Allogene Therapeutics, Inc. (ALLO) Earnings Call Transcript & Summary

Hello. Thank you for standing by for this conference call. [Operator Instructions] Please be advised that today's conference is being recorded. [Operator Instructions] I would now like to turn the conference over to Christine Cassiano, Chief Communications Officer. Ms. Cassiano, you may begin.

Thank you, operator, and thanks to all of you for joining our call this morning. Before market open, Allogene issued a press release announcing that the FDA has removed the clinical hold on all of our AlloCAR T clinical trials. This press release as well as today's webcast are available on our website. Here with us to discuss today's news will be Dr. David Chang, our President and Chief Executive Officer; and Dr. Rafael Amado, Executive Vice President of Research and Development; and Chief Medical Officer. During the Q&A, they will be joined by Dr. Eric Schmidt, Chief Financial Officer. [Operator Instructions] During today's call, we will be making certain forward-looking statements. These may include statements regarding the timing and ability to advance our clinical trials and regulatory matters among other things. These forward-looking statements are based on current information, assumptions and expectations that are subject to change. A description of potential risks can be found in our most recent SEC disclosure documents. You are cautioned not to place undue reliance on these forward-looking statements, and Allogene disclaims any obligation to update these statements. I'll now turn the call over to David.

Thank you, Christine. Good morning to you all, and happy new year. Today, we are excited to share the news that the FDA has lifted the clinical hold on all of our AlloCAR T programs. You may recall back in October that we reported a single case of chromosomal abnormality observed in a patient treated in our ALLO-501A Phase I trial. The investigation into the chromosomal abnormality concluded that the abnormality was an isolated event that developed in the patient after the cell product was administered. It was unrelated to TALEN gene editing or Allogene's manufacturing process and had no clinical significance. Specifically, the abnormality was not detected in any manufactured AlloCAR T product or in any other patients treated with the same ALLO-501A lot. It involved regions of the T cell receptor immunoglobulin genes going to undergo rearrangement as part of the T cell or B-cell maturation process. We are grateful that the FDA, which has been highly engaged expeditiously completed its review and agreed that we have satisfactorily addressed all clinical hold issues. Since our inception, we have invested heavily in product science and manufacturing. This core competency allowed us to complete our analysis and respond to the FDA's question in less than 2 months, with the hold being lifted in 3. Having concluded our investigation, we are even more confident in the fidelity of our TALEN gene editing platform, our overall approach to manufacturing and the caliber of our manufacturing and R&D teams to expeditiously handle any unexpected challenges. I would like to thank the team at Allogene led by Dr. Rafael Amado, and our Chief Technical Officer, Dr. Alison Moore, for their hard work to resolve this situation in a timely fashion. I would also like to thank our Scientific Advisory Board and clinical trial investigators who supported us throughout this endeavor. Overall, while the experience is not one that we had wished for, it has served to enhance our knowledge and strengthen our results when encountering complex scientific problems. As such, I believe we are better positioned than ever to resume our goal of delivering allogeneic CAR T therapy to patients. Now I would like to turn the call over to Rafael.

