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

Okay. Good morning, everyone. My name is Matthew Holt, and I'm part of the JPMorgan Equity Research Biotech Team here. It is my pleasure to introduce our next presenting company, Allogene Therapeutics. Presenting today for Allogene is the CEO and Co-Founder, David Chang. And please note that following the presentation, we're going to have a breakout in the Olympic Room, which is down the hall to the left. So with that, I'll turn it over to David.

Thank you, Matt, and Happy New Year. It's great to kick off 2020, updating our investors and supporters about what Allogene has been doing and what it intends to do throughout the year. Much of what we have done over the past 2 years is really laying down the foundation. And starting to move with our pipelines, as we prepare for 2020 and beyond. And hopefully, through the presentation, you'll be convinced about how we see the future, the way that we see it, and we'll also join us in make -- the progress that we will be making throughout the year. There will be forward-looking statements. And first of all, let's ground about the Allogene itself. Allogene, as the name stake is really focused on leading the future of AlloCAR T therapy, allogeneic CAR T therapy. What we have done over the last 2 years really laying down the foundation, starting with the people, where we stand with a fully hired management team plus 200-plus employees, where we stand right now. And the pipeline, which we believe is the industry-leading with the 2 key programs, ALLO-501 and ALLO-715 about to deliver the data in the first half and the second half of this year. What's enabling us is the strength of our capital position, where we ended the third quarter of last year with $600 million in cash. And as we think about the future, we are ramping up the partnership and business development activities. We previously have announced our collaboration with Notch Therapeutics in the iPSC space. And also, this morning, we announced a collaboration with SpringWorks on BCMA, CAR T using the gamma secretase inhibitor, and we'll talk a little bit more about that later on. So AlloCAR T, this is how we see where we are, what we intend to do and how we see the future. The platform is really what we have been working on. The AlloCAR T platform that we are embracing is based on TALEN gene editing technology, also using proprietary lymphodepletion, that is based on ALLO-647, our anti-CD52 antibody. Also important in our space is the manufacturing. And we are working on building our state-of-art manufacturing facility, which will provide not only our clinical supplies, but eventually, if we are successful, commercial products as well. That's going to enable us to advance our robust AlloCAR T [ plant ] portfolio that now includes 3 clinical stage as well as 7 preclinical programs across both hematologic malignancies as well as solid tumors. And certainly, this is a field that's undergoing rapid innovation. And we are also focused on building up a preclinical work towards the next-generation technologies. That includes turbo CAR T, which improves T cell fitness and working on immune invasion -- evasion, which is an alternative to immune suppression technology that we are taking. And also working on the solid tumor targets as well as renewable cell source for our products using the iPSC. Now it's been about 2 years since we started talking about the benefits of AlloCAR T. And now I stand more convinced that the allogeneic CAR T is what's really going to revolutionize this space. And that's based on access, cost, speed and reliability as well as continuing innovation. Simply put, we believe that this will enable us to provide more reliable cell products at a affordable cost to more patients. And we believe that's really essential for the growth of the cell therapy space. And we also have to be grounded as we think about this space. Whenever new innovation comes in, it's not necessarily the first innovation, but the subsequent innovation that really expands the field. We listed here some of the examples, recombinant growth factors. From the first product that was approved in 1982. For the subsequent innovation that's really based on post transcription and modification that with a multi, multibillion-dollar franchise across different companies. The same applies to the monoclonal antibodies. The first product in this space was OKT3 anti-CD3 antibody in 1986. It took another 20 years for the field to really expand as the humanization technique as well as making human monoclonal antibody technology came in vogue. And that led to the products like Humira, Avastin and Herceptin, all of 3 were approved in 1998, if I believe. Same applies to gene therapy. And cell therapy space on the rightmost. The first product here is Kymriah approved in 2017. But what's really coming in as a next-generation innovation is the application of gene editing, which will allow the realization of allogeneic cell therapy. So allogeneic cell therapy, I think there is a little bit of misunderstanding that people simply equating allogeneic cell therapy the same as autologous. Allogeneic cell therapy, I would say, is fundamentally different from what is being done in the autologous cell space. What will enable the allogeneic cell therapy is being able to overcome the fundamental immunology process of differentiating yourself from one another. As we use the cells that are derived from the healthy donor, with the intent of manufacturing cells from there and using it an -- in unrelated and multiple unrelated patients. The first thing that has to be addressed is so-called the graft-versus-host disease, where AlloCAR T could react against normal tissue in the recipient or the patients. We believe that this is very well controlled with the approach that we are making. The second one, which is slightly more tricky is the rejection of the graft, where the patient's immune cells will react and destroyed the AlloCAR T cells before they can carry out enough antitumor activity. We have a proprietary technology with a -- and the reagents we believe -- that we