will initiate at Dose Level 2, and this is a dose at 6.25 times 10^5 cells per kilo that has already been administered to eight patients in the FCA cohort has been cleared by the DSMB as a single dose. 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. Now the amended protocol with the two-dose regimen is outlined on this slide.
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. The two-dose regimen arm is now open at DL-2 times two doses. That's 6.25 times 10^5 . In conclusion, for 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 one patient at dose level two 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.
The one patient, the long-term responder, who has a long-term MRD-negative CR now past 12 months. Overall, the data support further study for UCART123 after FCA lymphodepletion in patients with relapsed/refractory AML. Based on what we've shown in terms of the expression, the expansion patterns, the cytokine profiles, and the responses, the study is now enrolling in the FCA two-dose regimen arm. Again, we're employing a prophylactic tocilizumab dose prior to each cell infusion. I'll move now to the BALLI-01 study, UCART22. Just so that, as a reminder, this is our Phase I/II A 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.
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 in 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 122 blast expression greater than 20%, 70%, and relapse 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.
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 five 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, 1 gram per meter. With alemtuzumab, the cyclophosphamide dosing was reduced to 500 milligrams per meter squared, with the addition of alemtuzumab, 20 milligrams a day for three 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. I'll proceed with a review of the data that was originally presented at ASH last year. This was looking at up to 12 patients that were dosed with UCART22. This showed a very promising safety profile. Again, the median age 30, with a high risk, again, patients that were very refractory. 60% with BALL with recurrent genetic abnormalities and a third of the patients with the Ph-like mutation CRLF2. In terms of median lines of therapy were three, but up to six were seen. These patients, the majority, almost three-quarters, 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 two to four. Looking at the safety, there were no DLTs seen to date, no ICANS seen to date. There were no UCART22 severe-related TAEs. Three patients had CRS, but these were mild cases of CRS, with two being Grade 1 and one being Grade 2. They're responding quickly and resolving with either no therapy or in the case of Grade 2, a dose of tocilizumab. Finally, there was one patient that did have an investigator-assessed graft versus host disease in the skin.
Importantly, several things. This was not confirmed by biopsy, but however, this patient did receive and fail a prior allogeneic stem cell transplant. What was shown both in the peripheral blood and 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 and the marrow and likely mediated the graft versus host disease that was seen. Now I'm gonna show you the patients that responded that were treated with Dose Level 3. This was 5 million cells per kilogram. We dosed five patients with FCA lymphodepletion, and these are the responders. Patient 1 was a 34-year-old male.
As you can see, heavily pre-treated, 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.
A long-term MRD negative CRI. They have gone on to receive a DLI from their prior allo transplant donor. 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 an MRD negative state at this point in time after seven months. Patient two, a young female, 24. Again, very high risk. Failed, as you can see by the cytogenetics with inversion three, inversion 11, additional cytogenetic abnormalities. Received high-dose chemotherapy for induction, 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 an allogeneic stem cell transplant, which she relapsed from as well. Failing both an allo transplant 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. They are currently out over at day 117 today in an MLFS without receiving further therapy at this time.
The third responder out of the five patients was a 57-year-old male, who again received multiple prior lines of therapy. This patient's prior therapy included blinatumomab, a allogeneic stem cell transplant. Autologous CD19 CAR T cells and inotuzumab ozogamicin, the CD22-targeted ADC. This patient failed all four of those in addition to chemotherapy. Had one day of Grade 1 CRS at day 8, for which they received a dose of tocilizumab. Otherwise, no ICANS, no HLH. This patient has achieved an MRD negative, full MRD negative CR. They are currently at day 71 and continue without having any interval therapy after the UCART22 cells. A summary of the UCART123-- UCART22 DL3 data that I've shown you.
There were five subjects that were dosed at Dose Level 3 with the P1 product at 5 x 10^6 cells per kilo. Again, this was the product that was made by the CMO, this was using FCA lymphodepletion. No safety issues, no Grade 2 or higher CRS in any of these five patients that were treated. Out of the five, we had a three out of five clinical responses for a 60% overall response rate in this very heavily pre-treated, high risk patient population that failed. All of these patients, again, failed both an allogeneic stem cell transplant and autologous CD19 CAR T cells. We saw 1 MRD negative CR, an MRD negative CRI, and an MLFS.
