Hello, thank you for standing by, and welcome to the Allogene Therapeutics 2024 Platform Vision Conference Call. After the speaker's presentation, there will be a question and answer session. To ask a question during the session, you need to press star one zero one on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star one one again. Please be aware that today's conference is being recorded. I would now like to turn the call over to Christine Cassiano, Chief Corporate Affairs and Brand Strategy Officer. Ms. Cassiano, please go ahead. Thank you, operator, and happy New Year. Today, after market close, Allogene issued a press release that previews our 2024 Platform Vision, which we will also discuss at our upcoming JP Morgan presentation on January 10th. We also issued a joint press release with Foresight Diagnostics. Today's press releases and this webcast are available on our website. Following our prepared remarks, we will host a Q&A session. We ask you to limit your questions to one per person, as we will keep this call to an hour and do our best to get to as many questions as possible. Joining me today are Dr. David Chang, President and Chief Executive Officer, Dr. Zachary Roberts, Executive Vice President of Research and Development and Chief Medical Officer, and Jeff Parker, Chief Financial Officer. We're also pleased to welcome Dr. Alex Herrera, Chief, Division of Lymphoma and Department of Hematology and Hematopoietic Cell Transplantation at the City of Hope. Dr. Herrera will provide his thoughts on the opportunity in frontline consolidation and be available for questions during the Q&A. During today's call, we will be making certain forward-looking statements. These may include statements regarding the success and timing of our ongoing and planned clinical trials, data presentations, regulatory filings, future research and development efforts, manufacturing capabilities, the safety and efficacy of our product candidates, and 2024 financial guidance, 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 press releases and latest SEC disclosure documents. You're 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, and welcome to 2024 as we kick off an exciting year for Allogene. A year that has the potential to forever change the way CAR T products are used. Last year, economic challenges forced many companies to think differently. As a leader in allogeneic CAR T, we asked for even more from ourselves. We used this as an opportunity to critically evaluate our entire approach to make sure we are doing our best for investors and patients. Until now, CAR T development has been defined by how the trial's CAR T are made and used. It has built an entire field, one that has become increasingly competitive. But as an industry, are we really creating new options for patients when so many are targeting the same diseases in a similar ways for the same group of patients? When that happens, what is the impact to clinical trial recruitment, market opportunity, and even more importantly, how does this ultimately benefit patients? We asked ourselves these hard questions, even if it prompted hard choices and challenged our teams to think differently. We hinted at some of this during our last quarterly call, and today, we are excited to share with you our bold new vision for 2024. We believe now is the time to rethink development and trial design based on unique attributes of allogeneic CAR Ts, to do what no autologous CAR T has done before. This entirely new approach to development, being first, fit, and well fast, creates an advantage for our investigational allo CAR T products now and in the future, while providing a clinical framework to generate far more competitive CAR T products and dramatically expand opportunity. The result has been reinvigorating to our teams, to the key opinion leaders who have been part of this process with us, and even in discussions with FDA. Four core programs demonstrate this new approach that allows us to tap into the unmatched potential of an allogeneic CAR T. The foundation and cornerstone is ALPHA3, the industry's first pivotal trial for frontline consolidation in large B-cell lymphoma. When we spoke of an earlier line trial, LBCL, most anticipated that we are targeting second line, but our ambitions were more bold. This groundbreaking trial has the potential to leapfrog all other CAR Ts and embed cema-cel. This is cema-cel, previously referred to as ALLO-501A, in frontline treatment and making it available in community cancer centers, where most newly diagnosed patients are managed. What's incredibly exciting about the direction of this program is that we believe it differentiates cema-cel while dramatically expanding the market opportunity. The outcome of this pivotal trial could allow cema-cel to be embedded in the frontline setting, where autologous therapies are far less feasible. Cema-cel could be immediately accessible in community cancer centers following treatment with standard R-CHOP to boost cure rates, potentially rendering late-line treatments obsolete. This opportunity to change the treatment paradigm for patients with LBCL has driven our decision to deprioritize our third-line ALPHA2 expanded trial in LBCL. The second is our new ALPHA2 cohort for the treatment of chronic lymphocytic leukemia. We believe a fifth allogeneic CAR T is perfectly poised to address this market, as it could potentially address a limitation of autologous CAR T, where poor T-cell fitness is a known barrier to efficacy. Next blends what we understand about CD19 with one of our most exciting platform technologies, Dagger. One common question we often received in 2023 centered on our plans in autoimmune diseases. It is, without question, one of the most interesting new areas for CAR T. While others are racing to enter the clinic with similar approaches, we are leveraging our experience in developing allogeneic CAR T to best capitalize on their differences. We are rooting for these first-generation approach to be successful in resetting autoimmune diseases to establish their potential. Then, like what we are aiming to do with our frontline consolidation trial in LBCL, we intend to lead with a different kind of first. ALLO-329, our first next-generation CD19 Dagger program, will focus on scalability and reduce our chemotherapy-free lymphodepletion, positioning AlloCAR T product to transform autoimmune disease management and meet the inevitable demand of the market in a way only this kind of allogeneic CAR T product can do. The last of our core program is, of course, focused on solid tumors, one of the last and probably the largest frontier that is yet to be fully