believe will enable us to control the rejection of the graft. So first topic, what we know over the years is the T cell receptor is the molecular mediator of the graft-versus-host disease. And what can be done with the advent of gene editing is selectively eliminating T cell receptor in our AlloCAR T cells. And what the data as we have accumulated, this is as we presented in -- at ASH 2 years ago is that graft-versus-host disease is essentially controlled by this approach. In 21 patients that we have treated, there was only 2 patients with grade 1 graft-versus-host disease, that was inconsequential in treatment. The other side of the equation is controlling the rejection. We do this by using ALLO-647 for selective lymphodepletion without affecting the AlloCAR T cells. The first technology is editing our CD52 in AlloCAR T cells. And the second technology that's allowing this is the use of anti-CD52 antibody ALLO-647. What this does is selective lymphodepletion of the host lymphocyte, without affecting our AlloCAR T cells. The importance of this was seen in the UCART19 study, which is shown on the right panel. There, there were 17 patients who were treated with a lymphodepletion regimen, that contains the anti-CD52 antibody. The overall response among those 17 patients was that 14 out of 17 achieving the complete remission. The other side of the equation was that there were 4 patients who simply got chemotherapy without getting anti-CD52 antibody, 4 patients, and none of those had cell expansion or the response that was desired. And also at the cellular level, we can see the differences in the depth of lymphodepletion as well as the speed of T recovery in patients who received chemotherapy alone, which is shown on the black line. And those patients who received both chemotherapy and anti-CD52, which is shown on the -- in green line. Now that leads to our pipeline, which I believe is one of the most robust CAR T programs in this industry. Starting from the top, programs that are directed against CD19 antigen, that includes UCART19 ALL, ALLO-501 in non-Hodgkin's lymphoma, the next-generation ALLO-501 A, again, for non-Hodgkin's lymphoma. Next, programs we cover the BCMA targets, starting with the ALLO-715, which is in the clinic. And announcement that was made today, planned combination study with nirogacestat, which is gamma secretase inhibitor. And then introducing today is a turbo CAR T program of ALLO-605. Below that additional targets that we are pursuing, CD70, which we intend to file IND this year, and ALLO-819 FLT3/AML. On the bottom are the solid tumor targets that we are also advancing, which includes both the targets that we have disclosed as well as the programs with undisclosed targets. Now on ALLO-501, this provides the primary objective as well as key secondary objectives, and the eligibility patient requirement, which really addresses relapse and recurrent large B-cell lymphoma or follicular lymphoma patients as well as those who have received prior AlloCAR T therapy. And we expect the initial data from this study to be presented in the first half of 2020. Next program is ALLO-715. Again, this program is in the clinic. We have listed the objectives of this study as well as eligibility criteria and the planned data release in the second half of 2020. What we have announced today is a clinical collaboration with SpringWorks Therapeutics. That's based on ALLO-715 and their gamma secretase inhibitor nirogacestat. The rationale for this combination approach has been validated from preclinical data as well as emerging clinical data that was presented at ASH 2019. What the combination suggests is that by using gamma secretase inhibitor, you can increase the BCMA expression in multiple myeloma, essentially taking the indication to the level of CD19 disease, as we know from the non-Hodgkin's lymphoma. What we are trying to achieve here is driving deeper and more complete and durable responses by enhancing the BCMA target expression for ALLO-715 in multiple myeloma. And we expect the combination study to be starting in the second half of this year. Now this slide really highlights just these 2 assets, CD19 and BCMA. The potential indications that we can exploit with these 2 assets. Where we are right now with ALLO-501 and ALLO-501A is third line relapse and refractory non-Hodgkin's lymphoma. Also listed there are different lines as well as different possibility within non-Hodgkin's lymphoma. And on the bottom, additional indications that we can go after with a CD19 directed therapy, that includes indolent lymphoma, MCL, CLL and ALL. Similar story also unfolds for BCMA. Initial entry of the ALLO-715 is in the third-plus line of Triple refractory patient population. Upon demonstration of proof-of-concept we intend to expand the pursuit of different indication across second, first as well as combination. And also post BCMA-directed therapy. I think this is really reflecting how the multiple myeloma field is evolving with the introduction of the BCMA-targeted therapies. And also listed on the bottom are the additional BCMA-directed therapy that could be useful, Waldenstrom macroglobulinemia. That's a little bit of mouthful. Our next program is ALLO-316, our anti-CD70 directed program. So CD70 is a very interesting target in a way that it is expressed both in solid tumors as well as many hematologic indications. We see this target as a potential bridge, as we advance the CAR T programs from hematologic malignancies to the solid tumors. On the right panel, we have shown the expression pattern of CD70 across different tissues, both in renal cell carcinoma and DLBCL, which are shown in pink as well as on the right corner, the normal tissue expression. There is a significant differential expression, which makes this a very attractive target for CAR T therapy. On the bottom shown is the in vivo efficacy model based on ALLO-617, using the renal cell cancer model. Shown under control is continued tumor growth, with a controlled treatment. On the bottom in red is what the AlloCAR T can do in this model, which is essentially eradicating the tumor. So that leads to this slide, what