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 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 in vitro 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. Just to summarize the two studies today.
For what I've, 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 significantly higher UCART123 cell expansion, and this correlated with improved clinical activity with one patient, obviously a long-term MRD negative CR now out past one year. The study is currently enrolling patients in the FCA lymphodepletion. We're using FCA lymphodepletion in a two-dose regimen arm beginning at 6.25 times 10 ^5 cells per kilo per dose. In addition, we're also using prophylactic tocilizumab prior to each cell dosing to help mitigate any severity of potential CRS.
For BALLI-01 or UCART22, I've shared with you the new data from the five patients that were treated at DL 3 of which had a clinical response for a 60% overall response rate. Those clinical responses in this heavily pre-treated, high-risk patients that again failed both allotransplant and prior CD19 auto CAR, all three of them, with 1 of them also failing additional Blinatumomab and Inotuzumab, for a full MRD negative CR, MRD negative CRI and an MLFS. These have been long-term responses, as you can see. Finally, that we are bringing, UCART22 Process 2 or P2, which is 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 André to talk about the manufacturing.
Thank you very much, Mark. Very quick overview of how the company functions. We have a New York facility that are essentially labs where we have all our payload gene editing platform. That's where the things start, where we have all our discovery, where the new CAR T are imagined and built. Once they're built, they're sent to Paris, and they function, of course, like they're 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. Once the the the the process is stabilized and we have all the analytics around the process, because you have to measure the products, then we make the raw materials, the buffers, the plasmid DNAs, messenger RNA.
We do AAVs, we do LVVs, and all these raw materials are sent to New York, you know, 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, cryogenic storage. This facility is ready, of course, for clinical supplies, making all these IMPs, such as P2 or UCART20x22. Also we have all the logistics to send them that is currently set at Raleigh. Once this is done, then it's looped up back to New York, where we have our clinical development team that conducts, of course, all the clinical operations and clinical science inside 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 will definitely give the rhythm for year 2023. We have four 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. 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 two-dose regimen for UCART123 at 6.5 then to the 5th cells per kg. We're also excited for the Dose Level 1 for UCARTCS1 in multiple myeloma. Last but not least, we're starting enrollment for UCART20x22 with the first dual allogeneic CAR T.
It's a non-CD19 CAR T for non-Hodgkin lymphoma, and the first in human data for this CAR T that has been totally made inside Cellectis, so top quality, of course. We're looking forward to present you, such a rich year for 2023 will be written by all these four 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.
Great. Thank you, André. At this time, we'll be conducting a question and answer session with our speakers. As a reminder, if you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. Our first question comes from Sean Tan from Jefferies. Please go ahead, Sean.
Hi, this is Sean Tan on for Kelly Shi. Thanks for taking our question. I have a two-part question for you, UCART123. Firstly, did you see a trend of correlation between cell expansion and anti-leukemic activity? My second question is, which two of the patients had the Grade 5 CRS , and can you remind us of the onset and duration of the event? Thank you.
Hi, Sean. Thank you so much for the questions. I think both would be for Mark.
Thank you. Thanks, and thanks for the question. In terms of the in 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 one patient at dose level 2 in fca, and 1 patient at Dose Level 2 high in fca. 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 anti-leukemic activity?
Yeah. As you can see in the FCA arm, we saw a significant higher expansion, about a 10-fold higher expansion than FCA. We did see, you know, this is where we saw our long, our most significant responders was in the FCA arm. We did see obviously also some blast reduction to day 14 in other patients in FC. As you know, as we pointed out and from the curve, those, there were some that also had early relapse. This is why, based on all this data, why we are bringing forward the two-dose regimen to give us an extra, an extra later boost of expansion and clinical activity to help with the response.
Okay. Thank you.
Thank you for the question, Sean. Our next question comes from Ben Paluch from Baird. Please go ahead, Ben.
Hello. Thank you for taking the questions. We have two. First off, would love to hear any additional information you could provide on the dose of alemtuzumab that was used in the study as part of FCA.