explored by CAR T. Our ongoing TRAVERSE trial in renal cell carcinoma advances the underlying Dagger approach to optimize CAR T cell expansion and persistence to maximize the potential of AlloCAR T in solid tumors. As we push for cell expansion, we observed treatment-associated inflammatory response in some patients, which is now being addressed with a specific management guidelines introduced in the protocol. Zach will go into a bit more detail on each of these core programs next. But before I turn the call over to him, I would like to reiterate the importance of our own wholly owned, state-of-the-art GMP manufacturing facility, Cell Forge 1, to these plans. We will continue to focus our manufacturing efforts on CF1, as we believe this strategic asset is critical to scaling for the future we foresee for CAR T. Lastly, the benefit of our 2024 platform vision now results in a streamlined trial footprint as well as focused pipeline prioritization, allowing us to implement the restructuring of resources this quarter. Importantly, this will reduce cash burn and is expected to extend our financial runway into 2026. Jeff will provide full 2024 guidance in our fourth quarter year-end 2023 calls later this quarter. Now, I would like to turn the call over to Zach. Thank you, David. By now, you can likely ascertain that we are very excited about this new approach to development. I'll start with a quick review of what we're doing in CLL, renal cell carcinoma, and autoimmune before commenting on the program that started it all in terms of driving a new way of thinking. Let's start with CLL. We believe that there is an opportunity to set a higher bar. There is a growing need for effective treatment in CLL, post-BTK inhibitors and BCL-2 inhibitors. While recent autologous CD19 CAR T data has been a positive step for patients with relapsed refractory CLL, these therapies are still not meeting the efficacy bar or expectations set in relapsed refractory large B-cell lymphoma. This is likely due in part to T-cell dysfunction and high circulating tumor burden in CLL, making the isolation of functional T-cells for autologous CAR T manufacturing difficult. Furthermore, there is strong scientific rationale to believe that AlloCAR T product, which is derived from healthy donor cells, could raise the bar and potentially create a clinically meaningful advance for these late-stage patients, with a one-time dose and simpler administration and logistics. The new phase I ALPHA2 cohort will include 12 patients treated with cema-cel. This study, driven by investigator enthusiasm, will leverage currently active ALPHA2 trial sites in the U.S., which should allow it to advance quickly. We expect to begin enrolling in Q1 2024, with initial data projected by year-end 2024. Next is ALLO-329, our next-generation CD19 Dagger program in autoimmune disease. We are applying our deep understanding of CAR Ts to design a next-generation allogeneic CAR T with reduced or chemotherapy-free conditioning, which we think will be critical to sustain the scale of the market while meeting the unique requirements of these patients. It bears pointing out that the risk tolerance for these patients is very different than those with cancer, in large part because of patient demographics, the wide availability of effective therapies... and rheumatologists' general lack of experience with chemotherapy, leukapheresis procedures, and cell therapies in general. Incorporating Dagger into ALLO- is designed to reduce or eliminate the need for standard chemotherapy while targeting CD19 positive B-cells and CD70 + activated T-cells, both of which are known to play a role in autoimmune disease. Initiation of this phase one trial with ALLO- is expected in early 2025. While this might be later than some of the competitor trials, differentiation in this space is key. CD19 CARs and cell therapies have begun to crowd the autoimmune space, with similar approaches targeting the same patients. We believe moving forward with an Allo CAR T that can potentially offer a milder lymphodepletion regimen, especially in this patient population, while still meeting the market demand, will prove to be the better long-term opportunity. I'll now talk about what we think could be the key to CAR T in solid tumors. A fundamental discovery in early CAR T trials was the use of tocilizumab and steroids, the "safety key" needed to mitigate treatment-associated CRS without compromising CAR T function or efficacy. We believe we have made the same cornerstone discovery in the TRAVERSE trial with ALLO-316 in RCC. We know how important this trial is, so we've been extremely careful in how we advance it. In this trial, we have observed remarkable allogeneic CAR T cell expansion persistence, which we believe is driven by the unique CD70 CAR biology that we call Dagger, that allows elimination of alloreactive host lymphocytes. This biology has brought the potential for clinical efficacy, not often seen in patients with relapsed/refractory renal cell carcinoma, but it has also resulted in a hyperinflammatory response in some patients as CD70 CAR T cells expand and persist. Leveraging recent advances in the management of hyperinflammation following autologous CAR T administration, we've developed a diagnostic and treatment algorithm similar to what we developed in our previous life in the early days of autologous CAR T development when dealing with CRS and ICANS. Like toci and steroids, this algorithm may mitigate the treatment-associated hyperinflammatory response without compromising the CAR T function needed to eradicate solid tumors. We have recently implemented a protocol amendment in the TRAVERSE trial to further maximize the benefit of ALLO-316. We are targeting a medical forum in the second quarter of this year for our next update from this trial, where we plan to discuss this algorithm. We believe this may be a critical advance for both the TRAVERSE trial as well as the industry at large. A more robust data update from the ongoing trial with the updated protocol is planned for later in 2024. I'll now wrap up my prepared remarks, closing with our commanding pivot in our CD19 program. This is something I am particularly proud to be a part of, perhaps even more so because I've had the opportunity to work hand-in-hand with our various advisors and potential investigators on its creation. The level of enthusiasm for this trial has been incredible, no doubt due to the fact that the desire for this type of study has been decades in the making, but it just wasn't possible until now. In order to make this kind of a trial happen, we needed two things. First, a sensitive MRD assay and