Thank you, David. The chromosomal abnormality was an anticipated finding, and we conducted a very thorough investigation into its nature and provenance. This was important work, which has the potential to impact the entire field of engineered cell therapy. And I'm very proud of our achievement and grateful for the tireless effort of our team to conduct an extensive investigation in 2 months and resolve the clinical hold on all our programs in just 3 months. This included the precise mapping of the chromosomal abnormality, the development of complex analytical assays, the analysis of large sets of clinical samples and the interrogation of multiple manufacturing lots. Through our efforts, we were able to sequence the genetic regions involved in the abnormality and determined that it was unrelated to our manufacturing processes. I believe our understanding of engineered cell therapy is meaningfully enhanced relative to where we stood just a few months ago. As we have gone through this exercise, we do believe that we're now advantaged based on the detailed learnings from this investigation and feel increasingly confident in our approach. We believe we are even better positioned to lead the field in bringing an AlloCAR T product to the market. Earlier today, we began notifying our clinical trial investigators that the FDA holds have been lifted. Clinical sites have been keen to reengage, and we look forward to working with the site so that we can treat patients across our AlloCAR T development programs as quickly as possible. Allogeneic CAR T therapy is a rapidly developing field that continues to evolve both in scope and impact. We are privileged to stand at the forefront of this incredibly innovative therapeutic area and understand that we will encounter novel findings, which will challenge us as we pioneer this field. While we have experienced over the past few months in dealing with this situation, it's in many ways a microcosm of what the cell therapy field has experienced over the past 5 to 10 years. Learning curves are steep. The pace of innovation is fierce. Complex challenges will arise that require new levels of sophistication and the regulatory bar, especially as it relates to product quality will continue to be raised. The companies that end up succeeding in this field will be those with the experience, talent and resources needed to meet these challenges. Having gone through this investigation, I am confident that the team at Allogene has the inevitable knowledge, experience and perseverance to lead. Having achieved our objective of timely resolution of the clinical hold, we now must turn our attention to the greater goal of bringing AlloCAR T therapy to patients. As I have previously noted, the patient in whom the abnormality was observed was unable to receive autologous CAR T therapy and fail all prior regimens. This case highlights the very meaningful unmet clinical need in relapsed/refractory non-Hodgkin's lymphoma. We look forward to concluding our end of Phase I discussions with the FDA and plan to initiate our Phase II trial of ALLO-501A in relapsed/refractory large B cell lymphoma around the middle of this year. The trial initiation will represent another step towards fulfilling our mission to provide allogeneic CAR T therapies faster and more reliably to patients suffering from some of the most difficult-to-treat cancers. And with that, we will now open the call for questions. Operator?

[Operator Instructions] Our first question comes from the line of Tyler Van Buren with Cowen.

Congratulations on the update. It's great news. I have 2 questions. The first one is, you mentioned that you're now advantage and in a better position to bring in AlloCAR T product to market. So, to that end, has the investigation prompted you to incorporate any additional screening measures to your manufacturing process? Or is it sufficient as it stands. And the second one is, as you resume clinical activities, how do you envision the pace of enrollment moving forward? And have your priorities for enrolling certain clinical trials changed from 3 months ago?

Tyler, thanks for those important questions. I mean throughout this investigation, much of it was led by Rafael. So I'm going to ask Rafael to respond to both of those questions.

Thanks, Tyler. So as I mentioned before and David mentioned as well, the investigation really didn't uncover any involvement of TALEN gene editing. And there was really no evidence of any other abnormalities in any of our products. We undertook very extensive testing across all 5 INDs. So as a result, there are no new measures that we need to employ with regards to our processes or release assays or anything else with regards to manufacturing. And we're very pleased to be able to continue with the current process. With regards to the pace of enrollment, I don't think this issue really affects what will happen with regards to enrollment in the trial. We have continued throughout the process of the whole to engage with FDA on the design of the clinical trial and on the CMC issues, and that's been very productive. And we continue to -- those discussions towards launching the Phase I study. The investigators remain very engaged. And as I mentioned before, that [indiscernible]. And we anticipate that enrollment will continue just as briskly as it has in the past years during our Phase I study.

And Tyler, as Rafael said, this is relatively very clean removal of the clinical hold. There is almost no changes that we have to do in the manufacturing of our AlloCAR T product.

Our next question comes from the line of Mike Yee with Jefferies.

I appreciate the questions and the update. We had 2 questions, but they're related. Can you talk to any monitoring or other amendments to your planned studies, particularly managing patients or anything related to this event that may have to be implemented? And then going forward, should Wall Street expect that this type of event is plausible due to other external factors not related to [ TALEN ] gene editing and describe what is possible? And is it material and disclosable if something happened again? Maybe talk to that.

So Michael, this is Rafael again. I mean with regards to the impact on the studies, the impact is minimal. Obviously, we already -- as any gene editing program informed patients, and we have updated the informed consent as it relates to the potential for chromosomal abnormalities to occur. Other than that, there really hasn't been any impact with regards to the studies. And in general, I think the broader impact to the field, it is thankfully, at least in our case, really highlighting the fidelity of our TALEN gene editing technology. So this is something that we were very gratified to see in that -- we haven't actually had to make any changes, as I said before, because we could definitively identify these areas of breakpoint that were away from the TALEN side. So in general, as I said, we personally don't have any more obligations regulatory-wise with regards to this event. But whether or not there will be other repercussions in the field, I think remains to be seen with regards to what may happen in the future.