Thank you, Ben. Mark, over to you.
Yeah. For the AML study, the dose was selected just based on the fact that with, you know, 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 the alemtuzumab would be active against the host T cells and K cells. Secondly, in terms of, we wanted to keep the cyclophosphamide dose higher because of the anti-leukemic activity of cyclophosphamide in AML. Therefore, we wanted to minimize any potential, help minimize the potential infectious complication if there would be any infectious complications from adding alemtuzumab to the regimen.
We wanted to use enough that we could sustain lymphodepletion throughout the DLT period, but not too much that would cause more problems.
Understood. Thank you for that. As you look forward, or excuse me, as you look ahead and plan to do the consolidation dosing, how did you decide on the 10-14 day window for the second dose? There's others out there that I believe use 28 days between doses. Which role do you to use a shorter window, and is there any risk for toxicity surrounding giving two doses of CAR T in such rapid succession?
Thanks for that. Yeah. The reason why we're doing this is importantly that by doing this within the DLT period, we know that we can get lymphodepletion out past day 28. That return of the host lymphocytes is what will, you know, 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. It enabled us to bring this window in 10-14 days.
What we've seen is most of the CRS, or those complications are actually, you know, resolved or resolving 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. 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. 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. Therefore, by putting this second expansion in there, we're allowing for further, 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.
Appreciate that very much. Thank you. All set.
Thanks for the questions, Ben. Our next question comes from Aashiq Mubarak from Citi. Please go ahead, Aashiq.
Hi, team. Thanks. This is Aashiq Mubarak at Citi. Thanks very much for taking my questions. We had just two. 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 would consider the sort of maximum range. The second part of my question is that I think many of us are familiar with CRS, with cell therapies in areas like lymphoma and multiple myeloma, but maybe less so with AML. AML, of course, by definition, these patients are very aggressive and very sick. We're just wondering if you can comment generally on the capacity for these patients to even tolerate maybe a low-grade CRS relative to those other tumor types. Thanks.
Thank you, Aashiq. These are both great questions. I'll pass it to Mark to answer both.
Okay. Yeah. Thank you for the questions. I think let's start with the first one in terms of the dose. I think you know where we're at, right now with UCART123, as we said, we are beginning a new treatment regimen, so we're just starting with first patient with a two-dose regimen, with UCART123. We are beginning at 6.25 times 10 ^5 . As you saw, I mean, this was a dose that was shown to be effective. We have the long-term responder out over one year in an MRD-negative state from this. We know it's can be an effective regimen. We have to see how this double dose regimen is this two-dose regimen is tolerated and look at what we're seeing in efficacy.
There is a potential to dose escalate after that. 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. 22, I think the same issue, I think there's no further escalation planned for the DL1, the P1 product. You saw the patients at Dose Level 3 with the 60% overall response rate. There, as we're bringing the P2 product or wholly made at Cellectis product into the clinic now because of the data that was seen in vitro in terms of showing it being significantly more potent, we did drop that down to 1 million cells per kilogram at Dose Level 2.
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. We could very well be at a good dose with the P2 product as well. 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, 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 a pretty very well. I mean, the, you know, we aggressively treat this situation. The investigators are all aggressively treating with tocilizumab. There's early, you know, bringing in early use of dexamethasone if needed, et cetera. There have been, you know, 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.
Great. Thanks for all the color.
Thank you for the questions. Our next question comes from Shunrata Mishra from Goldman Sachs. Please go ahead, Shunrata.
Hello, team. Congratulations on the data. I'm Shunrata on for Salveen. I have two questions. The first is on UCART22. Is there a subset of patients that are responding better to UCART22 compared to the rest? The second on UCART123, were there any specific features about the 1 patient that was MRD negative that contributed to this response? Thank you.
Thank you, Shunrata, for your questions. I think these would be both addressed by Mark.
Yes, thanks for the question. For to address the 22, in terms of moving forward, I think, you know, this, the UCART22 will be the first allogeneic CAR T-cell product to be used in ALL as we move forward. You know, so I believe there's 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. I think that's, you know, that will play in. I think to your point in terms of responders that, how we could, you know, assess them, these patients that we're showing you for Dose Level 3, they really have failed everything. They failed everyone. The responders all failed allogeneic stem cell transplant.
