Cellectis S.A. Q4 FY2020 Earnings Call

Greetings. Welcome to the Cellectis Fourth Quarter and Full Year 2020 Earnings Call. At this time, all participants are in a listen-only mode. A question-and-answer session will follow the formal presentation. Please note, this conference is being recorded. At this time, I will turn the conference over to Simon Harnest, Chief Investment Officer. Simon, you may begin.

Thank you, and welcome, everyone to Cellectis fourth quarter and full year corporate update and financial results conference call for the 2020 fiscal year. Joining me on the call today with prepared remarks are Dr. André Choulika, our Chief Executive Officer; Dr. Carrie Brownstein, our Chief Medical Officer; and Eric Dutang, our Chief Financial Officer. Yesterday evening, Cellectis filed its annual report and issued a press release reporting our financial results for the fourth quarter and year ending December 31, 2020. These reports and press releases are available on our website at cellectis.com. As a reminder, we will make forward-looking statements regarding Cellectis financial outlook in addition to its regulatory and product development plans. These statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted. A description of these risks can be found in our most recent Form 20-F filed with the SEC and the financial report, including the management report for the year ending on December 31, 2020, and subsequent filings Cellectis makes with the SEC from time to time. I would now like to turn the call over to André. André, please go ahead.

Thank you, Simon. Good morning, and thank you, everyone for joining us today. 2020 has been focused on advancing our company objectives. Despite the challenges the world is facing, Cellectis has achieved key milestones. And we are incredibly grateful and proud for all the hard work achieved by our team, our partners, and our stakeholders during this challenging year. Showing the progress we've made in 2020, while moving into 2021 determined on our commitment to a cure. We’re thrilled to share with you over the next half an hour this progress and our vision on an exciting future for Cellectis. In 2020, we fully entered into clinical development of our first three wholly-controlled clinical programs. With our pioneering allogeneic UCART cell programs in ALL, AML, and multiple myeloma. We are developing alternative targets to the overcrowded CD19 and BCMA landscape. We have already shared early data on our ALL program BALLI-01 at ASH in December. All three programs are currently enrolling patients in Phase 1 dose-escalation trials. We are investigating different regimens for depletion. While 2020 was an extremely challenging year with a significant impact on logistics, Cellectis successfully completed the construction of our in-house manufacturing facilities on time in Raleigh, North Carolina, and in Paris, France. Both facilities are now up and running with a tech transfer between Paris and Raleigh happening in the first half of this year in order for Raleigh to start manufacturing GMP UCART cell batches in the second half of this year. Successful product development is highly dependent upon manufacturing from stable clinical supplies to drive the execution of our clinical plan to ensuring consistent quality and meeting regulatory expectations. Our facilities in Raleigh and Paris will allow us to achieve a large degree of manufacturing independence, which is one of the most important value drivers for any cell and gene therapy company. We expect to achieve this by year end and believe this step will propel Cellectis further ahead as we continue to lead this class of cell therapy companies. Our clinical execution strongly accelerated during 2020 as we established a world-class team of clinical experts from the CAR T-cell and hematology oncology space around our Chief Medical Officer, Dr. Carrie Brownstein, who joined us from Celgene. Carrie and her team have been instrumental in establishing a broad clinical presence for Cellectis within seven of the top U.S. heart hospitals, giving us unprecedented access to large patient populations from which to enroll into our clinical trials. Additionally, we expanded our general management and global manufacturing team with top talent. We appointed Mr. Jean-Pierre Garnier as the Chairman of the Board of Directors in November 2020. Jean-Pierre is a seasoned leader with decades of experience within the global biopharma industry, most notably as the previous CEO of GlaxoSmithKline. From gene editing to CAR T-cells, Cellectis has always been a strong scientific leader in this space. As an example, Nature Magazine recently ranked top organizations in terms of the number of patents filed and owned in the CAR T-cell space. In this ranking, Cellectis became the fourth institution worldwide just behind Upenn, BMS, and Novartis. In the same publication, among the top 20 CAR T-cell inventors, six, close to one-third, are from Cellectis. This is a great achievement overall. We are also listed as the number one biotech company in the study. And this is just for CAR T, and I'm not talking about gene editing. Yes, we are a leader in this field, and we have plenty of followers. On the business development front, we're pleased about our recent agreement with Cytovia Therapeutics, which we announced last month. This partnership leads us to expand our TALEN gene editing platform into iPSC-derived Natural Killer Cells and Chimeric Antigen Receptor, CAR NK cells for a series of different tumor types. We will be responsible for developing custom TALENs that will be used by Cytovia to edit iPSCs to be differentiated into NK cells addressing multiple gene targets for therapeutic use in several cancer indications. Cytovia will conduct the development of the mutually agreed-upon therapeutic candidates, and we will be eligible for up to $716 million of development, regulatory, and sales milestones, as well as a single-digit royalty payment on net sales. We will also receive an equity stake of $15 million in Cytovia stock as well as an option to invest in future financing rounds, which will allow us to be part of Cytovia as a growing value driver. Together with a research collaboration and exclusive worldwide license agreement with Iovance on gene-edited tumor-infiltrating lymphocytes announced last year, this partnership shows the growing attraction and relevance of our TALEN platform as the gene editing solution of choice for cell therapy. We're looking forward to seeing these next-generation gene edited cell therapy programs become a reality for cancer patients. Our partnerships with Allogene and Servier are also gaining momentum and further establishing our growing allogeneic CAR T platform value. Allogene presented initial data from the ALLO-715 program in relapsed refractory multiple myeloma at ASH in December 2020. The first data set ever presented on an allogeneic cell therapy targeting BCMA. In this initial data readout, 31 patients treated with ALLO-715 were evaluable for safety and 26 patients were evaluable for initial efficacy. Allogene is now moving into the next step in this study, namely optimizing cell doses and lymphodepletion, and plans to provide an update on ALLO-715 later this year. Allogene also initiated a cohort exploring ALLO-715 in combination with a gamma secretase inhibitor with their partner SpringWorks Therapeutics, and is on track to submit 94 ALLO-605, the first TurboCAR targeting BCMA for multiple myeloma in the first half of this year. Regarding CDI9, Allogene presented initial data on 22 NHL patients treated with ALLO-501, of which 19 were evaluable for efficacy. At ASCO 2020, in parallel to ALPHA, the Allogene ALLO-501A ALPHA2 trial is designed to enroll a homogeneous patient population focused on relapsed refractory LBCL, and was recently granted fast-track designation for the treatment of this population. The ALPHA2 trial is designed to potentially move into pivotal Phase 2 trials, should the data support it, which would make us eligible for milestone payments. Allogene will be assessing the best course of action for pivotal trial in the second half of this year, setting this product into a trajectory to potentially become the first-ever approved allogeneic CAR T-cell candidate in the world. Finally, we're excited about the third target licensed to Allogene, CD70 entering the clinic this year with the TRAVERSE trial evaluating ALLO-316 in clear cell renal cell carcinoma. This is our first licensed allogeneic CAR T targeting solid tumors and we are eligible for milestone payments for the first patient dose. In addition, further derisking our allogeneic CAR T platform, our alliance with Servier and Allogene are major value drivers to select this. The agreement on CD19 was amended last year and now makes us eligible for up to $410 million in development and sales milestones, plus low double-digit royalties on sales. The licensing agreement with Allogene on 15 additional allogeneic CAR T targets makes us eligible for over $2.8 billion in potential future milestone payments, plus royalties on sales. With that, I would like to hand the call over to Dr. Carrie Brownstein, our Chief Medical Officer for an overview of our proprietary clinical programs. Carrie, please go ahead.