Yes. So Michael, the second question that you asked is a very important one. And so let me just expand our response on that. When we found this -- learned about this finding, I mean, we knew immediately the potential impact gene editing and chromosome changes and not only to what we are doing as well, but also potential impact to the cell and gene therapy. I mean, one -- that underlies why we took such an extensive investigation in to what has [ come ] to that particular patient to really get down to the bottom of it. I mean, certainly, the question about whether something like this will happen in other cell and gene therapy studies. I mean, given the history and given that we are dealing with live cells, certainly, the possibility is there. When it happens, I think what's important is how each company handles situations like this and come up with an explanation that will not derail the entire field. And certainly, our findings, I think, has a very little impact on what we do. And certainly, the finding that this has nothing to do with the TALEN gene editing is very reassuring. So stay tuned on this matter, but this really highlights one of the importance of investing in the manufacturing, especially product characterization and quality assurance and quality control of the cell products.

Our next question comes from the line of Salveen Richter with Goldman Sachs.

Two questions here. One on the time lines for data across your portfolio, given the update today? And then secondly, in discussions with the FDA as you were working through the chromosomal abnormality and the assay work and so forth. What, I guess, standards have been set for the case where something like this may occur in the future?

So Salveen, this is Rafael again. In terms of time lines for data, we obviously just came off the hold, and we are engaging with investigators, IRVs, clinical sites and so on to resume our trials. So I think it's difficult for us today to come up with specific times where data flow will come. But we will commit to really getting back to the investor community with more details about that. But suffice it to say that we are putting full energy in getting these studies resumed and restarted. With regards to chromosomal abnormality standards may occur, I think, obviously, that is up to FDA to make decisions. And I think it will depend on the nature of the finding. In our case, I think we were able to define precisely the nature of the abnormality and also the fact that this was naturally occurring process. Obviously, there may be findings in the field of gene editing that may occur in the future that may require further investigations depending on their nature, the provenance of the alteration, et cetera. And so it is -- this is a very nascent field, and it may evolve to the point that other release assays in the future may be required. But as a result of what we found, as I said before, there's really nothing else that we need to do based on this finding.

Our next question comes from the line of Jason Gerberry with Bank of America.

So just to confirm, it sounds like this FDA discussion that happens before you start your pivotal for 501 is more of a check-the-box administrative type of [ hoop ] and you would not expect any impact in terms of your ability to [ pool ] 501 data for purposes of -- as you think about a regulatory package. And then I realize you're not in a point where you can talk specifically about time lines, but there's a lot -- we expected to learn in 2022, about 715, either consolidation or GSI combo. So can you give us a sense, did you enroll any patients with those approaches prior to the clinical hold? And assuming that you can get back and running sometime in the first half, could we get a fulsome update by end of year to understand better your BCMA strategy?

So Jason, with regards to the FDA discussions, I mean they have proceeded, I think, in a very thorough fashion, and it's been really collaborative. As you know, we -- this is a co-development of ALLO-647 as well as 501A and all discussions have taken place on both fronts as well as very detailed discussions on CMC which continue, as David alluded to. So we are very enthusiastic and confident that we're going to be able to arrive at a position where we can launch this trial. In terms of the time lines of 715, we had begun enrolling, as we had announced before on nirogacestat on consolidation as well as on the TurboCAR, ALLO-605 programs, and they were put on hold and they're going to resume as soon as practicable. Hopefully, we will be able, as we said, in 2022 to give an update. But as I said before, it depends on how the pace of [indiscernible] is and how quickly we can resume the activities. But clearly, there's a lot of energy, a huge unmet need and a huge desire from the myeloma community to put patients in this trial. So I'm optimistic that we will be able to continue these trials very briskly in terms of approval.

Our next question comes from the line of Mark Breidenbach with Oppenheimer.

Congrats on speedy resolution of the clinical hold, of course. Kind of a 2-part question for me. First of all, can you use existing stockpiles of AlloCAR cells as your clinical sites begin enrolling again or will new batches seem to be manufactured? And the second part of the question is a little more science. If I'm understanding correctly, it sounds like the issue was related to a VDJ recombination error. And if that's the sense, I'm wondering if you can give us any more color on what type of recombination error occurred? And more importantly, why a VDJ recombination would be occurring in relatively mature T cells that have been infused into the patient. My understanding is that this process usually occurs or is restricted to very early stages of T cell maturation. Thanks for giving any color on that, if you can.