They all failed autologous CD19. You know, two of them failed venetoclax-based regimens, and one of them failed blinatumomab as well as inotuzumab. They all had significant longer and long-term responses. I think this is broadly applicable in terms of patients who have, you know, these patients have failed everything, so in terms of responding. I'm sorry, the second follow-up? The second follow-up regarding the 123 patient. In assessing the 123 patient, the long-term responder, the fact that 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.
Looking at either, you know, 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, again, Can you guys still hear me?
I hear you, Mark.
Yes, we can. Shunrata, any other questions?
No, that's it. Thank you so much.
Okay, great. Thank you. Our next question comes from Luisa Morgado from Kempen. Please go ahead, Luisa. Luisa, you might be on mute. We'll just go to the next question while Luisa figures out her audio. Our next question comes from David Dai from SMBC. Please go ahead, David.
Sure. Thanks for taking my questions. couple of two questions, actually. One is just around the CRS events, the grade five CRS events we've seen. Can you tell me more about the two 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.
Yeah, 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, in these patients, as you know, happened very early in the treatment period, you know, within the first week. That was before they had in their day 14 bone marrow. In terms of getting any kind of extensive bone marrow analysis, that was not able to be done for these two patients.
Peripherally, their disease burden was minimized by the lymphodepletion regimen and was followed peripherally. I hope... Does that answer your question?
Yeah. Thanks, Mark. next question just around the, your overall view of the manufacturing process for UCART20x22 and CS1. Is the long-term plan to bring those, both UCART20x22 and CS1 in-house?
Maybe, David, I think this one would be best answered by, André.
Well, yes. Thank you. 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 start off with a CMO, then you're locked with the CMO for the rest of the cycle lifecycle management of the product. Plus, you know that the definition of a product for manufacturing essentially defined by the process. Who owns the process owns the product. We intend to own the product ourselves, and we have everything internal, and it's extremely cost effective.
Beyond this, what we realized that the quality that is produced internally with Cellectis staff that is extremely motivated and knows very well the product, and they've been owning these products for more than 10 years now, gives product with incomparable quality at the end and robustness that we hope to show you next year through UCART22 trial that is internally manufactured and UCART20x22. It's UCART22, sorry, UCART20x22 will probably follow for this course because it's already programmed.
Got it. Great. Thank you so much for the color.
Thanks.
Thanks for the questions, David. Our next question comes from Silvan Tuerkcan from JMP Securities. Please go ahead, Silvan.
Hey, good morning. Congratulations on all the data, and thanks for taking my question. I just have two quick questions. First, is there any effect of, I mean, you've talked about this initial cell dose, on the efficacy of UCART123 that you can already point to. Did you calculate, for example, the effect, effector to target ratio of, you know, CAR Ts per reduction in the small patient population? My second question is, if you could please talk to the exact commercial setting that you're envisioning here for UCART22. Seems like you are working towards a regimen here. Congratulations on speeding that up. It would be great to hear your description about, you know, the future here. Thank you.
Great. Thank you so much, Silvan. Two interesting questions. I think let's start with Mark for the clinical question and then maybe André for the commercial question.
Okay. Great. Thank you for the question. Unfortunately for at least for the, these are data that you're talking about that you know, 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.
For the commercial setting, yes, Cellectis is planning very soon to start some of the expansion that can be transferable. It depends on the patient population. For example, ALL is a small population. It's also a niche. Because, like, there's a scarcity of patients, we're talking about, like, 6,000 to, like, 8,000 patients if they're in for in the US 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, you know, talquetamab. There's absolutely no allogeneic CAR T. If you want to treat these patients with an allogeneic approach, then it's blank.
The only option could be potentially UCART22. We're very excited by this product, and we think that an organization such as Cellectis, improving the future, could definitely implement this. For non-Hodgkin lymphoma, we think, for example, that UCART20x22, which is an exciting product also, could potentially be done through a partnership because the population, instead of like being 6,000, it's 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. That would make sense more in a partnership. Finally, UCART123, you know, sits between the two. It's like between two, like the 10 to like 22,000-25,000 patients, either in the U.S. or in Europe.