Thank you, André. I would like to start with our first proprietary product, UCART22, our CD22 directed TALEN gene-edited allogeneic off-the-shelf CAR T-cell product candidates currently being evaluated in patients with relapsed and refractory B-cell acute lymphoblastic leukemia or B-ALL. We presented preliminary data from patients enrolled in the first two dose levels of our Phase 1 dose-escalation trial BALLI-01 at the American Society of Hematology Annual Meeting in December. This is the first publicly released data from Cellectis BALLI-01 clinical trial. As of the November 2, 2020 data cutoff, seven patients were enrolled and five patients received UCART22, following lymphodepletion with fludarabine and cyclophosphamide or FC preconditioning. One patient failed training, and one patient was discontinued prior to the administration of UCART22 due to an adverse event related to the lymphodepletion regimen. Importantly, no patient experienced dose-limiting toxicity, immune cell associated neurotoxicity syndrome, graft versus host disease, adverse events of special interest nor Grade 3 or higher adverse events or serious adverse events related to UCART22. No patient discontinued treatment due to a UCART22 related treatment-emergent adverse events. Two patients in dose level one achieved an objective response of complete remission with incomplete count recovery or CRI at day 28, one of which attained a complete remission or CR at day 42 and proceeded to hematopoietic stem cell transplant after subsequent therapy with inotuzumab. One patient in dose level two achieved a noteworthy reduction in bone marrow blasts of 60% at screening to 13% at day 28, after treatment with UCART22 and subsequently progressed. Host lymphocyte reconstitution was observed in all patients within the DLT period, and correlative analysis of UCART cell expansion and persistence remains ongoing. We are encouraged that UCART22 demonstrated preliminary signs of activity at low dose levels with FC lymphodepletion without unexpected nor significant treatment-related toxicity. Our next step is to evaluate and optimize the cell dose and lymphodepletion in order to augment these early responses. We have added an arm to the trial in which we explore the addition of alemtuzumab, an anti-CD52 antibody added to the FC lymphodepletion regimen, which we call FCA, which is expected to result in a deeper and more sustained T cell depletion and thereby promote expansion and persistence of UCART22 cells. We are currently enrolling patients in dose level two with FCA, and we plan to give an interim clinical data update on this cohort in the second half of this year. Coming to UCARTCS1, our CS1 directed TALEN gene edited allogeneic CAR T-cell product candidate being evaluated in patients with relapsed or refractory multiple myeloma. We collected preliminary translational data from the first group of patients enrolled last year, and we plan to share an early look at this data in the first half of this year. Similar to BCMA, CS1 is a widely and consistently expressed target on the plasma cells of multiple myeloma. Interestingly, CS1 is also expressed on other immune cells, including T cells and NK cells. Cellectis is uniquely positioned to leverage this important myeloma target, because through the use of our gene editing technology, we are able to knock out CS1 from the T cells prior to inserting the CS1 directed CAR, which avoids T cell fratricide during manufacturing. An additional differentiating factor is that our UCART CS1 cells self-generate lymphodepletion through targeting CS1 expressing lymphocytes, and thus do not require additional preconditioning with a CD52 directed antibody. While the FDA had placed a clinical hold on this program last year following a patient death in dose level two, which occurred toward the end of the 28-day observation period, this hold has been since lifted with updates to the protocol and the study has resumed. Next is UCART123, our CD123 directed TALEN gene-edited allogeneic CAR T-cell product candidate being evaluated in patients with relapsed and refractory acute myelogenous leukemia. This program is addressing one of the highest unmet medical need populations, and the successful CAR T-cell program in relapsed and refractory AML could be a significant paradigm shift for patients. Our current clinical product is an enhanced version of UCART123, which includes updates to the manufacturing process and incorporates the CD52 knockout to allow the use of an FCA lymphodepletion regimen. We are currently enrolling in our Phase 1 dose escalation trial with two study arms, one with FC and one with FCA lymphodepletion. Enrollment in both arms is ongoing, and the data obtained will give us great insight into the CAR T-cell kinetics and host lymphocyte recovery using both strategies. We are looking forward to sharing this data from the program when available. Building on the technology platform of our current proprietary clinical program, I would like to add that we plan to submit INDs and initiate new clinical trials this year for novel proprietary product candidates targeting additional oncology indications as well as genetic disease settings. We look forward to sharing additional information in the near future. Our licensed allogeneic CAR T-cell development programs are making great progress as well. As André mentioned before, this year we are expecting rich clinical data flow from Allogene and Servier from our licensed CD19 programs in relapsed refractory NHL and from Allogene for the BCMA program in multiple myeloma at various medical meetings, further validating the allogeneic CAR T-cell approach, which we invented and pioneered. With that, I would like to hand the call over to Eric, our Chief Financial Officer for a more detailed overview of our business development activities. Eric, please go ahead.

