Good afternoon, and thank you for joining. I'm Sam Semenkow, one of the senior biotech analysts here at Citi, and it's my pleasure to be hosting Allogene's Executive Vice President and CMO, Zach Roberts, as a part of Citi's SMID Biotech C-Suite Virtual Fireside Chat series. Zach, welcome, and thank you so much for joining us today. Thanks so much for having me, Sam. If anyone live on the call has any questions during the session, please go ahead and email them to me directly at samantha.semenkow@citi.com, and I'd be happy to ask them on your behalf. So, Zach, why don't we sort of jump right in? Maybe at a high level, let's just talk about Allogene's pipeline and where you are today as a company. Sure. So, Allogene was founded in 2018. We have been, since the beginning, a company focused on allogeneic cell therapies, initially for oncology indications, and now we've recently expanded into autoimmune indications as well. We currently have three clinical programs that are ongoing. We've got our lead pivotal program with its CD19 off-the-shelf allogeneic CAR T product called cema-cel, and this is being developed in a very unique indication in what we call frontline consolidation for large B-cell lymphoma, and we'll have plenty of time, I think, during the call to talk more about this ALPHA 3 trial, so I'll save that for later. The second program, another oncology program, is a solid tumor program in advanced and metastatic renal cell carcinoma. This product is called ALLO-316, and it's targeted CD70. And we recently showed the culmination of a phase I program at ASCO just earlier this summer, and very exciting data in that program. We saw a 31% overall response rate in patients with multiply relapsed refractory metastatic RCC, and these responses were quite durable, really a first for the field, especially as it pertains to allogeneic cell therapies, again, another off-the-shelf product. And then the third and final clinical program is our autoimmune program, as I alluded to previously. This product is new and novel in a few ways, also healthy donor-derived off-the-shelf, but it's the first dual-targeting CAR that targets both CD19 and CD70. And this was really designed to enable targeting both pathogenic B cells, but also pathogenic T cells. And these are T cells that specifically upregulate CD70 on their surface. CD70 is a marker of T cell activation. And there's another unique feature of the CD70 molecule, CAR molecule, in that it incorporates what we call the Dagger technology. And a way of shorthand in thinking about what Dagger is, is it's essentially built-in lymphodepletion. And so these cells, once we infuse these allogeneic CAR T cells, resist the patient's immune system from rejecting them. And by doing that, they actually garner a proliferative burst, so they begin to expand on their own. And we were actually able to show in that kidney cancer program that we can do this with markedly less lymphodepletion than is generally required for allogeneic cell therapies. So I share this to illustrate one of the defining features of this 329 program, is that we are bringing this to autoimmune patients with less or even no lymphodepletion at all and relying entirely on this built-in lymphodepletion that we call the Dagger effect. So that's a very high-level summary, Sam, of Allogene's history as well as our current pipeline. Yes, thank you for that. You gave us a lot to work with there, and you're correct. So let's start with the cema-cel ALPHA 3 trial. You mentioned this as a unique indication. It absolutely is, but let's talk a little bit about that opportunity of that unique indication. What's the size of the market, and where do you think that cema-cel could really deliver in that space? Yeah, so one of the exciting things about this trial is that it incorporates a new disease assessment tool that is rapidly becoming standard in diffuse large B-cell lymphoma, which is called the minimal residual disease or MRD. And what MRD enables a clinician and a patient to do is, even in patients who appear to be in remission, they can get this additional very sensitive, very specific blood test. So it's not a scan, it's a blood test that measures circulating tumor DNA. And if circulating tumor DNA is found in the blood, that is a very strong indicator that these patients will have their cancer come back. And sometimes it's very quickly, and sometimes it actually can be many months, but it gives both doctor and patient a better understanding of what to expect from their cancer. So with that kind of foundation, we looked at the market opportunity here, and even incorporating what we believe will be the uptake of MRD in the coming years, we assess this to be approximately a $5 billion global opportunity because it essentially will capture most of the patients, if not all of the patients, who eventually go on to relapse with their DLBCL and are currently being treated with salvage regimens like autologous CAR T. So we really have, kind of in a manner of speaking, sort of leapfrogged the second and third lines and found ourselves right between frontline and second line. So it's a fairly large market opportunity globally. Okay. And there are no other cell therapies or any other drugs targeting this population currently, correct? Currently, no. Okay. Do we have any indication that there may be others entering the space, or that just hasn't happened yet? So we spend an awful lot of time talking to lymphoma physicians, both global KOLs, but also community doctors. And what we find is, nearly universally, people think that this is a very forward-looking study design and one that stands probably the best chance at improving frontline outcomes in large B-cell lymphoma for the last 25 years. So we believe this is a good idea. We think it's a solid study design, and we expect there will be competition. We hear rumors from time to time that there may be something in the works, but so far we haven't had anything concrete come to our awareness. Got it. Okay. So then maybe let's talk a little bit about the study design, and maybe it could be helpful to walk through the patient flow of the study design and how they get from screening to enrollment and into the study. Sure. So before I get there, it probably makes sense to just level set on what a typical patient journey is today in the current standard of care with a new diagnosis of large B-cell