I'll answer these questions, Mark. I think they're incredibly insightful, by the way. So with regards to new batches, obviously, we stopped treating patients and we tested all the batches for the presence of the chromosomal abnormalities, and we believe that these batches are ready to be used again. So we will continue to proceed with the material that we have. We will make material as needed, but the old material is still viable. I think the question about whether this is something that occurs obviously in [indiscernible] only, there is actually plenty of literature that rapidly proliferating T cells and B cells can rearrange, the T cell receptor and the B-cell receptor, even if they're postfinding and they're mature cells. And alterations can occur even spontaneously, actually in patients as a result of this. So these are fragile areas of the chromosome that are subject to rearrangement. The machinery that actually exerts the rearrangements is active in these cells, particularly upon proliferation. So it's not something that hasn't been described in the past. So even though most of it occurs [indiscernible], it does occur also in mature T cells.

Our next question comes from the line of Michael Schmidt with Guggenheim.

I guess I had one on the planned registration study for 501A, that it sounds like you're getting ready to initiate that in the middle of the year. I guess, as we think about the study, perhaps relative to the ZUMA-1 trial of the TRANSCEND NHL study from Celgene. What are some of the differences in patient population that you would anticipate in your study compared to those? And are there enrollment criteria that are perhaps different or similar to those studies?

So Michael, the population would be relapsed/refractory across a variety of aggressive lymphomas. I think it will look very similar to the studies that led to the initial approvals of [indiscernible]. We are aware that there are patients that may move into second line, and we plan to continue to expand the program as time goes on, but there will still be sufficient patients with relapsed/refractory disease that will be able to come into the study. And there may be other subsets of patients with refractory disease that may be eligible as well. But in general, it will be the population that you are accustomed to seeing in the trials that led to the initial approvals.

Our next question comes from the line of Reni Benjamin with JMP Securities.

Congratulations on the update and lifting of the clinical hold. Rafael, you mentioned that there were updated and informed consent documents. And I was wondering kind of outside of this, do you need to monitor every new patient now for something like this going forward? And I guess related, how comfortable do you feel the FDA is with this finding such that if they saw it again, they would not put you, I'd say, on a clinical hold. Or do you feel that the discussions have been more along the lines that they're kind of saying, well, let's see how the remaining clinical trials go. And if something happens, we will want you to get to the bottom of kind of explaining why it might be happening?

Yes. Great questions. I think with regards to the first one, I think the answer is simple, we don't have obligations beyond the ones that we already have to monitor patients. We will -- obviously, if there's something occurs, like another finding occurs, we will be able to go back and do the work that's required in collaboration with FDA. But as it does a matter, of course, beyond changes in informed consent, there are no changes in terms of monitoring. I think with regards to the confidence of FDA, FDA just like us, found this as a pretty novel finding. And obviously, it's in the context of gene editing. So when you find something for the first time, it's important to actually try to get to the bottom of it. And we understood their concerns, understood their questions and we worked pretty diligently to resolve all these findings, Particularly, what is the provenance of the finding, where did it arise? And are there other implications for other patients? What about other batches. Those kinds of questions, which I think are fundamental to understand. In the future, I think, again, it will depend on the nature of the finding. But I believe that if there is a finding that is new and concerning with regards to the potential for this to impact manufacturing, particularly and impact patient safety, there will be a response from regulatory authorities. And -- but the nature of the finding that will lead to that and the nature of the questions, I think it will -- it's still to be defined. And as I said, we're all learning as we go along, and we've learned a great deal from this finding and hopefully, even though this wasn't a pleasant situation to be on hold, we are now pretty strong with regards to what we've been able to learn. So again, stay tuned when you start in a new field, there could be new findings that occur. And I think the reaction of both regulators and companies will be according to the nature of the finding and the potential consequences.

Our next question comes from the line of Dane Leone with Raymond James.

Congratulations on getting the clinical hold resolved. Two quick ones for me. Can you maybe just give us a heads up in terms of when you might be able to have a handle on providing a time line for IGNITE and TRAVERSE specifically and when we might be able to see first data from there, whether maybe on your 4Q earnings call, you might be able to clarify time lines? And then second question, just housekeeping actually from ASH, but were you guys ever able to resolve whether any patient and help to have been previously treated with CD19 CAR T? I know that had been outstanding for those patients that had prior CD19, but I think your team was looking into that.