Thank you, Carrie, and good morning. Before I provide a brief overview of financials for the quarter and year end, I'd like to spend a few minutes on some of our business development activities in 2020, and in early 2021. In particular, at the beginning of 2021, we announced our alliance with Cytovia, which includes up to $760 million of development regulatory and sales milestones, and we also received single-digit royalty payments on the net sales of all partnered products commercialized by Cytovia. We also received an equity stake of $15 million in Cytovia stock or upfront cash payments of $15 million if certain conditions are met by December 31, 2021, as well as an option to invest in future financing rounds. In 2020, we announced our collaboration with Iovance, on gene-edited TILs with significant undisclosed development and sales milestones, plus royalties on sales, along with an amendment of our partnership agreement with Servier with up to $110 million in development and sales milestones plus low double-digit royalties on sales. For the latter, we will potentially receive in 2021 a milestone payment from the first pivotal trial of ALLO-501A in Large B-Cell Lymphoma. Finally, as a reminder, we are also eligible to receive up to $2.8 billion in development and sales milestone plus high single-digit royalties on sales from Allogene related to 15 targets. We will potentially receive in 2021 a milestone payment from the launch of the TRAVERSE trial of ALLO-316 in renal cell carcinoma. Now on to our financials. The cash, cash equivalents, current financial assets and restricted cash position of Cellectis, excluding Calyxt, as of December 31, 2020 was $244 million compared to $304 million as of December 31, 2019. This difference mainly reflects $28 million of proceeds received from Servier in the first quarter of 2020 and the receipt of $21 million set guaranteed loans, which were offset by $102 million of other net cash flows used in operating, investing and lease financing activities. This cash position is expected to be sufficient to fund Cellectis's standalone operations into late 2022. This runway discounts any future milestone payments. The consolidated cash, cash equivalents, current financial assets, and restricted cash position of Cellectis including Calyxt was $274 million as of December 31, 2020, compared to $364 million as of December 31, 2019. The net cash flows used in operating capital expenditure and other activities were $86 million at Cellectis and $44 million at Calyxt in the full year of 2020. The net loss attributable to shareholders of Cellectis excluding Calyxt was $54 million in the full year of 2020, compared to a net loss of $75 million in 2019. The $21 million increase in the net reserves between 2020 and 2019 was primarily driven by a significant increase in revenues and other income of $44 million, which was partially offset by an increase in SG&A expenses of $5 million and a decrease in financial gains of $19 million. The consolidated net loss attributable to shareholders of Cellectis including Calyxt was $81 million, or $1.91 per share in the full year of 2020 compared to $102 million, or $2.41 per share in 2019. The consolidated adjusted net loss attributable to shareholders of Cellectis excluding non-cash stock-based compensation expenses was $67 million, or $1.77 per share in the full year of 2020 compared to $79 million, or $1.86 per share in 2019. We are laser-focused on spending our cash on developing our deep pipeline of wholly-owned product candidates in the clinic and entering operations at our state-of-the-art manufacturing facilities in Paris and Raleigh. On the other hand, our focus on maintaining an efficient corporate infrastructure should enable more limited growth in G&A spend. With that, I would like to hand the call back to André for concluding remarks. André, please go ahead.