we will do in 2020, our clinical milestone. First is initial -- communication of the initial Phase I ALLO-501 Alpha trial data, which we expect to occur in the first half of 2020. Also initiating ALLO-501A clinical study in the same time frame. In the second half of this year, we plan to communicate the initial Phase I data coming from Universal ALLO-715 trial. And also file the IND towards the year-end, potentially bleeding into the first half of 2021, filing the IND for ALLO-317, which will be our third program -- CAR T program targeting CD70. What's enabling our ability to advance the clinical program at the speed that we are doing is the manufacturing support. We have invested quite a lot in the manufacturing, building up the team as well as building up the facility. So that we can really control the cell manufacturing. Currently, at our headquarters in the South San Francisco facility, we take care of all the process development and quality control as well as making -- developing assays for product characterization. We also are in the process of building out a facility in the East Bay, not far from our headquarters, that will include -- that will enable essential in-house manufacturing of all the cell products, starting with a clinical and eventually as we launch the product -- commercial products. We expect this facility to be ready for GMP manufacturing in 2021. Until then, we will continue to rely on contract manufacturer support, which has served us very well up to today. So how can we think about the future of the AlloCAR T platform. I mean there are many things that we can do, but I would like to highlight how we see this space. And what we view as an important aspect. One is improving the T cell fitness. The lead program that we are advancing here is the Turbo CAR, which I'll talk a little bit about as well as continuous manufacturing improvement that we are introducing. We are also working on other technologies, such as site-specific integration, which will enable more homogeneous cell products. Another area is preventing the graft rejection beyond what we are doing, and this is really looking not just for next year or next few years, but really looking into the future, enhancing the lymphodepletion and also working on the immune evasion. We are also trying to grow the field by improving the targets, adding additional targets, such as CD70 DLL3, but also looking at other technologies that will allow us to go into the solid tumors more freely. And lastly, iPS, which I believe is really the future of this field, as we go from the healthy donor derived cells to clonally derived iPSCs, that will enable us to have truly homogeneous cell products for the field. And the Turbo CAR T, this really describes at the high level, what this is. We all know that cytokine can stimulate the potency as well as durability of engineered T cells. What we have done is collapsing all the cytokine signaling into an engineerable format and expressing in the -- in our CAR T cells. This allows -- this avoids the -- some of the adverse events associated with the wider use of the cytokines, but -- and also focus all the signaling within the AlloCAR T cells. Potential benefit includes minimizing systemic toxicity and not stimulating the vast majority of the host immune cells. And delivering the survival benefit selectively to the AlloCAR T cells. And we are hoping that this approach will improve the efficacy of the CAR T cells and reducing the CAR T cell dose requirement. And also overcoming exhaustion to enable the CAR T cells to work more effectively in solid tumors. And we have been working on this for a number of years. And this highlights some of the early data that we have been generating in this space. On the left panel is a tumor model, where we compare BCMA CAR versus BCMA TurboCAR. What we are seeing is with the BCMA TurboCAR, we can get much deeper response and much long-lasting response. And this is shown at the individual animal level, which on the right panel BCMA CAR in the middle and BCMA TurboCAR on the right panel. And as I've said, in this analysis, while I'm not showing the data, TurboCAR T has shown to improve the engraftment, persistence and also has shown to be less prone to exhaustion in preclinical models. And we are very hopeful this kind of technology will really continue to expand the allogeneic CAR T field. Lastly, iPSC, this is really something that we are thinking, not just for -- in the next few years, but really as the future. A lot of work needs to be done in the iPSC. And that includes our main reason for entering into the collaboration with Notch Therapeutics, which is really leveraging their proprietary platform that allows the differentiation of iPSCs into the functioning T cells. And also critical in this setting is a use of iPSCs to clonally expand specific genetic codification in the iPSC cells. So the whole idea is that at the end of the gene engineering, you will have a master cell line that we can apply the differentiation technology to make them into functioning T cells. And the collaboration, as we have previously announced, gives us exclusive rights to indications in non-Hodgkin's lymphoma, leukemia and multiple myeloma. And as a part of the collaboration, given our strategic interest, we have taken a decision to hold a 25% equity in Notch Therapeutics. So to conclude my presentation, Allogene is really about leading today and creating the future for the allogeneic CAR T therapy. We have the portfolio, probably the world's best in the CAR T space with 17 different programs. We have the team with the experience and the knowledge in the cell therapy space. We have the capability, which has been significantly enhanced over last 2 years, really having the fully integrated in-house capability for discovery, translational research development and cell manufacturing, all the core components of what has to be done in this space. And certainly, we are exercising our scientific leadership as we try to advance the new platforms and new technologies. With that, thank you very much for your attention, and I wish all of you a fantastic 2020.