Yes. With regards to the time lines, as I said before, it's difficult to say exactly when we will know about IGNITE and TRAVERSE. We're extremely excited about both trials. And I think the resumption, hopefully, will be brisk. There's a lot of interest from investigators, as I said before. And we will present data when we have a meaningful data set. And as soon as we think that is the case, we will do it in the context of a scientific forum. With regards to the ASH data set, there were patients that had received AlloCAR T therapy, 1 or 2 patients that in consolidation to we were able to determine that there were no patients there that had received actual AlloCAR T therapy. There was CD19-directed therapy, but not AlloCAR T. So that's sort of the outcome of the investigation in that consolidation group.

Dane, let me just add on. I mean I know that many of you have questions about our clinical study time line. I just want to realize that we just came off the clinical hold. It's just too early for us to map out the study reactivation and enrollment projections and data communication. So just give us a little more time to sort some of those operational issues out and we will update the time lines on our solid tumor programs as well as what we are doing in the multiple myeloma space. And certainly, with the pivotal study, we are projecting that the study will start midyear 2022.

Our next question comes from the line of Luca Issi with RBC Capital.

Congrats on coming off of clinical hold. I have 2 quick ones. One on the science. Wondering if you can comment on what percentage of the cells collected from the biopsy actually had the abnormality? I think you mentioned in the past that it was just a minority of the cells collected. So wondering if you can share the exact percentage today. And maybe related, wondering if you can comment on the nature of the abnormality. Was this a translocation, a deletion, an inversion, a substitution, like any color there would be super helpful. And then maybe related -- obviously, your PR mentioned the starting period trial is pending FDA discussion. And I know this question was asked before, but can you just maybe elaborate on what's gating to actually start that trial?

Thank you, Luca, for the questions that are also very good questions with regards to the particular percentage of cells that carry the abnormality. There are a lot of details that we uncover through the process. I can tell you that it was a percentage of the lymphocytes. So it wasn't all the cells in the patient. But with regards to the evolution, the number and how it evolves over time, all I can say is that we investigated this pretty thoroughly with pretty precise assays. And we don't want to jeopardize our ability to be able to publish this, and we're working pretty quickly to actually try to get this in the public domain through scientific press. And then the other question is with regards to FDA discussions. There are discussions across both clinical front and CMC front. Again, very happy that FDA continues to be engaged during the hold, which is really important because this sort of speaks of their interest in us being able to get these programs into registrational trials. We are advancing some of our manufacturing work streams. We're planning and identifying new clinical trial sites and all these activities we anticipate they're going to take us to midyear to complete. There are, as you know, a lot of CMC issues and the CMC bars, I said in my prepared remarks, is going up as well. And so we are ultimating discussions with what it would take to actually start the study so that we don't have any CMC issues during the conduct and eventually when we get results and are ready to market the product.

Our next question comes from the line of Raju Prasad with William Blair.

Congrats on the resolution of the hold. I wanted just to get a clarification on the regulatory outlook on chromosomal translocation frequency. I recall when kind of the hold was initially put into place that was kind of a big discussion point. Can you maybe just give some context on the frequency of chromosomal translocations that are in your release criteria as well as kind of how the regulatory body looked at that with regards to the resolution of the hold?

Yes, [ Raju ], let me take that question. In terms of product release criteria, we haven't really gone into any of the details on that. That's an evolving area. And we are working closely with FDA as we advance the clinical program. I mean, certainly, you may or may not understand the release criteria does evolve as we have more experience from the product manufacturing. And so that certainly was an experience that I had when I was developing axi-cel [indiscernible] Kite, and we certainly expect a similar sort of evolution of how we set the release criteria. So that's that -- and sorry, what was your second question?

Just a commentary on the regulatory outlook on translocation frequency?

Yes. I mean I think translocation, certainly, those are the ones that gets monitored. And certainly, we have been able to keep all those changes in a very well-controlled manner. So I don't really expect that to be changing in any significant way. I mean, certainly, what we have been doing is refining the assays to better characterize those events. And I think those are all moving in the positive direction. Another thing that I want to sort of emphasize is that allogeneic CAR-T, you may recall that our strategy of lymphodepletion is a transient lymphodepletion to allow cells to expand and carry out the antitumor effect. By nature of our lymphodepletion when the patient's immune cells reconstitute and we expect this to occur in the period of 6 to 8, maybe extending up to 12 weeks. So a relatively short period of time, immune system of the patient will reconstitute. And when that happens as what body normally does in foreign cells, such as allogeneic CAR T cells that we infused to the patient are expected to be eliminated by the patient's immune system. So let's not forget about that very important safeguard that is intrinsic to how we are delivering the allogeneic CAR T therapy.

