I'm one of the biotech analysts here at Guggenheim. I'm delighted to welcome the Allogene team. Here with me, we have Zach Roberts, the Chief Medical Officer, and Jeff Parker, the Chief Financial Officer. Maybe let's just start with kind of a quick debrief on the key learnings of the off-the-shelf CAR T space to date. Obviously, you guys are one of the pioneers of the allogeneic cell therapy space. Maybe just you know let us know what have been the key learnings and what do we know so far, and what are the key outstanding questions? Yeah. So I think, first of all, nice to see everybody. Thanks for coming. So I think the key learnings have, you know, since Allogene was founded about 5 years ago, are, you know, there's many things that we've learned, but I think the most important ones to highlight here are, number one, that an off-the-shelf allogeneic therapy like cema-cel can produce durable remissions that are analogous and comparable to what we see with autologous. And we showed that, over the summer, in, you know, several different, scientific presentations at international meetings, durable complete remission rate in relapsed/refractory LBCL of 42%. This is really very similar to what you see with autologous. So I would say that is probably the most important learning, is that this modality is an option for patients, and it does have the ability to really move the field forward. I think the second key learning to highlight is really just how difficult it has been for autologous manufacturers to address the unmet medical need in the indications where there are approvals. Mm-hmm. You know, as it's earnings season now, and we see sales from the autologous products sort of hitting a little bit of a ceiling, yet only getting 15%, you know, ish penetration into the market. What that tells us is that there is still a very large gap- Mm-hmm ... a very large amount of unmet medical need, that you need something that you can scale and administer in a more, sort of on a pharmaceutical, sort of approach and platform, as opposed to this sort of bespoke manufacturing. Mm-hmm. I would say those are the two key learnings. Got it. Great. I guess kicking off this year, you announced your 2024 platform vision. Maybe just walk us through kind of the multiple components there, and then how it will shape 2024 and the years to come. Yeah. So, I'll start with the cema-cel program, which is what we're calling ALLO-501A. This is our CD19 off-the-shelf allogeneic product. So prior to the announcement of the 2024 vision, we were focused on third-line relapsed/refractory LBCL exclusively with that product, so we had two ongoing pivotal programs, ALPHA 2 and EXPAND. And what we've done with the shift in for 2024 is focus now on frontline LBCL. So we've decided to deprioritize our later line therapies, and that was, you know, multifactorial, the decision behind that decision. But primarily it was, you know, us being able to read the tea leaves that this was going to be a diminishing market opportunity with all the competition that's come into the field over the last couple of years. And so, you know, the new program we call ALPHA 3, this is in patients who are just completed their frontline R-CHOP, so standard chemoimmunotherapy for newly diagnosed LBCL. And then we're introducing, through a partnership, a minimal residual disease test, that we will then stratify patients into those who are likely to relapse versus those who are likely to be cured, and we're gonna be treating the patients with MRD-positive disease. So this accomplishes really several things. First, it sort of jumps ahead of all of the competition right now for relapsed and refractory patients, so this will be the first opportunity that most of these patients will have to get CAR T. Secondly, it's allowed us to really push this modality, CAR T, into community practices, which to date have not made the investments required to deliver safely, autologous products. So it's really a multifactorial pivot in LBCL. The other thing that we've done is add a new cohort, actually to the ALPHA 2 footprint, and we've done that for operational efficiencies, where we'll be studying CLL. CLL is an area of growing unmet medical need as patients are progressing on the oral therapies that have been the mainstay of treatment for the last 10, 15 years. So there's a lot of interest in bringing cema-cel into patients with CLL, and this also dovetails nicely with the liso-cel data that was shared over the summer and is now under priority review at the FDA. So really, I think speaking to the growing unmet need there. We also gave some updates on our existing phase I program in renal cell carcinoma with our CD70 product, ALLO-316, and highlighting some data updates that we plan for later this year, but that study is ongoing. Then the last new piece of news that we introduced at J.P. Morgan was our first dedicated product for autoimmune disease, ALLO-329, which is a bispecific