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

Hello. Thank you for standing by, and welcome to the Allogene Therapeutics 2024 Platform Vision Conference Call. [Operator Instructions] 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 JPMorgan presentation on January 10. 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 Geoff 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 and [indiscernible]. 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 are cautioned not to place undue reliance on these forward-looking statements, and Allogene disclaims any obligation to update these statements. I'll now turn the call over to David.

Thank you, Christine, 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 use 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 autologous CAR Ts 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 similar ways for the same group of patients? And when that happens, what is the impact to clinical trial recruitment, market opportunity, and even more importantly, is 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 broadened 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 fast creates an advantage for our investigational alloCAR T products now and in the future, while providing a clinical framework to generate far more competitive CAR T products and dramatically extend 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 unmet 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 was anticipated that we are targeting second line, but our ambitions were more evolved. This groundbreaking trial has the potential to leapfrog all alloCAR Ts and invest Cema-Cel. This is Cemacabtagene Ansegedleucel 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 treatment obsolete. This opportunity to change the treatment paradigm for patients with LBCL has driven our decision to deprioritize our third-line ALPHA2 and EXPAND 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 CAR T cell thickness is a known barrier to efficacy. Next plan, what we understand about CD19 with one of our most exciting platform technologies, Dagger. One common question we often received in 2023 centers on our plans in autoimmune diseases. It is without question one of the most interesting new areas for CAR T. While others are waiting 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 front line 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 our 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 and solid tumors. As we pushed 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. Geoff 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 BCL2 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 expectation 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 an alloCAR T product, which is derived from healthy donor cells, could raise the bar and potentially create and clinically meaningful advance for these late-stage patients with a onetime dose and simpler administration and logistics. The new Phase I alpha 2 cohort will include 12 patients treated with Cema-Cel. This study, driven by investigator enthusiasm will leverage currently active alpha 2 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 the 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 for 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, leukophoresis procedures and cell therapies in general. Incorporating Dagger into ALLO-329 is designed to reduce or eliminate the need for standard chemotherapy while targeting CD19-positive B cells and CD70-positive activated T cells, both of which are known to play a role in autoimmune disease. Initiation of this Phase I trial with ALLO-329 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 alloCAR 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" team 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 on how we advance it. In this trial, we have observed remarkable allogeneic CAR T cell expansion and 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 relapse refractory renal cell carcinoma, but it has also resulted in a hyperinflammatory response in some patients that CD70 CAR T cells expand and persist. Leveraging recent advances in the management of hyperinflammation following autologous CAR T administration, we have 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'm 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 advisers 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 2 things: first, a sensitive MRD assay and a onetime 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 APLHA3 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 chemo immunotherapy 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, 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. APLHA3 takes advantage of Cema-Cel as a onetime off-the-shelf treatment that can be administered immediately upon discovery of MRD, following 6 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. APLHA3 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 I safety profile with low rates of CRS and ICANs already permits its use in the outpatient setting in relapsed/refractory patients and they further improve in patients with no radiological evidence of disease. Start-up activities for the APLHA3 trial have already begun. 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 the primary endpoint of event-free survival will initially include 2 lymphodepletion arms, one with standard fludarabine 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 so much, Dr. Roberts. So as mentioned, I'm the Chief of the Lymphoma Division at City of Hope and a 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, have led over 15 investigator-initiated trials and I've 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, CapSeQ and now this phasic technology that will be used in Allogene's proposed ALPHA3 clinical trial. The phasic assay is the most precise MRD assay in the lymphoma space, the most precise one that we've had. For years, we've been refining MRD technology to arrive at this time -- at this time point where we are ready to start conducting MRD-guided clinical trials. And with this assay, we're finally able to move forward with that aspiration. Make no 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 to make clinical decisions in lymphoma. And over and over again, even with inferior MRD assays to phasic, we've seen that circulating tumor DNA assessment is more sensitive and specific for detecting residual disease in PET. The proposed ALPHA3 trial, if successful, really would be transformative. As Dr. Roberts mentioned, about a third 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 8 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 APLHA3, we could intervene when there is a low burden of residual lymphoma 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 -- 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 -- about the clinical trial about lymphoma -- about the [indiscernible] chances of winning the Super Bowl sorry, just kidding.