lymphoma. So patients notice symptoms, a lump, night sweats, what have you. They come to their doctor, they get a biopsy, they're found to have diffuse large B-cell lymphoma. And then almost everybody, certainly in the United States, at least two-thirds of patients, maybe a little bit more, will get started on a very standard, very old regimen called R-CHOP, and that's actually five different drugs. Each drug has a letter in R-CHOP that stands for the drug, and that's given for six cycles every three weeks, one cycle every three weeks. And most patients, about 90% of patients who are treated with this or similar regimens, will achieve a remission, meaning that their cancer is in better shape at the end of this than it was when they started. And most of those patients will be in what we call a complete remission, meaning that their scans are completely clear, there's no evidence of residual tumor. About the remaining 10% will have what's called primary refractory disease. Those patients are, frankly, in rough, if they've got a sort of a tough road ahead, they will go directly to a second-line salvage regimen like autologous CAR T or bone marrow transplant, or increasingly a bispecific-based regimen. But for the patients who are in remission, about 2/3 of those patients will actually be cured. They will never hear from their cancer again, and 1/3 will actually have their cancer come back. So it's really at that end of therapy, at the end of the six months, that when you have a clean PET scan or a scan that suggests that you're in remission, that PET scan actually is not a very good disease assessment tool. There's false positives, there's false negatives. We've known about these for decades, but it's the best tool that we currently have that is widely used. Where the MRD tests are beginning to make major changes is if you layer on top of that PET scan an MRD test of these very specific performance characteristics, it will significantly improve your ability to prognosticate or see the future of what's going to happen. So let's say a patient has a complete remission by PET scan. If they get an MRD test and it's positive, we're about 90% sure that that patient's tumor is going to come back. They are going to relapse. So even though a PET CT is showing that these patients are clear of their disease, we know that their trouble is ahead. And conversely, if you have a PET scan that remains positive on some small amount, but their MRD test is negative, we actually are very confident, again, about 90% or so, that these patients will actually never relapse. And so those patients are very good to observe. So that's the frontline care. We won't talk too much about the second and third line, but just to round out this conversation, patients, even if they achieve a remission, who are destined to relapse, will go for some number of months, and then their disease will come back, and that is when they're eligible for a second-line regimen. And when I say come back, I mean they have a PET scan and/or symptoms that illustrate that their tumor has come roaring back. And that is actually a clinical emergency, and those patients need to be treated right away, which is one of the challenges that faces the autologous CAR T in that setting, which is currently the best we have to offer. But trying to get all that set up in the context of a rapidly progressing tumor can sometimes be a bit of a challenge. So that's really the focus of ALPHA 3, is if we treat those patients at the time of their MRD positivity, we are able to prevent that relapse from ever occurring. Before I let you go into the design of the study, I do have a client question that came in. They're asking, "What percentage of patients will remain MRD positive after R-CHOP?" A limited number of studies show 20%-25% MRD positive. So they're curious how you're thinking about that percentage. Yeah, so that's about right. If you take a single MRD draw at the end of frontline treatment, that's a reasonable number to guess that somebody is about 20% likely to be MRD positive even though they're in remission. What we do know is that pretty much everybody, of course, nothing is 100%, but pretty much everybody who eventually relapses will turn MRD positive before that clinical relapse. It's a question of whether we're actually measuring that MRD status at that time. But as these tests begin to gain support and backing and are increasingly being paid for by insurance, it's likely that MRD will become part of the longitudinal assessments that's performed on these patients, not just PET CT. So these patients will, even if they're MRD negative at the end of frontline treatment, they will at some point turn MRD positive prior to a relapse. So even though it's 20%, which is not exactly the total number of patients that we do expect to have their tumors come back, it's quite likely that that remainder will actually turn MRD positive prior to that relapse. Got it. So it's a sensitivity of the test or just a marker of when you have enough of that tumor that MRD positivity can then be detected? Right now, for ALPHA3, you're getting them right after they're cleared in remission of some sort, then they get the MRD test right after that. Is that correct? That's correct. And I'm just noticing my camera is getting a little bit blurry. My apologies for that. Let me just turn it off and turn it right back on. That seems to fix the problem. I don't know what's going on with it on this Thursday morning. That's absolutely. Thank you, Sam. That's absolutely correct. So we are performing the MRD test just a short number of weeks after the final cycle of that R-CHOP regimen or a similar regimen like Pola-R-CHP is completed. So we are at about the time that that end-of-therapy PET CT, which is currently standard, that's when we do this MRD test. Got it. So if that 20%-25% ends up being accurate, that's about the patient population that you can pull from to potentially enroll into ALPHA 3. Correct. But we actually believe that the commercial opportunity is more likely going to be reflected by any MRD positive patient, regardless of the timing of their last line of therapy. Yeah, that makes sense. Okay, thank you for that. So then maybe let's just talk about the journey into ALPHA 3. So they have been tested, or they finished their R-CHOP, they're in the sites being tested for MRD, they come back MRD positive. How do you get