a one-time powerful treatment that could be administered immediately upon discovery of MRD positivity. Between Allogene and Foresight, we now believe we have the right combination. The groundbreaking design of the ALPHA3 first-line consolidation trial builds upon the results demonstrated in the phase I ALPHA2 trial and leverages an investigational cutting-edge diagnostic test developed by Foresight Diagnostics to identify patients who have minimal residual disease at the completion of first-line chemoimmunotherapy for treatment with cema-cel. Although first-line R-CHOP is curative for many with LBCL, approximately 30% of patients who initially respond will go on to relapse. The standard of care after frontline treatment has simply been to watch and wait for the disease to relapse. In this setting, speed matters. Autologous talks about vein-to-vein time. At Allogene, we talk about brain-to-vein, which, by which we mean that as soon as the doctor determines that a patient could benefit from a CAR T therapy, one can be made available immediately, and treatment can begin within days. ALPHA3 takes advantage of cema-cel as a one-time, off-the-shelf treatment that can be administered immediately upon discovery of MRD, following six cycles of R-CHOP, positioning it to become the "seventh cycle" of standard frontline treatment available to all eligible patients with MRD-positive disease at the end of frontline therapy. ALPHA3 builds on the growing understanding that administration of CAR T therapies to patients with low disease burden improves both safety and efficacy outcomes. Cema-cel's phase one safety profile, with low rates of CRS and ICANS, already permits its use in the outpatient setting in relapsed/refractory patients and may further improve in patients with no radiological evidence of disease. Startup activities for the ALPHA3 trial have already begun. This, the study will randomize approximately 230 patients who are MRD positive at the end of frontline therapy to either consolidation with cema-cel or the current standard of care, which is observation. The design, with a primary endpoint of event-free survival, will initially include two lymphodepletion arms, one with standard fludarabine and cyclophosphamide plus ALLO-647 and one without ALLO-647. We believe that the outcome of this pivotal trial could be paradigm changing, but you don't need to hear this from me. I'll turn the call over to Dr. Herrera, so he can provide his perspective, and then we can go to Q&A. Dr. Herrera? Thanks, thanks so much, Dr. Roberts. So as mentioned, I'm the Chief of the Lymphoma Division at City of Hope and the Co-director of our City of Hope Clinical Trials Office and Research Infusion Center. I've led over 40 clinical trials developing novel therapies, including cellular therapies for Hodgkin and non-Hodgkin lymphoma. I've led over 15 investigator-initiated trials and have been the study chair on the steering committee of several phase iii clinical trials in patients with diffuse large B-cell lymphoma or Hodgkin lymphoma. My particular clinical and research focus is on diffuse large B-cell lymphoma and on Hodgkin lymphoma, but I see patients with and conduct research in all lymphoma subtypes. My primary translational research focus in my career has been on studying novel sequencing-based methods of assessing minimal residual disease, especially circulating tumor DNA assessment. I've conducted research with a range of MRD or circulating tumor DNA assays, including clonoSEQ, CAPP-Seq, and now this PhasED-Seq technology that will be used in Allogene's proposed ALPHA3 clinical trial. The PhasED-Seq assay is the most precise MRD assay in the lymphoma space, and the one—the most precise one that we've had. For years, we've been refining MRD technology to arrive at this time point, where we are ready to start conducting MRD clinical guided clinical trials. And with this assay, we're finally able to move forward with that aspiration. Making the mistake, taking this step really is crucial for our field and for patients with lymphoma. For decades, we've been using an imperfect imaging tool for PET scans, PET scans to make clinical decisions in lymphoma. Over and over again, even with inferior MRD assays to PhasED-Seq, we've seen that circulating tumor DNA assessment is more sensitive and specific for detecting residual disease than PET. The proposed ALPHA3 trial, if successful, really would be transformative. As Dr. Roberts mentioned, about a third of patients with aggressive lymphoma are not cured with standard frontline therapy. Typically, we wait for the disease to recur before we initiate treatment. Unfortunately, though, by that point, the lymphoma is usually galloping along, and we're often pretty far behind the eight ball. With this highly sensitive assay, 90% sensitive for detecting residual lymphoma at the end of frontline treatment, which is the time point where the test will be deployed in ALPHA3, we could intervene when there is a low burden of residual lymphoma and quickly deliver a proven off-the-shelf therapy to consolidate the initial treatment and hopefully cure more patients with the first course of therapy, which really is, you know, that's our, that's our goal. So I'll hand it back over to the team, but I'm happy to take any questions about MRD assessment, clinical, you know, about the clinical trial, about lymphoma, about the Dolphins' chances of winning the Super Bowl. Sorry, just kidding. Thank you, Dr. Herrera. Operator, we'll now open the call for questions. Thank you. At this time, we'll conduct a question- and- answer session. As a reminder, to ask a question, you will need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by when you apply the Q&A roster. One moment for our first question. Our first question comes from the line of Salveen Richter from Goldman Sachs. Your line is open. Good afternoon. Thanks for taking my question. With regard to the ALPHA2 trial and discontinuing the study in the third line CD19 setting or in the third line setting with CD19, you spoke to clinical trial recruitment, market opportunity, and clinical profile here. Maybe just help us understand how those factors played into it. And so when you look at cema-cel going into the frontline setting post-chemotherapy, your confidence that there is that opportunity there and that the profile will be reflective of what you need to see, and just speak to how big that opportunity is in the context of post-chemo and with the MRD aspect as well. Thank you. Thanks, Salveen. Happy New Year, and, you know, great question. You know, this is something that we have spent a lot of time, you know, thinking internally, as