Thank you, Eric. Again, we're very proud of the organization and team that we have built over the past years. We started treating the first patient in pediatric ALL in 2015 under a compassionate use protocol with the first-ever gene-edited allogeneic CAR T-cell therapy. Those babies are now young kids in school and continue to be tumor-free. This is what motivates our entire team to get to work every day with the mission to save lives and offer treatment options to cancer patients that have exhausted all other treatment options. Fast forward from 2015 to today, we are now a fully integrated gene editing biotech company with seven therapeutic development programs and clinical trials including three wholly-controlled targets based on our proprietary TALEN gene editing technology. To further expand our current clinical pipeline, we are in the middle of finalizing preclinical work on a series of new allogeneic CAR T-cell targets and other product candidates. We strongly believe that our proprietary cell and gene therapy platform, combined with our in-house manufacturing facility and our broad clinical pipeline, will lead to a paradigm shift in cancer therapeutics and cell therapies in general, positioning us at the forefront of this promising scientific field. With that, I’d like to open the call for Q&A.

Thank you. Our first question comes from Michael Schmidt with Guggenheim. Please go ahead with your questions.

Hey, guys, good morning. Thanks for taking my question. I actually had a question around your investment into the CAR NK space, that’s part of the Cytovia collaboration. I was just curious if you could share maybe how the Cytovia technology and approach together with your TALEN approach, how that might differ or compared to what others are doing in the CAR NK space, and longer term how you think CAR NK cell products might be positioned relative to CAR T products within oncology indications? Thank you so much.

Thanks, Michael. I appreciate the question, and thanks for joining us this morning. This is Simon. Very good question. We make very selective business development deals with very high-quality technology partners. We want to be very selective, as I said, because there is just such a wealth of new technologies coming into the market. And we think Cytovia is one of the best partners in the iPSC derived NK cell space. So that's obviously a space that captures a lot of momentum currently. And we can make a significant difference here by adding our TALEN gene editing. This collaboration is also positioned more as an investment for Cellectis due to the fact that we actually have an equity stake in the company rather than an upfront cash payment. So we are very encouraged by the progress of the company so far, and we're continuing to be very excited about the growth that can come out of this collaboration. As we said, we have obviously over $700 million in development milestones, regulatory milestones, some sales milestones. But for us, it's much more interesting to actually make a significant change to improve with gene editing what is a very wonderful scientific platform on the iPSC derived NK cell front. So for us, it's a foray into this phase, which will include some solid tumor targets as well. But without taking the focus and resources away from us to focus on our off-the-shelf CAR T-cell treatments, which we think are the best shots on goal for the targets that we’re pursuing. And André, feel free to add anything.