these patients enrolled effectively into the study? Yeah, so once they're MRD positive, their prognosis is communicated to them by their physician. They say, "Okay, this is not good news, frankly. It means your tumor is very likely to come back." At that point, they will sign informed consent for the trial and will undergo a few sort of screening assessments to ensure that they're appropriate for clinical trial enrollment. And then once those are complete and the patient's eligible, they are randomized into the study. And then the study design currently is a one-to-one randomization, either into the current standard of care for MRD positive patients who are in remission. And this will be my opportunity to say that currently, MRD is an experimental diagnostic tool. It is not baked into any recommendations for treatment decisions. The current standard of care in a patient who is in remission is to observe, regardless of their MRD status. That is the control arm in ALPHA 3 watch and wait or very close observation. Or they get randomized into the other arm, which is treatment with fludarabine Cytoxan-based lymphodepletion and a single infusion of our off-the-shelf CD19 CAR T cell, cema-cel. Got it. Okay. And I think one of the biggest questions I get from investors is, how are they going to enroll this study given it is a very novel indication? You've just said that the standard of care is to not treat. I know you have a number of sites, both community and academic. I'm curious, what are the challenges that you've seen in enrollment, and what have you done for mitigating? And I guess if there's an update you could provide today of how that enrollment is going at a high level, that I think would be quite helpful. Sure. So I would say that every study has its challenges. Every single clinical trial, there are growing pains when you first launch. An ALPHA 3 is, of course, no different. We are doing a lot with ALPHA 3. We are testing a novel modality. It's CAR T cells, but it's off-the-shelf CAR T cells. We are also implementing, as part of eligibility determination, this MRD test, which is currently not standard. I will say that it is rapidly becoming more widely used. When we first started, excuse me, talking about ALPHA 3, maybe two, two and a half years ago with doctors, we found that very few of them were using any MRD assessment as part of their standard patient management. We see that anecdotally, but also in sales information from MRD developers, that this is becoming more widespread. But in the early days of ALPHA 3, we had to really educate about the utility of MRD and why a doctor who has been giving R-CHOP and assessing disease with PET CT for decades would suddenly layer on this additional test. So we had to build support around the MRD. Many, many doctors are early adopters, and they're super enthusiastic about MRD, and so they loved ALPHA 3 right out of the gate as soon as we started talking about it. But then also educating the patients that it's not just about your PET scan. There is an additional piece of information that we need to collect. And changing that mindset with both doctors and patients that a PET CT is not telling you the whole story. So that was part of the early challenge that we faced in just really implementing this study. There are some other operational issues, like in the United States, CAR T cells are generally given by transplant doctors, and R-CHOP is generally given by lymphoma doctors, and at many academic centers, those two groups are separate. Oftentimes, they don't even sit in the same team rooms, so the study might sit in the transplant group, but we needed to facilitate daily communication between the lymphoma doctors and the CAR T group so that we could get the MRD screening rates up to where we needed them to be, so it took us a few months to figure all that out and then deploy. Sorry about my camera again, Sam. Let me just do this again, and then deploy mitigation strategies, and so that really was sort of end of 2024, early 2025. Since those mitigation strategies have been implemented, we not only have improved performance of the existing early sites that came online that were so eager, but also as new sites have come online, we have brought to them kind of a package of best practices on how to implement this study effectively, so those new sites are coming on sort of hitting the ground running, and so what we really have seen over the course of 2025 is markedly improved patient identification, markedly improved MRD screening rates, and that has translated into a study enrollment. Okay, and so that feeds into your expectation for the futility analysis in the first half of 2026. That reminds me, if I'm correct here, I believe it is up to 12 or about 12 patients in each arm that will be included in that futility analysis. That's correct. Okay. And what are the expectations there? What would be good for you to pass that futility and to move and continue the study? Sure. Before I answer the question, let me just put a little bit of context out there. So I briefly mentioned another frontline regimen that's often used in the United States, especially for patients with newly diagnosed DLBCL, and that's a regimen called Pola-R-CHP. It's based on a drug called polatuzumab vedotin or Polivy. And the R-CHP is kind of a modified R-CHOP. So it's essentially R-CHOP plus. That regimen was the first new regimen to be approved in DLBCL in 25 years, about 20 years or so, since R was added to CHOP. And that study had about a 7% improvement in PFS, and that led to approval of Pola-R-CHP. I think that illustrates very clearly that R-CHOP is a very effective regimen, and it's been really surprisingly difficult to beat it. With that kind of a backdrop, how we think about this futility analysis coming up that you just mentioned is if we can see a 30% improvement in the efficacy assessment that we're doing at that futility analysis, that would be a major advance in the frontline outcomes for these patients with newly diagnosed disease. I will point out that the efficacy assessment that we're using at that futility analysis is not the primary endpoint of the study, which is event-free survival, but rather looking at the MRD conversion. Everybody that comes into ALPHA 3 comes in MRD positive, as I pointed out earlier. What we're looking to see is whether that MRD positive becomes an MRD negative after they're