There is also a strong unmet medical need. There is not that many allogeneic CAR T. There is none of allogeneic CAR T that are developed in the field of AML. We believe that potentially Cellectis 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 a co-development or territorial development. Everything is still on the table today. We're thinking about the strategy for commercial, and of course, the pivotal trials can come very quickly in this space. We're excited about the future.
Thank you.
Thank you, Silvan. Our next question comes from Tiffany Marchell from William Blair. Please go ahead, Tiffany.
Hi. Thanks for taking our question, and congrats on the data. I was wondering if you could comment at all on the durability of responses with UCART22. 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. Thanks.
Thank you, Tiffany, for the questions. I think both would be directed to Mark.
Thanks, Tiffany Marchell, for the question. For the, I guess I'll address the second part first. I mean, as part of the inclusion criteria for this study, there has to be 70% expression of CD22 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. For your second question, the durability of response. For these patients at Dose Level 3, again, you know, these are, like we pointed out, I mean, the worst of the worst. They failed allo transplant. They failed prior autologous CD19.
to achieve a 60% response rate in these patients that has been, you know, very durable, as you can see, 71 days, 117 days, et cetera, this is, you know, this is fantastic. It's allowing them to, you know, some patients decide not to proceed with a second transplant, obviously. A durable response like this is amazing, given what they failed. I think the durability that we've been seeing is, you know, is quite good. It's very good. I don't know if that answers your question.
Yeah, that's great. Thank you.
Thank you for the question, Tiffany. Our next question comes from Yanan Zhu from Wells Fargo. Please go ahead, Yanan.
Thanks. Thanks for taking my questions. A couple on UCART123. How confident are you that the prophylactic tocilizumab could potentially help avoid a Grade 5 CRS? Then could the second dose of UCART123, even in the absence of lymphodepletion, still contribute to the occurrence of CRS or the severity of CRS? Thanks.
Thank you, Yanan. These are, two, very interesting questions, that are definitely for Mark.
Yeah. Thank you. In terms of the first question, using prophylactic tocilizumab. Yes, we, you know, 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. We think that by incorporating the prophylactic tocilizumab, that it 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, you know, one of the reasons to actually give it earlier on, you know, around day 14 or so, is to give it in a setting where the disease burden is actually minimized. These would be in a setting where the disease would be very, very low or just beginning to relapse after day 14. 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.
We expect to see much less severe CRS in the setting of a minimal disease burden.
Got it. Thank you. That's very helpful. Then on UCART22, I was wondering if I can follow up with one of the prior question about durability and perhaps frame the question this way. What kind of durability of response will support a viable product profile in this very refractory patient setting? Will this be mainly a bridge to transplant strategy? Thanks.
Okay. Thank you. Thank you for that. Yes, the durability that's seen here is with these three patients at Dose Level 3 is, you know, we think is really amazing in this patient population, given the fact of what these patients failed and how quickly they relapsed from their prior therapies. Certainly, the durability is enough to allow for any further treatment decisions for the patient as they progress. You know, I will also point out that given the, you know, what was presented yesterday at ASH in terms of the autologous 22, the durability for the allogeneic data here from BALLI-01 is significantly longer than what was shown for the autologous product yesterday.
Again, small numbers and apples and oranges, but still it's out there. I think the durability is very impressive. It will allow for further clinical decisions. I think to your point, when patients are as highly as refractory as these patients were, failing transplant, failing prior auto CD19 with essentially no other treatment options, yes, transitioning as a bridge to a second transplant, is always a, is always an option. It's obviously it's a, it's a patient decision and a personal decision on the patient whether they undergo a second transplant. But yes, it could be, the durability could clearly allow for that to happen, yes.
To loop up on your question of the if we think that this rate of response is enough to get a product into expansion in people, we think that, like, yeah, hitting a 60% today was like with P1. Like the first manufactured product is definitely a good threshold to push the product further into a potential BLA.