Okay, this is the Allogene Therapeutics breakout session. We have with us in the room here, our founder and CEO, David Chang; our Head of Research and Development, Rafael Amado. And this is Eric Schmidt talking to the microphone, and I know Matthew is here from JPMorgan. Matthew Holt, who's going to be moderating the session.

Awesome. Great. So I think I'll kick it off with a question or two and then we can open it up to the audience. But I guess, given that it's 1H '20, you guys have [ planned ] your first data update of 1H '20. Can you just -- you may not be able to tell too much about the specifics, but can you help set the stage of what we should expect [indiscernible] for readout for 501.

Yes. Thanks for that question. This is David Chang. Good morning, everybody. Yes, this is something that we have been asked multiple times.

Repeat the question.

Repeat the question. Thank you. So the question is, we have been guiding the Street that we will present the initial data from 501 in the first half. And the question, if I can rephrase is, what are you talking about? What are you going to present? And I have to say that really has been some of the key questions. There are certain things that we can say and certain things that we will defer to the actual data presentation. What I can say is that the study has been going very smoothly. And going back to the study design, this is a dose escalation study intended to demonstrate the safety and efficacy as well as potentially optimizing the lymphodepletion, which we believe is crucial to maximize the persistence as well as efficacy that's needed for the optimal therapeutic benefit. So the kind of things that would be relevant to understand all those things will be the extent of lymphodepletion that can be achieved with ALLO-647; the degree of cell expansion, which studies repeatedly have shown to correlate best with the response; and then actual response at the early time point, which will be at month 1, that's the time that we'd assess the tumor response. And then there's also a follow-up tumor response a month later. So some of the early responses will be included. And I know that based on my prior experiences, there will be a lot of questions about the durability of the response. And that's really going to be a time-dependent matter because the follow-up is something that we cannot control. And that's really -- time will tell. Rafael, do you want to add something to that? Anything else that I've forgotten?

No. I mean, I think that we're very happy with the progress of the studies. But as David mentioned, there are those finding trials, both in terms of cell dose and in terms of lymphosuppression. And we spoke about changes to the vertical to try to address what higher intensity of ALLO-647 could do to outcomes, and not just clinical outcomes, but also surrogate outcomes of what we think will lead to highest both persistence and duration of persistence. So it's -- we're in the exploratory phase and on track to deliver as per guidance.

And then, I guess, what's -- what about specifically on different NHL subtypes? Should we expect to see a mix? Should we expect to see maybe one type? Or like what should we expect for that in the initial?