enrolled in the study. And so what we're looking for is a roughly 30% or better delta between the MRD conversion in the two arms, observation versus cema-cel. We would consider that a pretty substantive improvement, especially given what historical improvements have been, even with approved regimens like Pola-R-CHP. Got it. Okay. And so for that readout, 30%, right? And that is based off the second line, Yescarta Breyanzi, sort of complete response, right? Is that correct? Yeah. So that's another way to look at it. So it's sort of a proxy. That's another way to look at it. So if these patients do progress, as we expect almost all of them will, the MRD positives, what is their likely outcome in the second line? And even though we have kind of anchored to ZUMA-7 and TRANSFORM, those are the large randomized trials examining Yescarta and Breyanzi versus autologous transplant in the second line salvage regimen. The sad truth of the current status of relapsed DLBCL in the United States and globally is that the vast majority of patients don't actually even get those therapies. They don't even get CAR T. They get something else that doesn't work as well as CAR T, or they get nothing at all. We actually see about a third of patients in the U.S., based on recent claims data shown at ASH last year, about a third of patients don't even get second line at all. There really is quite an opportunity to improve upon the outcomes in relapsed disease. MRD positivity is absolutely a proxy for impending relapse. Do we have any data that says people on this test that you're using can come in and out of MRD positivity? I'm wondering if there's any sort of, I guess, base level of potential false negative that we should expect in the futility analysis. Yeah. So that's uncommon. No test is perfect, but we expect that at a very low rate to occur. So typically what happens if you're MRD positive, you stay MRD positive. Now, we know from existing retrospective data that it's not 100%, and there are some patients who stay MRD positive for a long time, but it takes a while for their disease to recur. And in a very small number of patients, maybe 20%, even out three, four years, those patients have yet to recur even though they've stayed MRD positive. And in the case of toggling back and forth, that is an extraordinarily uncommon event. Okay. Great. Good to know. And then for going back to patient enrollment, I forget the phrase you used, maybe it was markedly improved in the cadence or success rate that you're seeing. I mean, does that give you confidence that you're going to meet the first half 2026 guidance for that futility analysis? Based on what you know right now, how confident are you? We are confident, and we are seeing good performance in enrollment. We're bringing on more sites every month. So yes, that is a solid guidance. I'm going to switch my cameras here, hopefully get rid of the, I don't know what's going on with this blurriness here. But let me just switch to my laptop, which might be a little bit better. You flipped. You did one of those flips. That's fun. Yeah. I flipped. Yeah. I flipped. Okay. We'll see if that works better for you. Okay. So then let's say you do pass this. Let's say at least 30% MRD conversion, right? You continue the study. You have a planned interim EFS analysis and then a final EFS analysis. And correct me if I'm wrong, but I'm not sure if you've been able to give guidance for the timing of that. Do you know when you might feel comfortable providing guidance on timing for those readouts? Yeah. So you're absolutely correct. We have not provided detailed guidance on the timing of the EFS analyses. There is an alpha spending interim analysis, and then there's the primary analysis. And we are deferring providing guidance until we do the update with the futility results in the first half of next year. Got it. So we'll know more then. And I assume that factors in the enrollment rates that you're having now and that you're seeing, and you'll be able to guide towards that. Okay. Just thinking about how long it might take for the study to reach the number of events needed for both the interim, but more importantly, I think the final EFS analysis, how long does it take for a patient that comes back MRD positive to generally progress in the watch and wait arm towards a second line or recurrence of their disease where they would need second line therapy? Yeah. So it's variable, as you would expect. The best data that we have to look at on this comes from the recently published JCO manuscript from our partners, Foresight Diagnostics, who is the group that is developing the test that we are using for this purpose. It's called PhasED-Seq. And in that group of patients, overall, the median time to progression for an MRD positive patient at the end of treatment was less than three months. So it tends to be a fairly rapid event, but there, of course, it's a Kaplan-Meier, and you do have some patients that take longer and so forth. So in any case, it happens quickly. And already on the study, we've had patients who have come back MRD positive and then for this or that reason didn't qualify for enrollment and randomization in ALPHA3. We're already hearing back that some of these patients are progressing very quickly within a few short months. The experience in ALPHA 3 seems to be bearing out with that recently published dataset from the Foresight group. I'll also add, this is another reason why we think an off-the-shelf cell therapy is really the best tool in this context because you have to act very quickly, arguably much more quickly than you can act with an autologous product. The other limitation to an autologous product is that there may not be very many T cells that have recovered from the six cycles of R-CHOP. That also brings into question whether even a bispecific would work very well because there's just not that many T cells to engage with your T cell engagers. So really bringing in a product that is built from fresh T cells derived from healthy donor in an off-the-shelf rapid way is probably the best modality to consolidate an MRD positive patient who in many cases may only have a few weeks before a clinical relapse. Got it. Okay. And maybe let's just talk about that. We've talked a lot about the study design and the patient dynamics, but we haven't really talked about cema-cel and the data you have supporting the