Well, it's, in fact something that is important for us because there is a lot of selection among all the gene editing technologies and we see more and more people that are focusing on TALEN interest because of the performance of the technology and the quality of the cells that comes out. Plus Cellectis is a one-stop shop in the field of gene editing. It means we have the electroporation technologies, we have the TALEN technologies, we have other gene editing technologies and we have a huge amount of experience in handling cells and editing them. On the fact of between NK T cells, etc., Cellectis is focusing on T cells. Cytovia is focusing on NK. We cannot be on all fronts. And we believe very strongly that the focus that we have on primary T cells is very promising and very straightforward currently because of the successes that we are starting to see in the field. The NK, we believe in them. We think Cytovia is the best partner to do it. But we don't think that Cellectis should spread itself into all directions. Why in the T cell space, we like primary cells? For the simple reason that T cells are more of a cocktail than NK cells. There’s of course different types of NK cells, but in the space of T cells is CD8, CD4, gamma delta, T-central memory, etc. So it's a cocktail that is part of the know-how at Cellectis and how to extract this from a leukopak of a healthy donor. And that's also not within the immediate reach of finding a product on something that would be a sophisticated product in there. Now, we believe in the iPSC and stem cell differentiation and something that we are very excited about the technology of Cytovia that comes out from very prestigious labs on the West Coast, and we think that it's going to deliver very strong results at the end.

Okay. Thank you.

The next question comes from the line of Gena Wang with Barclays. Please proceed with your questions.

Thank you. I have a question about the Cytovia partnership. Can you provide any details about the initial targets? Additionally, will Cytovia or Cellectis handle manufacturing? My second question concerns CS1. I understand that the clinical hold was lifted much sooner than anticipated. Could you explain what the FDA was seeking and what changes were made to the protocol for the program going forward?

Yes. Hey, Gena, thank you so much for the wonderful questions. Maybe I can take the first part of the question, and then I'll direct it over to Carrie, who is the Chief Medical Officer, who can answer a little bit of the background on the CS1 program. So for Cytovia, they will be responsible for the manufacturing of their NK cell programs. We provide the technology for them needed to make the gene editing part, which is a pretty straightforward system that we have perfected in-house and which we have already provided for example, Iovance's TIL programs for gene editing approaches there. So it's a similar setup. We haven't given too much color around the targets. Obviously, the company is still a private company and has the benefit to move forward without disclosing those targets too early, but the mix of solid and liquid tumor targets. And Carrie, maybe you talk a little bit about CS1. Thank you so much.

Yes, hi Gena. It's great to hear from you. We were very pleased with the lifting of the hold last fall. As we mentioned previously, the hold was initially due to a patient death at dose level 2 during the dose-limiting toxicity period. We are planning to share data soon from the first group of patients treated last year before the hold, and we will provide more details on the measures we took to restart the study.

Our next question is from the line of Salveen Richter with Goldman Sachs. Please proceed with your questions.

Good morning. Thank you for taking my questions. I was wondering if you could provide us with some timelines for the new programs moving into the clinic, such as those related to genetic diseases, as well as your plans to file INDs or develop these natural killer iPSC cell programs?

Yes. Hi, Salveen. Thank you so much. So first of all, the timelines for our new INDs that Carrie mentioned briefly on the call, this is something we will talk much more about this year as we're progressing towards IND filings. What we do want to show is that we have been quiet for the last couple of years on our preclinical development and our gene editing platform, while at the same time actually making a lot of progress on that front and we would really like to show the street what is under the surface of Cellectis because we are a world-leading gene editing company with a platform in T cells internally. We have partnerships with leading companies in NK cells and TIL, and we have a gene therapy program that we would like to really put front and center as a new pillar of value for the company. But for us, the biggest focus and timelines this year is it's getting very exciting with our clinical development of our current proprietary CAR T program. We are advancing this to the dose escalation phases that we mentioned. So we expect some very interesting data flow out of our current clinical programs. And then we expect new IND filings within 12 months. So bear with us just a little longer. I think we'll give more information in the second and third quarter of this year as we're getting really close to this IND filing.

Thank you.

Our next question is from the line of Hartaj Singh with Oppenheimer. Please proceed with your questions.

Great. Thank you for the question and all of the progress. Just one question. A lot of companies out in the field of problems locating things as simple as developing plasmids, mRNA, etc. How are you positioned with your Paris and Raleigh facility in this regard, also being autonomous by the end of this year? And then I just have a quick follow-up after that. Thank you.

Thank you very much, Hartaj, for the question. I think it's an important question. We took the decision in 2018 to start constructing our manufacturing plant, and we took a decision to split in order to go fast on the first phase, and because the second phase would be longer. So the first phase was essentially to build up a manufacturing plant, fully GMP to manufacture DNA, plasmids, mRNA, and vectors to bring the CAR inside itself. And that's operational since 2020 and stock-producing. Imagine, in 2020, with the COVID crisis, trying to order mRNA with what's happening in there, even a plasma, etc., it's becoming a real complication. And when I'm saying that Cellectis is full integration kind of one-stop shop goes from the idea at the bench, we can manufacture everything. All the raw materials to make a CAR T, mRNA, plasmids you can immediately have them. We have all the quality systems around us. We have all the vectors, all the mRNA, everything gets shipped to Raleigh. Raleigh is going to go operational this year. The cell and gene therapy is becoming a more and more tense market. And the fact that we can build everything internally, including sometimes the buffer, but the electroporation technologies are ours. So we can tune up all the little details around this. I believe, today and 2021 is one of the biggest strengths and it differentiates the company very strongly.