Well, let me just say, stay tuned. I mean, that's not really the primary objective of the study. I mean, primary objective, as I said, is safety, trying to come up with optimized lymphodepletion and also finalize our cell doses. I mean, those are the primary objectives. Yes, we are starting more than 1 subtype of non-Hodgkin's lymphoma. As covered in the presentation, we are going after relapsed refractory large B-cell lymphoma, known as DLBCL, as well as follicular lymphoma. The reason that we're doing that is we believe that both indication, of course, is a great opportunity for the CD19 directed therapies. And there's also a high unmet need in both of those indications.

And then, I guess, you alluded to this a little bit earlier, but on the protocol amendments that you mentioned on your Q3 call, can you just like go over at a very high level like what the logic or rationale behind these were? And any more, I guess, information like if we're going to see any as implemented in the first data set.

Yes. So the question is about the protocol amendment, which we have disclosed in the third quarter earnings call. And let me ask our Head of R&D, Rafael Amado, to detail what the changes are.

Yes. So the original study was written as a dose escalation of cells, 40, 120, 360 million transduced cells. And naturally, because of the potential risk of GvHD mostly and other safety issues, the lymphodepletion was, if you will, minimized with the lowest possible dose of antibody. We were not concerned about GvHD, and I think this is something that the UCART19 data has shown. But we were proceeding slowly as it was prudent to do. So as we've treated more patients, we've wanted to optimize lymphodepletion. So AMD-647 -- ALLO-647, sorry, is being increased. And in addition to that, we have expanded the inclusion criteria in a way that allows us to be more flexible, so we can backfill programs or cohorts that already have been deemed to be safe, while we are waiting for the ability to dose escalate because as many of you know, there is so-called refractory or waiting period between one patient and another when we're standing -- starting or finishing the dose. So we have the ability to put more patients to use higher lymphodepletion, we have included some provisions to be able to retreat some patients in the same conditions. And I think an area that I find very important is the ability to treat patients that have failed CAR directed therapy, which is a real unmet need now that CAR therapies are available. So we can treat patients that don't have robust graphs because it's an off-the-shelf product. We can treat them right away because the product is available, so we don't have to wait for manufacturing. And we are testing whether we can treat effectively patients that have failed CAR therapy provided that they still express the antigen. So those are roughly the key changes in the protocol that we're implementing at the moment.

And as most of you know, Phase I protocols undergo many amendment. And I've involved in a Phase I study that had more than 20 amendments. So I am somewhat taken aback about the attention that's giving to what we said about the protocol amendment. As Rafael has sort of covered, I mean, it really increases flexibility, and that's coming from having treated few patients. We are a lot willing to treat something different, and that gives us flexibility in terms of how we explore the doses and lymphodepletion.

Yes. And I would just add to that, that the dose we started with ALLO-647 was really very, very small. And having news on lintuzumab in the past, which is used at 90 milligrams, and is used repeatedly for 4 and even 6 cycles, the doses that we're using now are still way below what a cycle would be for a patient with CLL. This is a product that no longer is in use, but was used extensively 10 years ago and before. So we're very comfortable with the doses that we've chosen, and we just have to see what the benefit ratio is.

And I guess that the CLL population in that informed your new dose for ALLO-647, I believe it's going to be 39 mgs to 90 mgs.

Yes. The 90 mgs is the standard dose, as you know, in the multiple sclerosis indicated, which is where rituximab is indicated now is 60. And so it was mostly the cellular kinetics and the pharmacokinetics and pharmacodynamics of cell decline and recovery that informed us and also, obviously, the initial safety with initial patients that we've treated.

Does anyone have any questions?

Should I go to the microphone or stay here? I can stay here. I can speak louder.

Use the microphone so I don't have to repeat the question.

Sure. So I'm [ Cindy ] from [ PRC Oncology ]. And for UCART19, it has a unique situation. It's developed in U.S. by Allogene and developed in the rest of the world by Servier or Cellectis. And talking about the next step is maybe the pivotal trial. And it may be the pivotal trial and the global registration submission. So we know EMA and FDA has a very close communication, especially thinking about a UCART19 product. So part of it, also I know from the history, EMA has a lot of tedious requirements regarding the biologic submission. So the first question is, if there is some specific regional questions addressed by the regulatory from EMA, how that will impact on the development, especially such as a manufacturer or maybe pediatric trial for the development in the U.S.? And how are you guys going to handle this close communication between EMA and the U.S. so U.S. development won't be really impacted by unnecessary hurdles?