efficacy here. Can you just walk through? I know it's in the later stages, but one of the things that I found interesting is that the patients with lower tumor burden seem to have better outcomes, and that seems to work really well or correlate quite nicely with what you likely would see in an MRD positive patient. Can you just give a high level of that background for everyone? Sure. So cema-cel got its start, as cell therapies often do, in patients with relapsed refractory disease. And in this case, of course, it was large B-cell lymphoma. And we recently also published the results of that phase I in the Journal of Clinical Oncology. And the highlights are that the efficacy seemed on par with what the autologous products were delivering in a similar line of therapy. And we saw about a 58% complete response rate in the phase II regimen that we studied in that phase I. And as you point out, the less disease burden that you had at the time of your cema-cel, and all these patients, but these were not MRD positive patients. These were patients with full-on relapse. But there are patients who have very bulky and aggressive relapses, and then there are patients who have slow-growing and small relapses. And so in any given population, you're going to have a spectrum. And so what we wanted to learn was whether we saw what was emerging in the autologous field that patients who have low disease burden when they receive their CAR T cell infusion, what are their efficacy outcomes? And this has now been shown in several different settings in the autologous setting, several different therapies in the autologous setting, that treating patients with low disease burden means that they have better outcomes, both safety and efficacy. So we looked at this, and we looked at patients who had low disease burden, and we sort of arbitrarily cut a line at 1,000 millimeters squared of the sum of product diameters, which is relatively small, but not very small, still visible on scan. And 100% of those patients achieved a complete remission to cema-cel. We also looked at another serological marker of disease aggressiveness and burden, which is lactate dehydrogenase. It's a blood test. And in the patients with low or normal lactate dehydrogenase, which is a marker of low disease burden and low disease aggressiveness, over 80% of those patients achieved a CR. So this really does, number one, replicate the findings in autologous, but number two, and very significantly, strongly indicates that if we take that even further into a patient whose only evidence of disease is this ultra-sensitive blood-based molecular ctDNA test, that we will be able to induce durable complete remissions in those patients even more effectively than in patients with relapsed refractory disease. I have a question from another investor coming in. Did you ever check MRD status in patients from the phase I study after cema-cel treatment? The short answer is we had a few samples that were appropriate. You kind of have to plan for MRD testing. There's like a special tube that you have to draw. We did go back as we were talking about ALPHA 3, and we looked at these results for a reasonable number of patients, not all. We did have some samples and were able to show that we were able to clear MRD in some of those cases. Okay. Some of the cases. And did it correlate with the lower tumor burden cases? It was a mix, so we had some patients who had high disease burden who did very, very well on that study, and you can go back and look at the swimlane plot from the JCO. We've got patients that are out past four years. Several of those patients did have the low disease burden, but there were also some patients with sort of more measurable disease. Okay. Interesting. And then going back to the patient enrollment piece, I'm wondering if there's any framework you could share. I doubt you could give specifics about the rate of the number of patients that are going into screening and the ones that make it through screening and then the ones that actually go into enrollment and remain in the study. Is there any framework on how you could talk about what that funnel looks like? Yeah. So I think the biggest piece of that funnel that we talked about came up a bit earlier, which is what the MRD positive rate is and that sort of 20%-ish range. So without getting into all the nitty-gritty details here, one of the other things that we learned about this study and its execution is that getting to patients early in their treatment course actually is much better for their kind of likelihood of actually conducting MRD test and then coming into ALPHA 3 than waiting until the very last minute. Because often what patients will do when they've been given a diagnosis of LBCL, they've immediately been told by their doctor that they have a very good chance of being cured of this cancer, which is true. That is what sort of clicks with folks. And then they go through their six cycles of R-CHOP. They expect to be cured at the end because that's what they've been told. They have a clean PET scan, and they're like, "Okay, it's time for me to take that cruise that I've booked to reward myself for getting through this successfully." To then come back and say, "Well, we also have this other test, which will tell us more accurately whether your disease is ready to come back." Patients in the early days were like, "What are you talking about, doc? This feels like a bait and switch." So we now talk to these patients quite a bit earlier, and that comes with both pluses and minuses. On one hand, we find these patients early. They get put into a logbook. We follow them through. We get the MRD test. But what also happens is we don't really know what's going to happen with those patients when we talk to them after their first cycle or their second cycle. Some of those patients, about 10%, will have primary refractory disease and will blow through the R-CHOP and need to go on to second line auto CAR. That patient obviously is not going to go on to get MRD tested. Some patients will have toxicity to R-CHOP, and they'll decide they don't want any more therapy, or they'll develop a new comorbidity. So we do see a sort of narrowing of that funnel even before we do get to MRD testing, and then we see about a fifth of those patients coming back as MRD test positive. Once we clear that MRD positivity, we're dealing with a smaller pool of