Great, great. Thank you, André. And then just a quick question on UCART123. I think last year with the new IND you had mentioned, that you'd be looking at patients with maybe a better performance status, maybe a slightly younger group of patients. And there might be a little bit more of a window between the core - between doses, has that change? Are you still sort of going through those initial phases of that escalation protocol? Thank you for all the questions.

Hey, Hartaj, maybe I can take it and I can hand it over to Carrie. So we're currently dosing patients at dose level 2 at the arm of addition of alemtuzumab to the preconditioning cycle. So we actually do two arms of the study in parallel, one with and one with alemtuzumab. And Carrie, maybe you'd take over here for the patient population retreating and the dose escalation plan forward.

Thank you for the question. As Simon mentioned, we currently have two arms open in the trial, and we are assessing whether to use alemtuzumab in this patient population. It's important to note that patients with AML are somewhat unstable and are a challenging group to treat. They are often older and may have poor performance status. Therefore, it's crucial to consider preconditioning with alemtuzumab because it can introduce its own complications. In terms of performance status, the protocol allows for the inclusion of individuals with relapsed refractory disease, and we've incorporated eligibility criteria to ensure that we enroll patients who can tolerate potential side effects, such as cytokine release. However, patients with AML can be unpredictable. I am proud of the strong medical team we've built in the leukemia space since I joined last year. We maintain close communication with our investigators, discussing patients and their criteria to ensure this study is suitable for them. I feel confident that we are enrolling patients who can handle our treatments, allowing us to seek answers in this very challenging patient population.

Great. Thank you.

Our next question is from the line of Yigal Nochomovitz with Citigroup. Please proceed with your question.

Great. Hi, André, Simon, and Carrie. Thank you very much for taking the questions. I just had one on UCART22. Could you clarify what you mean by the correlative analysis of cell expansion and persistence? Do you mean correlation of cell expansion persistence with response? And will this analysis determine whether you need to adjust the lymphodepletion regimen? Also, could you comment on your current stake in Calyxt? Is that something you would consider selling to further finance the company? Thank you.

Yes, thanks, Yigal. Maybe first question for Carrie, and I can start with the second question really quick. So for Calyxt, we're over 50% shareholders in the company. We love what the company is doing. They actually have what we believe is a very strong period of growth ahead of them. So please monitor their earnings call as well, that just happened yesterday. It's a wonderful company with a scarcity value because it's the only publicly traded gene editing company in the agricultural space currently, with a full focus on sustainability and improving crops in the ag space for consumer consumption. Again, something that we don't expect anytime soon. Carrie, if you want to answer the question on 22, thank you.

Yes, of course. The correlative analysis encompasses all of our translational work, where we will examine the recovery of lymphocytes, including T, NK, and B cell subsets, and correlate that with our expansion data on the UCART cells as well as their efficacy. We are closely monitoring this to determine the best path forward and assess whether we need to make any further adjustments to the preconditioning in order to optimize the success of the UCART cells.

Okay. Thank you very much.

You're welcome. Thank you.

The next question is from the line of Wangzhi Li with Ladenburg. Please proceed with your question.

Hi. Thank you for taking my question. I have two questions. The first one is about the new programs you anticipate filing IND this year. Carrie also mentioned a new direction for genetic disease. Can you share more details regarding the number of new INDs expected this year? Is it one program or multiple programs? Additionally, for the genetic disease, can you elaborate on the direction or area you plan to pursue? Any information would be appreciated. My last question is about the CAR NK partnership. Can you provide some high-level insights on the target? Will it overlap with your current CAR T targets or could there be some shared targets?

Thanks, Wangzhi. Very good questions. I will have to say short answer for the first question. We will provide more color on our programs that are previously undisclosed in the second quarter of this year. So we will give you all the details then. And just rest assured it's a very exciting program where we think we have a huge differentiating technology for. So it's something that currently cannot be done with any other technology. For the second question on NK cells, André, do you want to give a little more color on the targets? I don't believe we have given that color.

Hi, Wangzhi. While we haven't shared specific targets since that pertains more to Cytovia, it’s clear that many in this field are looking at what Cellectis is doing. If you're interested in our activities, the market is a great source of new ideas. We are certainly planning to move forward quickly. However, on the Cytovia front, we unfortunately cannot disclose any information right now, except perhaps to expect updates in the second quarter regarding our preclinical pipeline. We're thrilled with the ideas we've been developing together.

Our next question is from the line of Biren Amin with Jefferies. Please proceed with your questions.