Thank you, Doctor. Operator, we'll now open the call for questions.

[Operator Instructions] And our first question comes from the line of Salveen Richter from Goldman Sachs.

With regard to the ALPHA2 trial and discontinuing the study in the third-line C19 setting or in the third line setting with C19, 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.

Happy New Year and great question. This is something that we have spent a lot of time thinking internally as well as talking with the investigator to really understand what's happening in the Large B cell lymphoma area. The foremost is the existing unmet need in the frontline setting where 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, waiting for their disease to recur before they can act on it. This is the patient population that we are going after with the APLHA3 study. So essentially, when you roughly think about 30,000 patients being treated in the frontline setting, 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 since we expanded the clinical study footprint of APLHA2 and expand in Europe, we were beginning to see a 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 APLHA3 study, and if we are successful, and we have a 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, 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 APLHA3 study. So we have to factor that in together with how we prioritize our resource and came to a conclusion that the best course what we need to do as a company, and that also includes commitment to the patients and investigators is to deprioritize and eventually shut down the ALPHA2 and EXPAND study. And frankly, this is the right decision. And I wish that we could have made a decision earlier except that the assay -- the partnership that we have just entered with 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 the assay. And this is what's really enabling us to really take the right course of action with Cema-Cel. And we'll see. I mean we are really prioritizing. And as we have said in the prepared remarks, study activation activities are already underway.

And our next question will come from the line of Brian Cheng from JPMorgan.

Based on what you have seen so far, how should we think about Cema-Cel's benefit in terms of event-free survival as consolidation in the front line? And in the MRD positive patients 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 and maybe I'll ask Alex to weigh in as well. So there's 2 concepts to keep in mind with this study. First is this assay, which is -- as David mentioned, is an absolute foundational part of this APLHA3 program. And what this assay has done, which no assay before it has been able to show, is essentially 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 and 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 make it 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 2 items coming together at the same moment, patients are relatively healthy coming out of frontline therapies. They are in remission and we're able to deliver a treatment to them while they're in a state of no radiological evidence 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 front line. 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, Zach. I agree. I think it's -- this is really what we've been driving towards in the field. Like I said before, PET scans are really imperfect tool. That's what we have had available to us, but these MRD assays have always even 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 -- if a patient is MRD positive at the end of therapy, the likelihood of their relapse is really high. And so given that information, I think what Zach said is right on point, intervening with an off-the-shelf therapy that is -- has proven efficacy. But also, I think the point that CAR T cells 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? These therapies have led to durable responses in patients with relapsed/refractory disease. It's one of the -- this is -- these are the only therapy that we have CAR T central 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 and efficacy is likely to be high is a really, really exciting opportunity. And look, patients are excited to wait for their disease to relapse. It's a really high stress time. If you had a highly sensitive test, that can 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.

And our next question will come from the line of Michael Yee from Jefferies.

Thank you. Happy New Year. A 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 of how you think about that. And 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 on that study and maybe Dr. Herrera can explain whether he thinks that's going to work because I think that's head to head versus R-CHOP.

Sure. So maybe 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 relapse. So the data that has been again shared publicly by Foresight, looking at a pool of 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 6 and 12 months. So these patients tend to progress quickly. That subgroup of patients that you alluded to who I alluded to, which progressed within weeks, that's probably about 1/3 of overall MRD-positive patients again, according to the data from Foresight. And those patients can progress within 1 to 2 months. And 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 for -- just to sort of frame this up, 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 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 for that matter, we -- given the fact that this EFS that we expect between 6 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. And 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 a 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.