patients, but they tend to actually end up in the trial because the opportunity is so compelling. Even for patients who are randomized ultimately to the observation arm, they are getting something more than they would be getting if they were just being cared for outside of a clinical trial, namely more frequent clinical visits, more frequent scans, critically, right? We're scanning these patients more often because we really want to see that disease come back sooner, or if it does, we want to act on it quickly. So we're able to offer something comforting to these patients who are MRD positive and are now expecting their disease to come back any day if they come into ALPHA 3. Got it. Okay. That's really helpful. And then so for the final EFS analysis, I'm going to skip ahead all the way to that. Any framework you can say on the number of events that you're expecting and what, I guess, is the powering for a successful study on that readout? Yeah. So we haven't provided a lot of the details on the statistical design of the trial, and I won't do so today, but suffice it to say that the bar is pretty low here. This study is designed treatment against observation. There's a huge opportunity to improve upon outcomes, specifically in this ultra-high-risk patient population who's MRD positive. And you can see that manifested in the overall study size, which is only 220 patients that need to be randomized. Got it. And so that's a good segue because now I want to talk about the commercial market. So let's say, I mean, well, for one, this is novel. It will take education and physician engagement in a commercial launch. But I'm curious. These sites that you have right now, they're the ones that are going to have experience with cema-cel right out of the gate. So perhaps they are early adopters. When you look at the population of patients, total patients in the U.S., let's just say, that are being treated at these sites, do you have a sense for what the opportunity is for the early adoption just solely in those sites? And then maybe we could talk about how it expands out to other sites that obviously will have interest in this if approved. Yeah. So that's a great question, Sam, and it gives me a chance to kind of talk about our commercial strategy in kind of a big picture sense. So I worked at Kite, as did Allogene's CEO, and I was involved in the ZUMA studies and led to the approval of Yescarta. And one thing as exciting and as transformative an experience for me as that was, one of the things that was sort of plainly obvious along the way was not very many patients are going to be able to get this treatment for any number of reasons: insurance, but primarily it's who your doctor is. And 80% of patients in the United States don't get treated at places like MD Anderson and Dana-Farber and Moffitt Cancer Center and Fred Hutch, right? They get treated at their local community oncology practice. So if we were going to bring the promise of CAR T, the modality to everybody who could benefit from it, we really needed to break the mold about how and where this therapy was given. That was baked into our clinical strategy. We wanted to bring this trial not just to the MD Andersons and the Dana-Farbers and the Mass Generals. We wanted to bring it to community practices. If you look at our site activation list currently on ct.gov, you'll see about 50% of the currently open sites are community practices. Some of those, a non-trivial number of them, have no CAR T experience. These are local community practices that have, for many reasons, decided not to invest in the infrastructure needed to deliver a cellular therapy like autologous CAR T or bone marrow transplant. They are some of the largest proponents of ALPHA 3 because it's for the first time giving them access to this curative modality for their patients, and they're able to hang on to their patients. They don't need to refer them out to a big academic center. So right out of the gate, at the time of approval, you're absolutely right. The centers that were part of the clinical trial will have a head start, but this is a very different launch strategy than any autologous therapy ever was or will be because it's off the shelf. We ship it overnight. It's ready to thaw at the bedside and infuse. Most of our patients in the trial, and actually a significant number of the patients even in the phase I relapse refractory, are being fully treated as outpatients. So we call this therapy in ALPHA 3 the seventh cycle of treatment for patients at high risk. And that really is resonating with a large fraction of the community oncologists out there. So this is a little bit of a hint of how we think our commercial strategy and commercial launch is going to go. It's going to be a lot less complicated or costly as launching Yescarta was. Got it. Okay. And not to push, but do you have a sense for what that percentage of patient coverage is within your sites? It's really hard to guess. I mean, even with a fairly sizable number of U.S.-based sites, somewhere around 50 currently, that's probably not capturing a huge coverage of patients. It's really hard to achieve that with any clinical trial. You would need hundreds, if not thousands, of sites open to really come close to capturing a large percentage of patients. But what matters is that this is a therapy that is easily transferable to new sites. Got it. Okay, and is there a difference in how you need to educate the community physicians versus the academic physicians that presumably have a lot of experience with the autologous CAR Ts? Yeah. So 100%, right? I mean, again, drawing on my own experience of the early days of autologous CAR, that was, those therapies were brand new. There was CRS. There was neurotoxicity. All that stuff needed to be studied and learned and mitigated kind of as we were going through the trial. Our product tends to be pretty well tolerated, and it's very, very outpatient-friendly. That said, we don't want to just sort of drop it off at the front door of these community practices and say, "Go ahead and give this to your patients." So there's a lot of training that goes in, not just how to handle the product itself, but what to expect after the drug is infused and what CRS looks like, what neurotoxicity looks like, even though with a low disease burden, we don't expect much of that in the trial. We do want to make sure that patients are safe. One