Well, that's a loaded question, but let me ask Eric to clarify the U.S. versus European or ex U.S. about the existing agreement with Servier.

Yes. No, thanks for the question. Just a quick point of clarification. Allogene owns U.S. rights to the product, as you mentioned, UCART19, and Servier owns ex U.S. rights to the product, UCART19. But actually it's Servier that's leading the global development and regulatory approval of that product. So we have to defer to them on any comments that they'd want to make with regard to next steps and regulatory discussions. Sorry for that.

Yes. And the second question, I think it's sort of getting into a very technical level of how to coordinate what the feedback that we get from FDA versus EMA. This is a well-known issue. I mean personally I've been involved in developing a drug globally, both U.S. that we have to go out and engage through the scientific advisers and others to get information. And certainly, as we do that, one thing that I have learned, having worked in the CAR T space for a number of years, is that there's a lot of education that we have to do to the regulators. And so far, what was very clear is that regulators are very receptive. They're not set on any kind of sort of hard rules, and they are very engaging. And I'm very confident that coordination of the U.S. and European development will not slow us down.

Okay. I guess maybe going back to 501, what are the gating factors for initiation of the 501A trial? And should we be thinking about registrational trials in the allogeneic space in order to auto trials in terms of like patient population size and timelines?

Yes. Let me -- so the question that Matt was asking was about 501 versus 501A and whether there's any gating for introducing 501A. Let me answer that question, which is very simple. There's no -- everything is sort of in the work in progress. We don't see any difficulty in introducing 501A into the clinics, which we have said will occur in 2020. And the second question, Rafael, if you don't mind. If you...

Just for the webcast and those who are less familiar with the story. The reason that we're moving forward with 501A is that we've made a construct that's devoid of the rituximab off-switch that's inherent in 501. So right now, in our 501 studies, we need to screen out patients with NHL who have had recent rituximab exposure. And with 501A, we're hoping to overcome that challenge and make a therapy that's more broadly accessible to all.

Eric, thanks for that clarification.

Yes. So I think the question was in terms of registrational burden and what sort of studies we would need to get allogeneic products. I mean, I think that it is premature to be able to answer that question. And I think once we've had the regulatory discussions, dependent regulatory discussions, we should be able to update you. I think, obviously, the agency has a history and a track record of approving multiple products in an individual indication. I mean there are many diseases with multiple products in the same mechanism of action that each product is different eventually with its own benefit risk. And we believe that the allogeneic platform provides significant benefit to patients. So we'll obviously be highlighting the results of the trial and the results of the platform as we think of the most expedient way to bring our therapies, allogeneic CAR-T therapies to patients.

And then maybe a bigger picture question in lymphoma before we move on to some of your other programs. But given the updates that we've seen at ASH for a couple other modalities and also for an allogeneic competitor, just like thinking about in 5 years' time, where do you see allogeneic therapies slotting into the paradigm within lymphoma.

Boy, I wish I knew the answer to that question. But I mean the thing that I think is most exciting for the field, and that was really highlighted at ASH, is the plethora of products that have emerged since the advent of the fact that and the knowledge that engage in the immune system, particularly T cells, either through cell therapy or through bispecific antibodies can cause dramatic changes to patients that it wasn't that long ago, we seem to forget really, had no effective therapy. They had palliative therapy but no curative therapy. So again, historically, I think there are 15, 16 therapies in renal cell carcinoma. There's probably 12 or so in myeloma that are treated serially. So I think physicians and patients are going to find the space for each one of these products. I mean, to me, the key advantages will probably play out. Lymphosuppression will be highly optimized. [ Sales ] will be available on demand. Most patients that today cannot be treated because their graphs are very poor will have access to the therapy. Also, patients that have failed therapy in the past, whether it's antibodies or cell-directed therapy, will have access to it as well. There will there be issues as cost and benefit risk that will play a role. So my sense is that all these therapies will be used serially and the drugs are registered with initial studies, but then other groups will do studies to sort of assess eventually what their place is line of therapy it is, whether it's earlier or later, but my sense is that the role of the therapy will be quite obvious once the benefit risk is available to all of us.