The second thing is that if we have to wait to the data of P2, like I just definitely like to invite you for the next update on BALLI-01 for P2, because if we get a recommended phase II dose for the product that has been manufactured in-house, this would definitely push us into an expansion and a registrational trial if the response rate remains similar or if not better, because the product is the higher quality, we believe. That it's 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.
Got it. Thank you very much.
Thank you for the question, Yanan. Our next question comes from Luisa Morgado, from Kempen. Please go ahead, Luisa. Luisa, you might be on mute. All right, we'll go to the next question. Our next question is from Ingrid Gafanhão , from Bryan, Garnier. Please go ahead, Ingrid.
Hi, good morning. I have a couple of similar questions you already had before, but this time for UCART123 . If I understand correctly, AML can be a little bit elusive in terms of targeting. For UCART123, was the expansion anyhow related to the expression of CD123 at baseline? Just to follow up on that, have you had a chance to look at what happened to CD123 after you give the patients the first dose?
Thank you, Ingrid, for the questions. Mark, over to you.
Yeah, thank you for those. For the, actually, for the entry criteria into the study, they just have to be CD123 positive, 123 positive by their local flow cytometry laboratory assessment at the sites. We're not, at the current time, we're not indicating a particular percentage cutoff for enrollment into the study. To that point, there's... We're also in the process of determining and looking at some of the data to see if there is a correlation or not. I don't have, I don't have the an answer for you right now, but it is something that we are working on. I'm sorry, I missed the second part of your question.
Yes. I was curious. I'll change that a little bit. I was curious to hear, are you gonna look at the expression of CD123 again before you give them the second dose?
There won't be a decision point based on one twenty-three because it's, you know, biologically, it's probably unlikely that the expression pattern will change in a period of seven to 10 days. The peripheral blood is obviously being followed for a disease which will be, which will also encompass 123 by flow cytometry when they're when we're looking at their peripheral blood. There will be some measurement of that, yes.
All right. Thank you very much.
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. I think, given time, we'll have time to read one more question from the chat. We have a two-part question from Gena Wang, from Barclays. 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 115233 and 104218, despite having roughly 2x duration of cell expansion than the patient with complete response? I think that's definitely a question for Mark.
Okay. Thanks. Thanks, Gena, for the questions. I think from the, for the first question, to answer your question, there is no cutoff for expression level that we have currently in the study for UCART123. They just have to be UCART123 positive by the site's local hematopathology flow analysis. Arthur, I'm sorry, the second question again for the patients.
Yeah. About the two patients, 115233 and 104218, that had a lack of response despite having 2x duration of cell expansion versus the patient with complete response, if there's a rationale for that?
I have to look at that more closely, but I know for patient 115233, they had a very hyperproliferative leukemia. While there was some level of detection of blast reduction, it was just very hyperproliferative and relapsed very, very quickly. In fact, that patient was the one patient in the FCA cohort that recovered their lymphocytes before day 28, secondary to a very, very proliferative relapse in their disease very quickly. The other patient will have to look at and get back to her.
The second question from Gena is what would be equivalent doses of the 1 million cells per kg P2 product in 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 product. 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 product.
I think this concludes the written part of Q&A in the interest of time. I will hand it over to André for concluding remarks.
Well, thank you very much, Arthur. Special thanks to everyone that connected to this webcast this morning. We were extremely excited and happy to share this, these data with you this morning. 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's plenty of things that are happening currently in the company, we believe that 2023 is going to be very event-rich year for Cellectis. Of course, with these, like, four trials that are moving forward, we're excited to share with you data of P2 for 20, UCART22, because the process, the internally made process is definitely very differentiated. Same thing for 20 by 22 that has been manufactured internally. It's something that's very exciting for us. Non-Hodgkin lymphoma, non-CD19 product.
We're started, of course we're starting enrollment. Finally, there is also very much of excitement for the company for UCART123 double dose that we believe is something that is gonna change the trend in the ML for ML. Of course UCARTCS1 that's enrolling currently at DL1. 2023 You'll be very regularly updated on IND filings, but also on the older progress of the company. The company is entering into a very interesting phase. I would definitely thank you very much for this following for following Cellectis. Thank you.