Yes. Hi, guys. Thanks for taking my questions. Maybe on the myeloma program, given the clinical hold was lifted in mid-November, when do you expect to start re-dosing patients in that trial?

Yes. Carrie, would you like to take that one? Thank you, Biren. Good question.

Sure, absolutely. So once the hold was lifted, we started all of the downstream activities that would allow us to start re-dosing and we have already begun opening our sites and should be planning on first patients with re-dosing, hopefully very soon.

Okay. And then I guess, with any of these three programs, do you anticipate that you'll have sufficient clinical data by end of this year where you can make a decision to go into a pivotal cohort next year?

So our plans as of now are as we have the data available to give a good package of data, as I said before that’s meaningful. As I think we’ve previously stated, I think UCART22 is moving forward the most quickly. And that could be something that potentially we could consider, but we will have to depend on what we see with our data and how things move forward.

Great. Thanks for the questions.

The next question is from the line of Nick Abbott with Wells Fargo. Please proceed with your questions.

Good morning and thanks for taking our questions. First one is on UCART22. Have you demonstrated direct evidence of host immunity targeting UCART22? There's the correlation between T cell reconstitution and disappearance of UCART22. But have you actually identified which host cells are targeting the UCART22 cells?

Yes. At this point, please continue. Sorry. Yes, we're actively engaged in that work. We're particularly focused on understanding both cell recovery and identifying which cells are causing the rejection of the allogeneic CAR T. We're examining all the relevant data, although we don't have specific information to share right now. It's crucial for us to ensure that we maintain count recovery for a sufficient duration to allow the UCART cells to expand and function effectively. Additionally, incorporating alemtuzumab safely and effectively is a major objective for us this year. We'll analyze all the data to determine the best strategy for moving forward, whether in a pivotal study or otherwise.

Thanks. And that's a great segue to my second question, which is on alemtuzumab. Currently you're looking at 20 milligrams consecutively for 3 days. So, how long do you expect that to be effective at dampening down this host immune recovery? How much variability do you expect to see, and how long do you want to keep that host immune recovery down?

Yes, that's a great question. This all relates to the data. We know from previous studies involving allogeneic transplant that alemtuzumab is used in preconditioning and typically, you would expect the lymphodepletion to last around 6 weeks. It can actually last quite a long time because it's a monoclonal antibody with a very long half-life. Finding the right balance is crucial; we need to keep the host immune system suppressed long enough for the cells to effectively eliminate the leukemia, but not so long that it causes other problems. As we collect more data, I intend to make decisions based on that information. So, to answer your question, I can't specify how long it will last, as it will depend on what the data shows.

The next question is from the line of Raju Prasad with William Blair. Please proceed with your questions.

Hi, there. This is Sami on for Raj. Thanks for taking our questions and congrats on the progress. Based on your data and the data from Allogene to date, how are you guys thinking about re-dosing across your trials? And then also, could you remind us if you plan on enrolling patients refractory to BCMA therapies in your CS1 trial for multiple myeloma?

Absolutely. Carrie, you go ahead.

The second part of the question is easier to address, so I will start with that. In all of our trials, including BCMA and CD19, as well as other AUTO or ALLO CAR T therapies, we do not exclude patients. What makes our programs unique and exciting is our ability to enroll patients who have already failed one of these therapies. For instance, a patient who has undergone auto BCMA may not be eligible for ALLO BCMA. This approach allows us more opportunities because we are targeting alternatives, and we are among the few actively pursuing this in the ALLO field on a large scale. Therefore, it’s a significant and unique aspect of our programs, and the short answer is yes, those patients can participate in the study. Regarding re-dosing, one of the most important and exciting features of allogeneic CAR T therapies is the ability to re-dose. We are investigating this in our studies, and we look forward to sharing data with you when it becomes available.

Thanks.

The next question is from the line of an indiscernible caller. Please go ahead with your question.

Hi, all. Good morning. Thank you for taking my question. I acknowledge it may be difficult for you to speak for your partners. So to the best of your knowledge, when would you be expecting to hear something more from Servier and Allogene about their plans for UCART19, ALLO-501?

Thank you for the question. It's an important issue for us because it provides significant value not only from a financial standpoint but also in terms of validating our platform. UCART19 was the first product introduced by Cellectis in the clinic in 2015, which has since been renamed ALLO-501. ALLO-501 is equivalent to UCART19, but we have developed a new version, ALLO-501A, which excludes a built-in off-switch activated by rituximab. This change makes it easier to produce and allows the use of UCART19 or ALLO-501 in patients who have received rituximab, which is standard treatment for NHL patients. Currently, Allogene and Servier are collaborating on the ALLO-501A program. Allogene has recently announced a plan for an update regarding this program in the second quarter of this year at a medical meeting. In the coming months, we will have information on patients treated with both ALLO-501 and ALLO-501A. Both companies aim to initiate a Phase 2 study by the end of this year, which could serve as the pivotal registration trial. We are excited about this as it represents the first program we launched in the allogeneic gene-edited off-the-shelf CAR T cell space, and it is on track for potential product approval in the next 18 to 24 months. Expect news from Servier and Allogene soon, including data on this program in mid-year and the potential start of a Phase 2 trial by year-end.