well as, talking with the investigator to really understand, you know, what's happening in the large B-cell lymphoma area. You know, the foremost is the existing unmet need in the frontline setting, where, you know, 60% of the patients can achieve cure, but the remaining 30% of patients who initially respond, they are essentially in a watch-and-wait situation, you know, waiting for their disease to recur before they can act on it. This is the part patient population that we are going after with the ALPHA3 study. So essentially, when you roughly think about 30,000 patients being treated in the frontline setting, you know, 30% represents close to about 10,000. That is the patient population, which far exceeds the market opportunities that currently exist in the second or the third line setting. It was not an easy decision. I mean, you know, since we expanded the clinical study footprint of ALPHA2 and expand in Europe, you know, we were beginning to see pretty nice uptick in the enrollment rate. But when we take a step back and look at what we are trying to do with the ALPHA3 study, and if we are successful, and we have, you know, high belief that based on the profile of cema-cel, this will be a highly effective treatment in the consolidation setting. When we think about if this study is successful, essentially, you know, we will push more patients into the cure, and fewer patients will be needing the second-line treatment. The second line and ultimately the third line, the market will diminish based on the outcome of the ALPHA3 study. So we have to factor that in, you know, together with how we prioritize our resource and came to an ultimate conclusion that the best course for what we need to do as a company, and that also includes, you know, commitment to the patients and investigators... is to deprioritize and eventually shut down the ALPHA2 and expand study. And, you know, frankly, this is the right decision, and I wish that we could have made decision earlier, except that, you know, the assay, the partnership that we have just entered with the Foresight, the assay to diagnose these patients who are MRD positive, the sensitivity and the specificity of the assay was not quite at the level until Foresight introduced their assay. This is what's really enabling us to really take the right course of action. You would, you know, it would cema-sell, and, you know, and, you know, we'll see. I mean, you know, we are really prioritizing, and as we have said in the prepared remark, study activation activities are already underway. Thank you. Thank you. One moment for our next question. Our next question will come from line of Brian Cheng from JP Morgan. Your line is open. Hey, guys. Thanks for taking my question this morning, this afternoon. Based on what you have seen so far, how should we think about cema-cel's benefits in terms of event-free survival as consolidation in the front line? And, you know, in the MRD positive patients with, that's being treated with standard of care, what is the typical event-free rate there? Thanks, Brian. This is Zach, and I'll start, maybe I'll ask Alex to weigh in as well. So, there's two concepts to keep in mind with this study. First is this assay, which, as David mentioned, is an absolute foundational part of this ALPHA3 program. And what this assay has done, which no assay before it has been able to show, is essentially, you know, a very high positive predictive value, meaning if you have MRD-positive disease at the end of treatment, you are very likely to progress. And the data that Foresight has already shared publicly with this assay in LBCL has shown that, in fact, you may progress very quickly, within a matter of weeks after completing therapy. And that's certainly something that is typical in routine clinical care. Sometimes these patients just may get into remission and then blow right through and progress. So the assay is one critical component. The second component is the intervention, and of course, we're going to be administering cema-cel to these patients. Now, what is another attractive component of this design is that patients who have low burden of disease when they receive CAR T cells, whether it's Allo or autologous CAR T, tend to have better outcomes, both safety and efficacy, so lower rates of CRS and ICANS, more durable remissions. So these two items coming together at the same moment, patients are relatively healthy coming out of frontline therapy, they're in remission, and we're able to deliver a treatment to them while they're in a state of no radiological evidence of disease. So for these reasons, we do believe that this will be a highly efficacious therapy, and it will meet that unmet need that is carved out by MRD positivity at the end of frontline. But maybe I'll ask Dr. Herrera to weigh in and add any color he sees there on either the test or the intervention. Thanks. Thanks, Zach. Yeah, no, I agree. You know, I think it's—this is really what we've been driving towards in the field. Like I said before, PET scans are a really imperfect tool. That's what we have had available to us. But you know, these MRD assays have always even, you know, kind of in their infancy, were typically better than our usual imaging. And now they're really quite sensitive and quite specific. The event rate for, you know, if a patient is MRD positive, you know, at the end of therapy, the likelihood of their relapse is really high. And so given that information, I think what you know, Zach said is right on point. You know, intervening with an off-the-shelf therapy, you know, that is, you know, has proven efficacy, but also, I think the point that CAR T cells tend to be, you know, tend to be better tolerated, there's less toxicity at a lower, when there's a lower burden of disease is a really key point, right? You know, these therapies have led to durable responses in patients with relapsed refractory disease. It's one of the, you know, this is, these are the only therapies that we have, CAR T cell transplant, that we know can lead to durable responses. So administering that at a low burden time point when toxicity is likely to be lower, you know, and efficacy is likely to be high is a really, really exciting opportunity. Look, patients aren't excited to wait for their disease to relapse. It's a really high-stress time. If you had a highly sensitive test that could say, "Hey, look, your likelihood of relapse is really high," I think most patients would take the opportunity to get additional therapy to try to prevent that relapse from happening. Great. Thank you. Thank you. One moment for our next question. Our next question will come from line