benefit that we've been able to draw on is that many of these practices are using bispecifics, which are approved in later lines, and they come with CRS. They come with neurotoxicity. So they've become a little bit more comfortable dealing with drugs like tocilizumab and steroids and managing these patients. So the time was really right for us to bring this to those practices because they already had a functional knowledge of what a T cell toxicity looked like. So some of our work is done, but we're obviously being very careful, and we want to make sure that everything is being done safely. Yeah. That's a good point. Okay. So we spent a good amount of our time on ALPHA 3. I just want to give an opportunity. What haven't we touched on that you think is really important for everyone to understand? I think this came through during our conversation, and I'll try to keep it brief, but I mean, what we're really doing here is transforming care, and that's hard, but it's always hard when you're transforming care, and we really are looking ahead to what DLBCL management is going to look like in the very near future with MRD, and we expect that there will be additional trials that, like ALPHA 3, is such a compelling thought to be able to consolidate a low disease burden, so I would look at this opportunity as truly transformative, and that comes not just for the care of patients, but also for Allogene and the market opportunity that we talked about at the beginning. This is really a fairly sizable and exciting opportunity for us as a company to really put an impact here in this field. Got it. Okay. Great to hear. And we'll look forward to that, the futility analysis in the first half. But let's talk about your autoimmune asset, ALLO-329, which also has data expected in the first half. So your intro talked about it, dual CD19, CD70. I guess just walk us through the phase I basket study that you've initiated and the study design and how you're handling lymphodepletion in this trial. Yeah. So as I mentioned, this therapy has, through this Dagger technology, built-in lymphodepletion, and that was very well documented in our Kidney Cancer Program, which also has the CD70 CAR. So for interested listeners, that presentation is available on our website. You can see some data around this Dagger effect and why we think it's so important. So when we were designing ALLO-329, we really did it from the ground up for patients with autoimmune disease. And we knew that one of the biggest barriers to widespread uptake of cell therapies for autoimmune patients is they don't want chemo, and I don't blame them, and their doctors don't want to give chemo. So we had to have a plan for that. And it just didn't feel right to us to take an asset that was designed for oncology and just bring it into autoimmune and hope we can do it without LD, lymphodepletion. So that's where the CD19, CD70 idea was born. So as I mentioned, we baked it into the study design. We actually have two parallel cell dose escalation arms, as you do typically in a phase I. You dose escalate on the number of cells that you give, one with Cytoxan alone, so some lymphodepletion, but as I said, a dose that is commonly used in rheumatology patients. So it doesn't include fludarabine. It's not a super high dose of Cytoxan. It's something that they might be offered in their usual clinic. And then there's a parallel arm with no lymphodepletion at all, no chemotherapy, nothing else. So we're really excited about this. Doctors are really excited about it. It is truly differentiated. We are starting to see now some other sponsors starting to play with no lymphodepletion. They don't have the benefit of the Dagger that we do, though. And you mentioned the basket design. This is a true basket study. We've got four indications: lupus, lupus nephritis, if you count that as a second, inflammatory myositis, and systemic sclerosis or scleroderma. And what makes this a very flexible design is we don't have targets for individual indications. So our first dose cohort could be one of each or two of one and one of the other. And it gives a lot of flexibility to sites, some of which have more myositis patients, some of which have more lupus patients. So there was a lot of flexibility baked in that the investigators have really liked. We think that this will help us with enrollments in this competitive environment. How do you handle which arm patients get enrolled into? Is it just random or based on the site, and is that how it's handled? You said they are enrolling in parallel, correct? Yeah, they're enrolling in parallel. I mean, without getting into a lot of specifics, it's likely going to be roughly one here, one there. We're not going to be looking at an individual patient and making a decision based on their characteristics or their diagnosis. Are they more appropriate for this or that arm? We really are going to try to enroll them in parallel, more or less alternating. There's not a formal randomization or anything like that. Got it. Okay. And then so for the initial readout, what data should we expect? Should we get data from both of these lymphodepletion cohorts? That is the goal. We expect in the first half of next year to have data from both of these arms, certainly in the early dose cohorts. This is a dose escalation study, and we're expecting some biomarker data looking at the change in the number of B cells and T cells in the periphery. Maybe there are surface phenotypes that have been reported by other CAR T data sets, and then some early safety and efficacy as well. Okay. Excellent. And I guess once we see that, we'll have a better feel for this. But you sort of alluded to some other companies taking away lymphodepletion or reducing it. And obviously, you have the Dagger technology, but is there any difference in how you handle the reduced lymphodepletion versus some of the others that are trying it in the field? Or is your Cytoxan level less or the same? I'm just curious if there are any other differentiating aspects in the design. Yeah, so I mean, again, I'll say that to be perfectly blunt, I mean, we came to this a little bit later than some of the other sponsors, and we had to be quite disciplined internally to not just rush into it with, say, cema-cel or whatever, right, and we really wanted to be focused and goal-directed, but really be quite systematic about what does the right product