Our next question comes from the line of Kalpit Patel with B. Riley.

Now that you have precisely defined the nature of the abnormality, can you comment if you find examples of similar types of case reports historically with auto CAR-Ts or any gene therapies, for example. And if there are no known case reports, can you comment if you expect the rates of the abnormality to be similar between all types of CAR Ts.

So I'll take the question. In the literature, in the cell therapy literature, there is really not a lot of data with regards to this. That's why my remarks before that this was kind of a novel finding that both regulators and us wanting to understand. Certainly, there's been K3 boards of integration, in particular, areas of chromosomes have led to high persistence. And those have been described, particularly by the UPenn group and so on. But in terms of chromosomal abnormalities, it's not something that regularly people check for other than in the gene editing space as David was saying, the translocations that are expected, those we obviously check for as far as release criteria. But other abnormalities, it's not something that people normally look at. So -- but having said that, there are data in the literature about chromosomal abnormalities has spontaneously happened in patients as the immune system reconstitute, and this is a normal process. These cells tend to be eliminated and those papers can be found in descriptions of both case reports and other series. It's not very abundant literature but also something that really has been described as a normal process without any clinical consequences.

Our next question comes from the line of Ben Burnett with Stifel.

Just a quick question for me. For the pivotal Phase II study, I guess, just given some of the results in the ALPHA2 in patients previously exposed to CD19-directed therapies. I guess can you talk about enrollment in the Phase II pivotal? And will that exclude those patients that have previously seen CD19 therapies.

Yes, Ben, this is Rafael. Based on our experience and also even the autologous experience with regards to retreatment, we believe that these patients do not benefit significantly from retreatment. So we do plan to exclude these patients going forward in the pivotal trial.

And if I could just ask one other kind of follow-up question around the discussion of the abnormality. And I guess just this notion that it occurred as a result of rapid T cell proliferation. Is it your opinion that this is just going to be a known risk that the field has to live with? Or I guess is there any appetite or push by the FDA to maybe seek a next-gen version of CAR T cells that result in perhaps more controlled or slower proliferation?

So Ben, let me take on that question. Obviously, this is something that the field is learning. I mean I think the big distinction that has to be made is whether this kind of process is happening in the body in a normal setting. And certainly, our investigation and review of the literature suggests that events like this normally occurs in the body. Whether we like it or not, somatic cells such as T cells are known to undergo changes, including some structural changes to the chromosome. We believe what we have uncovered is really in such a process. And as it happened, it happened in the AlloCAR T cells because that's where we are looking for this kind of event. As Rafael has said, these changes could be occurring in patients' normal T cells. And we know from how the body reacts, I mean these don't really have any clinical consequences. I think these are the important learnings. So from -- personally having been involved in this field for the last decade, I don't think this should really have any significant impact. I think what is going to sort of ease the situation even more is being able to characterize this and provide some kind of analytic assay to answer some of these important questions. So going forward, stay tuned. I mean certainly, from this experience, we mapped out the process and how to do it. And we will continue to do so if events like this happen in the future. But I do not think it will have the consequence that we have experienced, where we were placed on a clinical hold for the entire program. And certainly, I hope that FDA also understand this nuance of the cell therapy and manage the situation properly.

Ladies and gentlemen, thank you. That concludes our question-and-answer session. I would like to...

Yes. Before we conclude, let me just make a final remark. And I just want to thank everybody for joining us today. As pioneers in this innovative field, we expect to the first in kind of rare and unexpected findings as we have experienced over the last 3 months. We have dosed more than 130 patients to date with our gene edit AlloCAR T products and have reported our extensive safety experience at several medical conferences. Our experience combined with the results of this investigation, make me more confident than ever about the future of allogeneic CAR T therapies. Our team is eager to continue our work with all our partners as we resume study activities and look forward to a productive 2022. Thank you very much.

Ladies and gentlemen, that concludes today's conference call. You may now disconnect. Everyone, have a wonderful day.