of Michael Yee from Jefferies. Your line is open. Thank you. Happy New Year. Couple of good questions, but they're all under one topic. Following on the last question, can you explain a bit what you think the actual median EFS is for MRD positive patients coming off R-CHOP? Like, is that months? Is it years? And you just made a comment that some people could progress in weeks. Obviously, I'm not sure CAR T would benefit that specific group. So can you just describe what you think the Kaplan-Meier curve is for MRD positive EFS patients? Because that would give us some understanding of the time course of the study and the overall time and cost of the study. Even though I think the study will work, I just want to understand the timing and how you think about that. The second question is related, which is that even though you are the earliest stage CAR T study, my understanding is that there's ZUMA-23 running head-to-head versus R-CHOP. So maybe it would be helpful to understand your thoughts around that study, and maybe Dr. Herrera could explain whether he thinks that's gonna work, because I think that's head-to-head versus R-CHOP. Thank you. Sure. So maybe I'll, I'll again, take a first crack at it, and then I'll let Dr. Herrera weigh in as well. So your first question, Mike, on the timing of the relapses. So the data that has been, again, shared publicly by Foresight, looking at, you know, pooled cohorts from multiple different clinical trials, multiple different settings, has indicated that the EFS, PFS, which overlap highly in this setting, is actually very short. Median is somewhere between six and 12 months. So these patients tend to progress quickly. That subgroup of patients that you alluded to, who I alluded to, which progress within weeks, that's probably about a third of overall MRD positive patients, again, according to the data from Foresight. And those patients can progress within one to two months. So it's a great moment, I think, for us to point out that this is one of the unique attributes of an off-the-shelf therapy that allows us to intervene specifically for those ultra high-risk patients who are bound to relapse very soon after completion of treatment. So just to sort of frame this up, you know, this is a blood test that will be performed at the end of treatment. We'll get those results within days, and then immediately for patients who are MRD positive, they'll be randomized to either observation or treatment. So we expect to be able to initiate lymphodepletion and CAR T cells very, very quickly in these patients within, you know, a very short window after their MRD positive test has come back. So this is actually one of the unique attributes of an off-the-shelf treatment that we think is important for this trial. And, you know, for that matter, we, you know, given the fact that this EFS that we expect between six and 12 months in the treatment arm, we do expect to have a significant impact to that EFS and potentially plateau that curve out well above what can be expected in the observation arm. The second question that you had, Mike, was on ZUMA-23. This is a fundamentally different design that we're proposing here. So in ZUMA-23, they are using clinical tools to ascertain the risk profile at the time of diagnosis, like the International Prognostic Index. That is a clinically validated, albeit crude tool, to really understand whether patients are going to have a good outcome to R-CHOP. In fact, many of those patients will actually do well with R-CHOP or a similar chemo immunotherapy regimen. What we're doing here is we're actually allowing the disease biology to declare itself over the course of R-CHOP treatment, and if they have residual disease at the end of that therapy, we have our answer. We know this patient is in an ultra high-risk category, so we're targeting intervention for that group right away. But maybe Dr. Herrera, you can add some color there, too. Yeah, no, I think, you know, Zach's right on point. You know, the median time that a patient's gonna progress when they're MRD positive at the end of treatment using Foresight's assay, you know, is probably between that 6-12-month time point. But the relapses happen, you know, if you look at the curves from the publicly available data from Foresight, the relapses happen, start happening within a month already. So I think there's a huge advantage to having an off-the-shelf tool that you can use. But just some first for, like, some additional color, you know, I would say that overall, you know, again, you know, with the data that we have available, more than 80% of the patients who are MRD + are gonna relapse within two years of that kind of end of treatment blood sample being collected. So... And it's probably, you know, probably two-thirds are gonna be relapsing within the next year. So, you know, this is a test that, you know, really suggests if a patient has you know, MRD detected, it's a really high likelihood they're gonna relapse, and acting quickly will be, will be extremely helpful. I agree, also with the point that, you know, this, this really is a different trial. I think one of the challenges with trying to introduce CAR T cells as a replacement for our current frontline therapies in aggressive lymphoma, aggressive B-cell lymphoma, is that our current therapies are fairly effective, right? So, you know, we've had trouble designing trials, you know, similar to ZUMA-23, and I was part of designing ZUMA-12, for years now, because at the end of the day, you know, two-thirds of patients and typically with clinical trial populations, it's higher, like 70%-75% of patients are gonna be cured with our frontline therapies. That's a high bar, right? And so in this trial, we're not sure... You know, the idea is that you know, we're not going to replace frontline chemo immunotherapy, which is effective. You know, the idea that Allogene proposes to undertake here is to add on to that, right? So, and using a really sensitive tool, saying, okay, rather than, you know, the way we usually do trials in frontline treatment of lymphoma is we're going to add on a therapy to R-CHOP, let's say, right? Like polatuzumab vedotin. You know, or we're going to substitute one drug in, et cetera. So we're exposing everybody, the entire population of patients with diffuse large B-cell lymphoma, to an additional therapy. But two-thirds of them, 70%-75% in a clinical trial, were going to be cured anyways. Here we're using a really, like, sensitive and specific tool to say, "Okay, we gave you your frontline therapy. This, you know, this population of patients, this, you know, let's say 30%, one-third of patients who are