Yes. No, I think Zach's right on point. The median time that a patient is going to progress, when they're MRD positive at the end of treatment using Foresight's assay is probably between that 6- and 12-month time point. But the relapses happen -- 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 for like some additional color, I would say that overall, again, with the data that we have available, more than 80% of the patients who are MRD positive are going to relapse within 2 years of that kind of end-of-treatment blood sample being collected. So -- and it's probably 2/3 are going to be relapsing within the next year. So this is a test that really suggests that a patient has MRD detected, it's a really high likelihood they're going to relapse. And acting quickly is -- will be extremely helpful. I agree also with the point that 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 and Hodgkin lymphoma is that our current therapies are fairly effective, right? So we've had trouble designing trials similar to ZUMA-23 and now as part of designing ZUMA-12 for years now because at the end of the day, 2/3 of patients and typically with clinical trial populations, it's higher, like 70%, 75% of patients are going to be cured with our front-line therapy. That's a high bar, right? And so in this trial, we're not -- the idea is that we're not going to replace frontline chemo immunotherapy, which is effective. 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 -- the way we usually do trials in frontline treatment and lymphoma is we're going to add on a therapy to R-CHOP, let's say, right, like Polatuzumab vedotin, 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 2/3 of them, 70%, 75% in the 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 population of patients, this, let's say, 30%, 1/3 of patients who are likely to relapse, we found the great majority of them with this test. And now, so we're refining who we're going to introduce this intervention into this more limited population who's very likely to relapse. That's kind of building on the population of patients that were already cured, now the ideas, let's see who else we can cure with adding this therapy to frontline therapy.

Makes sense and appreciate that 6- to 12-month data point.

And our next question will come from the line of Tyler Van Buren from TD Cowen.

Definitely some exciting updates on the differentiated strategy and forgive me for asking one more ALPHA3 question. But is there any historical precedent for treating MRD-positive 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?

Tyler, thanks. So to our knowledge, there is -- this is the first pivotal study that's been proposed that uses MRD as an eligibility criteria. 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, obviously, we're not going to go into detail there. But suffice it to say that 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 the study design. They recognized that the risk of the patients with MRD positive was extremely high as defined by this tool. And so the bar there is actually quite low, Tyler. 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 and anything else you may have to do -- have to say on the potential improvement for the patients who are MRD positive.

Yes. So 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 and the 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 there is some precedent for the idea of using -- for the concept of using MRD as a decision point. But in diffuse large B cell lymphoma certainly in the front line setting, this is -- this would be the first that I'm aware of. But truly, this is where we've been building towards for a long time. I mean, in the field, as investigators we wanted to refine the populations that we expose to these therapies, so whether it be cellular therapies or other novel therapies, we've been wanting to refine that for as long -- we've been -- people use the IPI like in ZUMA-23. We've been trying to refine populations for a long time. And now that assays are finally there for us to be able to do that. So I think -- so what was the second half of the question? I apologize.

Just about the unmet need and what...

Yes, yes. So truly, I think if, let's say, we're not carrying about 1/3 of patients with our frontline therapy. If you look kind of what's the curability of those patients once they relapse later on, the bar is pretty low. I mean in CAR T cells -- with CAR T cells studies, we've always used SCHOLAR-1 as a comparison, but the outcomes are truly dismal if you just wait around for the relapse. And I think if you look at the second line randomized trials using cellular therapies in diffuse large B cell lymphoma, we're still -- it's still a minority of patients who are remaining in a durable response. So the bar is low, relatively speaking, but I think there's great potential. I think if you had, let's say, if you decrease the chance of relapse by 1/3 or toward 25% to 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 having this potential for more than that. But I think if you were able to reduce the risk of a relapse by a quarter at least, but I think getting to 1/3, I think that's an incredibly meaningful result.

And our next question will come from the line of Jack Allen from Baird.

Great. 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 APLHA3 and deprioritize the DLBCL ALPHA2 study, was that made based on any data that you've seen from APLHA2 study? And when might we get to see some of the data from the APLHA2 study? Any early thoughts there would be great. And then looking forward, as it relates to MRD testing in this APLHA3 study, how do you anticipate the change of standard of care from R-CHOP to Polivy R-CHP could have any impact on this study?