I mean as the answer indicates -- and the question that Matt, you have asked is that that's a very complex question. I mean that includes many things as efficacy, safety and convenience, whether therapy is hassle-free or not. And at the end, what I've seen repeatedly is physicians really sliding our treatment. And we believe that allogeneic, what it's affording, I mean, the convenience and ready to go products, I mean, I think that's going to make a lot of difference in people's choices.

Okay. So moving to BCMA. I'm going to ask you a similar question to the one I asked on 501. Set the stage for us for what to expect in your initial update expected by the end of this year, and whether we should expect it to be pretty similar to the 501 update or if there's any obvious [indiscernible] for analysts.

So the question that Matt is asking is moving to the next program, that's 715. As we update the data in the second half, what to expect. I'm just going to make that answer very short. Essentially, the aspects that we covered for 501, the same things should be -- that's what we are focusing on.

Great. And then you touched on this in your prepared remarks, but for nirogacestat, what intrigued you about this asset? And without going into too much detail, are we looking for -- Eric, do you think you can grade the response rate, have more durable responses? Or how are you thinking about, based on what we know today and how this will play out in combination with your BCMA?

So by the way, nirogacestat deal is something that Rafael really spearheaded. So I'm going to ask him to answer that. We are really excited about that combination, by the way.

I think the -- obviously, the rationale is -- should be obvious by now, I think. Well, David explained it and there was data at ASH this year from the Fred Hutchinson Center Group, where they use another molecule, gamma secretase inhibitor, to continue the levels of BCMA expression to remain very high. And that's because GSI is essentially a cleaver of the molecule on the surface. So the idea is that the density of antigen, which is known to be important in CAR T therapy, would remain very high in the presence of CAR Ts. And potentially that the initial burst of activity which may drive durability would be much higher. So there are many Gamma Secretase inhibitors in the past, a lot of companies have them for the development of various diseases, including Alzheimer's and other malignancies. And now they're sort of making a comeback because of the potential to increase the BCMA expression and decrease BCMA soluble levels because BCMA soluble levels may trap the CAR and make it inactive. So we have chosen to partner with SpringWorks. They have a good molecule, their molecule is in development that -- we believe that's really important because having the molecular proof in 1 indication may make it easier for co-development, should that time arrive. But at the moment, we're just simply fixed on moving that combination as soon as possible into the clinic and look at the safety and efficacy. And although a lot of relapses occur with BCMA positive disease, as you may have heard, we still believe that having high-density of target is important, and these products really increase the BCMA molecules in the surface by up to tenfold or so in general. So we're pretty excited about testing it. And it will be one of several strategies to increase BCMA activity, including the TurboCARs, which is -- were introduced today for the first time, which will also be tested in BCMA.

And are you able to share more on your TurboCARs, like in terms of cytoplasts, what cytokines you guys are looking at or...

I mean there is a lot of flexibility in terms of what we can do. I mean, I think this is really -- okay, stepping back, the question is, can you tell us a little bit more about the TurboCAR. I mean this is really realizing what we have been saying about what can be done in the cell therapy. This is additional gene engineering, not just a stepwise, one product going to the next product, we can all package this into a single cell. And TurboCAR is really taking the CAR T fitness, T cell fitness to the next level. I mean the signaling that gets used for the CAR is signal 1 and signal 2, costimulatory as well as the CD3 signaling that everybody has been talking about. What that still doesn't provide is the cytokine support. So that some in the field, people consider as a signal 3. And what the TurboCAR is doing is packaging in signal 3 into the CAR construct. And in terms of what could be the nature of the signal, we can manipulate that to the various different degrees, whether that's more centered towards IL-7, IL-15 or other cytokines. That's the flexibility that we have with that technology.

And then maybe just to touch on ALLO-316. What gave you confidence that this should be your next target to go after? And just, I guess, anything you can say on what needs to be done to design the [indiscernible], that will be helpful.

[ I mean confidence ] is really how we think about therapeutic index, based on different targets. I mean we have looked at it -- this expression. We have done many preclinical work to feel comfortable about this target. Certainly, we still have to test in humans. But when it comes to the target validation, this is really rising to the top of all different programs that we have. So that, plus the fact that that we can really move the field into the solid tumors, when I think about both from the practical, what we have to do as well as a strategic perspective, we all felt that this has to be the next target.

Thank you, ladies and gentlemen, our time is up.