likely to relapse, we've found the great majority of them with this test." Now we're so refining who we're going to introduce this intervention into this, to this more limited population, who's very likely to relapse. That's kind of, you know, building on the population of patients that we're already cured. Now, the idea is, let's see who else we can cure with adding this therapy to frontline therapy. Makes sense. Thank you, and appreciate the 6-12-month data point. Thank you. Thank you. One moment for our next question. Our next question will come from the line of Tyler Van Buren from TD Cowen. Your line is open. Hey, guys. Definitely some exciting updates in a differentiated strategy, and forgive me for asking one more ALPHA3 question, but is there any historical precedent for treating MRD+ patients immediately after R-CHOP in the front line? And, based on, related to that, based on your conversations with the FDA, specifically, what EFS benefit, perhaps by months or hazard ratio, would you need to show on the primary endpoint versus control for approval? Hey, Tyler. Thanks. Zach again. So to our knowledge, this is the first pivotal study that's been proposed that uses MRD as an eligibility criterion. I'll let Alex, in a moment, reflect on whether there have been other sort of exploratory proof-of-concept studies that may have occurred in academia, but this is the first time that it's ever been done at this scale. With respect to our interactions with FDA, you know, obviously, we're not going to go into detail there, but suffice it to say that, you know, we read with interest in the last few months and years their focus on biomarkers such as MRD as tools for the use in clinical development, including its use as a biomarker for patient selection. And so, we found that they were quite receptive and the conversations were really productive on this study design. They recognized that the risk of patients with MRD positive was extremely high as defined by this tool. And so the bar there is actually quite low, Tyler. You know, we, of course, want to cure every patient that we can cure, but because these patients do so badly and they end up going on to second-line treatment, there is a, it is. The bar is very low for an improvement there. But, Alex, can you speak to whether MRD has been used in other settings, such as what we're proposing for ALPHA3? Anything else you may have to say on the potential improvement for the patients who are MRD positive? Yeah. So, you know, really, the tools haven't been refined enough in Diffuse Large B-Cell Lymphoma to design trials with MRD as kind of a decision point for the clinical intervention. In Mantle Cell Lymphoma, in the, you know, NCI cooperative groups, we did a trial using an MRD assay to randomize patients to getting an autologous stem cell transplant compared to no transplant. So the, you know, there is some precedent for the concept of using MRD as a decision point. But in Diffuse Large B-Cell Lymphoma, certainly in the frontline setting, this is, you know, this would be the first that I'm aware of. But, you know, truly, this is where we've been building towards for a long time. I mean, in the field, as investigators, you know, we've wanted to refine the populations that we expose to these, to therapies, so whether it be CAR T, you know, cellular therapies or other, or other novel therapies, we've been wanting to refine that, you know, for, for as long... You know, people use the IPI, like, like in ZUMA-23. We've been trying to refine populations for a long time, and now the assays are finally, you know, finally there, for us to be able to do that. So, you know, I think... Sorry, what was the second half of the question? I apologize. Just about the unmet need and what, you know- Oh, yeah. What the, yeah. Yeah, yeah. So, you know, truly, I think if let's say we're not curing about a third of patients with our frontline therapy, if you look, you know, kind of what's the curability of those patients once they relapse later on? You know, the bar is pretty low. I mean, you know, in CAR T cell studies, we've always used SCHOLAR-1 as a comparison, but, you know, the outcomes are truly dismal if you just wait around for the relapse. You know, and I think if you look at the second line randomized trials using cellular therapy in diffuse large B-cell lymphoma, we're still, you know, it's still a minority of patients who are remaining in a durable response. So, you know, the bar is low, relatively speaking, but I think there's great potential. I think you know, if you had, you know, let's say, if you decrease the chance of relapse by a third or toward 25%-35%, I think that would be meaningful. But I think the potential is greater than that. I think when you're intervening at a low disease burden time point, with lead time, and you're gaining lead time by using this sensitive assay, I think there's potential for more than that. You know, but I think if you were able to, you know, reduce the risk of a relapse by, you know, by a quarter at least, but I think getting to a third, I think that's an incredibly meaningful result. Thank you. One moment for our next question. Our next question will come from the line of Jack Allen from Baird. Your line is open. Great. Thank you so much for taking the question. Kind of a two-parter here. I guess the first part, a little bit more backward-looking. I just wanted to clarify this decision to move forward with ALPHA3 and deprioritize the DLBCL ALPHA2 study. Was that made based on any data that you'd seen from ALPHA2 study? And when might we get to see some of the data from the ALPHA2 study? Any early thoughts there would be great. And then looking forward, as it relates to MRD testing, in this ALPHA3 study, how do you anticipate the change of standard of care from R-CHOP, CHOP to Polivy-R-CHP could have any impact on this study? Thanks a lot, Jack. Great questions as usual. So the first question is easy. No, we are fully believers in cema-cel. You know, we spent the entire 2023 showcasing the phase 1 data across multiple different international conferences. And we are as convinced as ever that this is an active treatment that's capable of putting patients into durable, complete remissions. And that's in a clinical setting, which is much more stringent than what's being proposed in ALPHA3, and these are patients with a lot of measurable disease by PET scan. So, no, we think that this is a you know, an active drug, active therapy that is uniquely well suited for intervention as we're proposing in ALPHA3. As far as when we expect to present that data, stay tuned. You know, we will be discussing that data presentation at