All right. Thank you so much. That was clear.

The next question is from the line of Jack Allen with Baird. Please proceed with your questions.

Hi, thank you so much for taking our questions. I wanted to ask about your thoughts with regards to the timing of getting the TALEN based product in the clinic and solid tumors. I know you mentioned that ALLO-316 is expected to enter the clinic in the coming months. But I was also wondering if you could touch on the timing with respect to advancing clinical products with respect to the Iovance and Cytovia partnerships as well? Thank you so much.

Thanks, Jack. Yes, it's a wonderful question. We think solid tumor approaches are really the next frontier for cell therapy, as this pertains to our partnership as well as to our proprietary programs that we're aiming to move into the clinic. So we mentioned this in the past that new INDs will also address solid tumor targets from Cellectis. So proprietary targets to Cellectis, I think will make an interesting development case here, but as you said also on the TILs and NK cell platform. So, we wanted to derisk our technology first and liquid tumors where we've seen really great responses with our CAR T cell approaches, and now we're expanding that beyond liquid tumors into solid tumors.

Awesome. Thanks so much.

Thank you. The next question is from the line of Soumit Roy with JonesTrading. Please proceed with your question.

Thank you for taking the question. In line with the previous inquiry, could you provide some general thoughts on addressing solid tumors, particularly in relation to the Cytovia deal? Are you identifying effective strategies with the iPSC NK cell line? How do you choose between gamma delta and alpha beta? Are you considering tissue penetration of cell types or T cell modification? What do you believe will be the key to overcoming challenges with solid tumors?

Carrie, maybe you want to provide some comment on that first? And thank you Soumit for that question. Carrie, go ahead.

Yes, sorry. I was on mute. I'm not 100% clear on the question to be honest with you. So, just in terms of which targets or I’m not …

Like the cell type, like are you still thinking alpha beta T cell is the right cell type to tackle a solid tumor or with Cytovia deal you’re indicating maybe iPSC NK cells are a better candidate for tissue penetration in the solid tumor versus liquid tumors?

Yes, that's a good question, but we don't have a definitive answer. I would refer to André for more insight on this matter. It's crucial for us at Cellectis that we possess the gene editing platform, which allows us to explore various approaches for liquid tumors, solid tumors, or other diseases. Applying this platform across different areas, whether it involves iPSCs, gamma delta, or alpha beta cells, is essential for addressing important clinical and research questions that remain unanswered. What’s significant is that at Cellectis, we are engaged in numerous potential strategies that could benefit patients in need. This is why being here is so exciting; we have the opportunity to make a difference in various ways, and we will determine the most effective strategy for addressing liquid tumors, solid tumors, or other diseases.

Yes. I cannot agree more with Carrie. The limitation that Cellectis has is not technical. We can do everything technically. Our gene editing technology is extremely powerful, and there is more and more papers that are coming, showing that the access of TALEN to any kind of DNA, and the precision of this technology and its accuracy and its specificity and the ability to promote DNA recombination, replacement, correction, etc., is unprecedented in this arena. Plus we have the other technologies. Our limitations are not technical for Cellectis. The problem is more focus of the company and also was for the past years on the manufacturing, but we just unplugged this blockage that we have. The manufacturing is internalized bit by bit, and this year 2021 will have no limit in terms of what we can manufacture for clinical supplies, but also for commercial supplies. Also, Carrie is building a huge and awesome clinical team around her from cleanups to translational, etc. and the limits are more people and what we can do, and of course, the finances of the company that have to follow on this. But we cannot spread ourselves on a thin layer. The problem is certainly not technology-wise, because we own it all. The problem is on the focus of the company, and I think we're really laser focused on what we're doing currently.

Got it. Thank you, and good luck with the upcoming catalysts.

Thanks.

Thank you. At this time, we've reached the end of our question-and-answer session. And I'll hand the floor back over to Simon Harnest for closing remarks.

Thank you so much. And again, thank you all for joining us. We'll have a couple of follow-up calls after this. Feel free to always reach out to me. And again, I'm very excited about this year because I think there's going to be a lot of clinical data coming that we're all very much eagerly waiting. So thank you again for joining us, and we'll speak to you soon.

Thank you. This will conclude today's conference. You may disconnect your lines at this time. We thank you for your participation.