design look like, so we spent a little bit of time with that. We brought this product forward, and then with the study design, the same exact thing. Let's design something that is fit for purpose, so I'll give you one example. I mean, the Cytoxan dose that we're using is the standard dose that is given to rheumatology patients of a drug that is given to rheumatology patients. It's not kind of like it, or it's like a CAR T dose, but we're giving it to rheumatology patients. It is the dose that these patients get. And we started with that in mind. So again, this isn't a, "Let's iterate. Let's hope for the best and work our way into something that suits rheumatology." Let's start with something that really will resonate with that population and that group of doctors. Got it. And is there your expectation that the CD70 piece of the equation, how necessary is that for when you remove lymphodepletion? I'm asking this because you mentioned there are a couple of other sort of endeavors out there for other assets. What are your expectations for how differentiated your data could be with CD70 and reduced or no lymphodepletion versus other assets that don't have CD70 and reduced and no lymphodepletion? Yeah. So I mean, I want to make sure that I put this out. We're speculating here, right, because ultimately, we have to run the study. And even once you have data, cross-trial comparisons are always tricky. But knowing what we know about the Dagger, we think we have a very good shot at getting robust cell expansion with low to no lymphodepletion. And I'll even say, without giving away too many details, that as we've been preparing a publication for the CD70 Kidney Cancer Program on the heels of the ASCO presentation that I mentioned earlier, we've performed some additional translational analyses, which has further built our confidence that this Dagger will propel these cells in the autoimmune patients to divide even in the absence of significant lymphodepletion. So based on those actual translational results as well as developing preclinical results, we think we have a really good chance of doing this. And I don't also want to give short shrift to the fact that CD70 is likely an important molecule in autoimmunity by itself, to say nothing of the dagger effect in cell expansion. We know that patients with treatment refractory and severe lupus and other inflammatory disorders have higher frequencies of CD70 expressing T cells in their bloodstream. We know that CD70 is important on B cells in these patients. So having the dual targeting of a relevant molecule on activated lymphocytes will give us additional benefit on the efficacy side, we expect. And while some may say that, "Hey, look, CD19 looks like it might be enough," I'm not sure we know that yet. I mean, we have heard that some patients are progressing, and certainly, we're seeing in vivo patients not having as deep a response as patients with autologous CAR. So it's quite likely that you might need to tackle the T cells on some level as well, even within the rheumatology disorders. That is probably going to be more significant as we expand into other diseases, neurology, endocrinology, gastroenterology, where classically there is a larger role for the T cells in that pathology. So a CD19 targeting B cell may not have much to offer in that case, whereas we expect to expand very aggressively outside of rheumatology once we've established proof of concept there. Yeah. No, when you start to add in other therapeutic areas outside of rheumatology, it gets quite a large, well, you multiply the TAM quite a lot. Okay. So that was very helpful. So I guess I want to just, one of my last questions is how Allogene is thinking about their capital allocation. You have two really interesting assets, one late stage, one much earlier stage. I think 316 is on pause for future clinical development. But how are you thinking about it going forward? And just remind us on your cash runway. Yeah. So we have cash runway into the second half of 2027. And from a company prioritization perspective, our sort of highest probability of technical success, I think, currently sits with ALPHA3. The design of that study, randomized, FDA-discussed and agreed design as a pivotal design, randomizing against observation, is not something that comes around all that often in oncology. We know it's an active therapy. We have a very sound clinical and commercial strategy there. So accordingly, most of our resources, time and dollars, are being spent on ALPHA3. That said, we are very excited about 329 and are looking for ways to move very aggressively with the expansion of that program upon achievement of proof of concept that we expect to share in the first half. And then 316, this data is potentially transformative. I mean, we've never seen, and when I say we, I mean as a field, we have never seen solid tumor data like what we presented in the kidney cancer trial at ASCO as an oral presentation in the main GU session. That has never been shown with an off-the-shelf CAR T therapy. We think that data is tremendously exciting. We are eager to move that program forward. As you point out, we're not internally doing that right now, but we are having partnership conversations on this program, and we're hoping to find a way to move that forward in the future. Got it. Thank you, Zach, for that. I guess that's the end of my list of questions. I just want to turn it back to you for general closing remarks you might have. Sure. Sam, thank you so much for this opportunity. It's really wonderful for us to be able to talk with your investors here. We think Allogene is a great opportunity. We've got a lot of very exciting programs, including a pivotal program up and running. It's a very, very exciting time in the field of cell therapy. I know it's been kind of a tough few years for the sector, but with companies like ours, new technologies like MRD and other things coming to the fore, I really feel like we've got a brewing renaissance here. And the next few months are going to be very telling for the field and for Allogene. So it's wonderful to be able to share that with your listeners. Yes. I'm looking forward to all of the data in the first half. Thank you, Zach, for being here today. It's been a wonderful conversation. Very much enjoyed it. Thanks, Sam. Okay. All right. Well, with that, Operator, we can go ahead and close the call.