a later date. And then what was your second question, Jack? Yeah. If we're gonna gain some insights as it relates to ALPHA3 and the standard of care being R-CHOP and the potential implementation of Polivy-R-CHP as well in that patient population. Yeah. Maybe, maybe I'll just put that one right to Dr. Herrera, and, you know, he was closely involved in that study. Sure, sure. Look, we haven't fixed diffuse large B-cell lymphoma yet. And so this one's pretty simple. There is a benefit, you know, when you add polatuzumab vedotin to, you know, when you substitute it in for vincristine. But you know, the benefit is modest, and there's plenty of room to improve on outcomes in frontline treatment of diffuse large B-cell lymphoma, right? We're talking about a 7%, 6%-7% improvement over R- CHOP. And the truth is that the uptake, you know, is, it's, you know, it's not gonna be 100%. You know, there are people using, you know, various biological features to determine who they're gonna give polatuzumab vedotin to or not. So, you know, I don't. I wouldn't anticipate that having an impact on ALPHA3, but it's a good question. Got it. Just to clarify, will Polivy-treated patients be eligible for ALPHA3, or will it just be R-CHOP? I'm just curious, given the CD19 dynamics around Polivy. Yes. We expect that patients who receive Pola-R-CHP who are MRD positive would be eligible for ALPHA3. Got it. In that Foresight, I'll just say a little bit more. In that Foresight data that's publicly available, there's MRD positive patients from many different first-line regimens, and all of them do poorly. So you know, to Alex's point, it could be that a small fraction of patients who receive Pola-R-CHP upfront get into CRs that are durable and are MRD negative, maybe a handful of percentage points more than R- CHOP-treated patients. But there's still gonna be plenty of those patients who get Pola-R-CHP in frontline who remain MRD positive. Got it. Thanks so much for taking the questions, and congratulations on these updates. Thanks, Jack. One moment for our next question. Our next question comes from the line of Kelsey Goodwin from Guggenheim. Your line is open. Hey, thanks for taking my question. I guess I'm just trying to understand kind of the existing infrastructure for MRD testing in frontline DLBCL. So what percentage of patients are being evaluated for MRD now? And I guess when are they being evaluated, kind of immediately post R-CHOP or in this watch and wait over time? And does this differ in the academic and community settings, and how should we kind of think about that? Thank you. Yeah, I'm happy, I'm happy to take this. Yeah. Go ahead. Thank you, Dr. Herrera. So the honest truth is, we don't really have a, you know, and a-- we haven't had in the field until now, really, an available assay that was reliable, that gave us information that we could act on clinically. So I would say a very, very small proportion of patients currently have these kinds of tests drawn at any point in their therapy. I think, you know, if you are treating a patient and you work at Stanford, where, you know, where the folks who have developed a lot of these technologies live, then I think some of those patients, you know, have been monitored using these tests over time. But the truth is that this trial, you know, if successful, would change all that, right? So if I had a reason to order the test because I, you know, if the test was positive, I could give a therapy that was good, that was gonna improve the progression-free survival, you know, increase the cure rate of, of the, of, you know, at front line, then I, then, then I would order it in everybody, right? So, so I think this, this has a potential, you know, a huge potential to swing and change that, that the way we practice in that way. As of now, it's, you know, it's. There are other diseases, mantle cell lymphoma, maybe, CLL, for sure, where, you know, where there's more uptake in the use of MRD, but in, you know, in the lymphoma space, we need trials like this to be able to really justify sending the test and, you know, it. We need a reason to act, right? Got it. Okay. Thank you. Thank you. One moment for our next question. Our next question comes from the line of John Newman from Canaccord Genuity. Your line is open. Hi, guys. Thank you for the update. Happy New Year. Just had a couple of questions here. The first one is for the frontline opportunity with ALPHA3. Do you plan to enroll this study mainly at U.S. sites, or would you use ex-U.S. sites to potentially speed enrollment? Then I'm also wondering, for both ALPHA3 as well as the work that you'll be doing with ALLO-329, will you be able to source those, the material there directly from Cell Forge 1 from the very beginning of the study? I think with the current ALPHA2 study, you were planning on using some material from a commercial manufacturing organization, but just curious if you'll be able to go straight from Cell Forge 1 with these other studies. Thanks. Hi, John. Happy New Year. You know, I'm going to give Zach and Dr. Herrera a little break and take those two questions. You know, so far, the feedback that we have gotten from the investigators as we introduced the concept for ALPHA3, I mean, as Zach has indicated, that has been uniformly and almost universally positive. I mean, so many times we have heard, "This is exactly the right study, and this is the study that we've been looking for." And along with that, you know, we have gotten very high level of enthusiasm, you know, for this study, to the point that we believe that 230 patient enrollment can be fully supported by the investigators in the United States. So, you know, we will initially start the study in the United States, and, you know, look for an opportunity to expand, you know, clinical trial footprint, you know, to outside the U.S. at a later time point. But, this is a study that will definitely have a lot of ease in terms of enrollment than the refractory study, ALPHA2, that we didn't carrying out. The second question about the, you know, supply of the clinical material, you know, for ALPHA3 study as well as ALLO-329. You know, I think we are really, you know, you know, you know, focusing and, you know, and, you know, trying to anchor manufacture of all our clinical materials, in, you know, from Cell Forge 1. So there are, you know, some transition period, but direction is that, you know, as we go forward, the studies will be supplied from the materials from CF1. Great. Thank you. Thank you. One moment for our next question. Our next question comes from the line of Luca Issi from RBC Capital. Your line is open. Oh, great, thanks so much for taking my question, and Happy 2024. Maybe circling back on prior questions around powering assumptions for Zach and maybe Dr. Herrera. Can you just expand a little bit more on the powering assumptions for ALPHA3? I appreciate you can make some really, really good assumptions on how the control arm will behave based on historic controls, but what assumptions have you made for the active arm? I'm not aware of any data in the first line consolidation settings for allo CAR T in MRD-positive patients. So wondering, how do you come up with assumptions for the active arm? In other words, how confident are you that 230 patients is actually sufficient to hit the primary endpoint? So any call there, much appreciated. And then maybe, David, quickly, any update on the ongoing conversation with Servier will be much appreciated. Thanks so much. Hey, Luca, Zach. Thanks for the question. So I'll take the first one. So there's a couple of different factors that went into the sample size. So first, you know, we do need to build a safety database in this patient population, as you know, it does bear pointing out that- ... These patients are in, in the majority of cases, they'll be in complete remission at the time that they receive their CAR T cells. So we need to make sure that the intervention that we are offering them is not overly toxic. So that was a consideration in designing the sample size. As far as the powering assumption goes, we won't go into detail there, but, you know, we do believe that this sample size will be adequate to demonstrate a meaningful improvement in outcomes in these MRD positive patients. Just adding to that, you know, this is an event-driven study, and how we factor in the sample size also factors in, you know, how fast the event can, you know, the target event can be reached. So, you know, there are many considerations on how we set the sample size. Obviously, you know, as we learn more about the event, event rate, that will be, you know, as the study progresses, we can provide more updates. This is Jeff. Just on Servier, nothing new to report, so it's the same as we've discussed in the past. So really status quo there. Got it. Thanks so much, guys. Thank you. One moment for our next question. Our next question comes from the line of Kalpit Patel from B. Riley. Your line is open. Yeah. Hey, good afternoon. Thanks for taking the questions. One more on ALPHA3, for the primary endpoint, event-free survival. How confident are you that this endpoint would be accepted, you know, maybe in the real world versus, an endpoint like overall survival, since these patients are earlier in the disease and the therapy sort of looks like it's part of R-CHOP? Yeah, thanks, Kalpit. I'll do the two-part answer. Again, I'll take the first bit, and then I'll ask Dr. Herrera to weigh in as well. So, you know, we think that EFS is the right endpoint for this trial. You know, it takes into account decisions made by investigators around the need for new therapy. However, you know, we suspect that it's going to be closely aligned with PFS as well. So with respect to, and of course, PFS is a widely accepted surrogate endpoint in, even in frontline studies, as in the POLARIX trial, which is what I'll ask Dr. Herrera to comment on. As far as, as far as the overall survival outcome goes, you know, we do not think that a demonstration of superiority with overall survival is going to be necessary. And I'll, again, point to the POLARIX trial, where this, the overall survival curves for the Pola-R-CHP and R-CHOP, KM curves were superimposable. But, and Dr. Herrera, would you mind commenting on the primary endpoint of EFS and the role of OS in frontline DLBCL studies? Absolutely. So, you know, OS, as you mentioned, was not significantly different in POLARIX. In diffuse large B-cell lymphoma, even though we are still not curing a majority of patients with our salvage treatments when they relapse or have primary refractory disease, you know, there are. You know, we do have effective salvage therapies, and so it, you know, it, it's become increasingly difficult to develop therapies that lead to an overall survival benefit in this disease. And I don't, you know, to my knowledge, regulatory agencies aren't requiring a survival, an overall survival endpoint for, you know, as a primary endpoint for clinical trials in frontline, in the frontline setting. Now, you know, obviously, there's potential here. If we're intervening at an early time point, we're improving the cure rate, there's always the potential that there may be an impact on overall survival. But, you know, I think waiting for overall survival benefits takes quite a long time. I think part of the, you know, an important part of why this trial is exciting is this proof of concept that you can administer MRD-guided therapy. And so for the field, I'm, you know, I think having an EFS or PFS endpoint is important to kind of show that proof of concept both for the therapy and for the assay. So it's, you know, look, we always wanna cure more patients. We want more patients to live in total, but, you know, I don't feel like it's necessary. I think reducing relapse rate, reducing the relapse rate is incredibly meaningful. You know, nobody wants to have their disease relapse down the road, need CAR T cells or a stem cell transplant or any of the additional therapies that we have to give. You can, you know, down the line, if you can, if you can, you know, people would rather, much rather, not have cancer at all, but be cured the, you know, on the first go around, if it's possible. Thank you. That concludes our question and answer session. I'll let you turn the conference back over to management for any additional comments. First of all, thank you for joining, you know, you know, our call today. I know that everyone's schedule is very busy. Also, we apologize that we could not, you know, handle all the questions. Certainly, we were dealing with a lot of questions, and I sense a lot of excitement, and I really hope that you are as excited as we are about what we have planned for 2024, especially with ALPHA3 study, which we believe is the right study at the right time. As the year goes on, you know, we will have opportunity to give you further updates. What we are really setting up here is really, you know, taking the opportunity to change the future of the CAR T therapy. We look forward to seeing many of you at the upcoming JP Morgan conference. Operator, you may now disconnect. Thank you. Ladies and gentlemen, thank you for your participation in today's conference. This does conclude the program. You may now log off and disconnect. Everyone, have a great day.