CAR T-cell. It's got a CD19 and a CD70 CAR, and that's really, we opted to go in that direction to differentiate ourselves from all of the CD19-only products that are currently in development or soon to be in development in lupus and other autoimmune indications, to really attack both B-cells and T-cells, and also create a pathway to lymphodepletion de-intensification, Which we think is going to be a critical component in truly realizing the opportunity in patients with AID, where risk tolerance is going to be different than it is for patients with relapsed refractory cancer. Mm-hmm. Yeah, great. Maybe let's start with cema-cel in non-Hodgkin lymphoma with a frontline consolidation strategy. I guess, how should we think about the commercial opportunity there? And then again, the registrational design, maybe just walk us through that trial. Yeah. So I'll probably take those in reverse order. So talking about the design of the study. So, this is a kind of novel trial and really built for efficiency and speed. Mm-hmm. If you look at traditional frontline studies, they're 800-1,200 patients, these sort of juggernaut trials- Mm-hmm. -that take years to enroll. The reason that those studies are so big is because they typically follow an add-on strategy. You take R-CHOP, which is a highly efficacious regimen, you add something else on, and because you're really looking for a handful of percentage points improvement in PFS, you need a massive sample size to really demonstrate that statistically. Mm-hmm. Our study is only 220 patients, randomized to cema-cel versus observation, which is another huge benefit that we have, as we're randomizing against simple observation because there is no standard of care therapy for patients who have MRD-only disease at the end of R-CHOP. The study will actually begin with a 3-part randomization. So patients who come in will be randomized either to observation, the current standard of care, and we expect those patients to progress very quickly, median is about 8 months. And then 2 treatment arms, one with our standard lymphodepletion, which is fludarabine, Cytoxan, and ALLO-647- Mm-hmm. which is our anti-CD52 antibody. And then that same regimen minus the ALLO-647. We'll treat the first handful of patients that come into the study in this fashion, randomizing 1 to 1 to 1, and then sometime in the beginning of next year, we will drop one of those lymphodepletion arms and then complete enrollment with just a 1-to-1 randomization. Mm-hmm. We will select the most appropriate arm based on emerging safety and efficacy data that we observe at an interim analysis. Primary endpoint is event-free survival. Mm-hmm. And as I said, we expect those events to be coming in very quickly because we are randomizing against nothing. Mm-hmm. As far as the market opportunity goes, this is one of the most exciting aspects of this pivot for us. So as, as you see the opportunity in third-line, the aggregate opportunity beginning to dwindle as patients are receiving second-line auto CARs or second-line, you know, bispecifics- Mm-hmm ... this opportunity really cuts the line in a way, because, as I said, every patient who completes R-CHOP, who eventually progresses, and that's about 10,000 patients in the United States alone, would be eligible based on their MRD positive result at the end of therapy. Mm-hmm. So it gives us access to a much larger patient population, which has a commercial benefit, but also an operational benefit because it erases all the competitive pressure that we were facing in third line. Mm-hmm. So it's, in our estimates, you know, about $3 billion opportunity, which is roughly 5-10x what we were forecasting for the third-line opportunity. Jeff, anything else to add on that? Well, I would say also with cema-cel and the allogeneic approach, and the fact that you don't need the leukapheresis to initiate the therapy, our efficacy and safety profile also being very favorable. In ALPHA3, we're gonna be implementing that study in community cancer centers- Mm-hmm ... which heretofore has been an issue that the autologous therapies have seen, that not being able to break into those areas of care. So we think that also improves the, you know, just the pattern of care and the ability to make this immediately available. Mm-hmm. Because if you think about first-line, R-CHOP, very effective. That's six cycles. We would be effectively the seventh cycle, very natural point at which they could get their MRD test. If it's positive, immediately have the option of getting cema-cel, and being allo, can be off the shelf. And without the leukapheresis being very easy to administer for these community oncologists- Mm-hmm ... they don't have to lose track of their patient to the academic center, which they like to keep hold of their patients. Mm-hmm. And so it's a very nice match for us, but we also think allows for a much faster commercial uptake. Yeah. Great. And maybe just quickly on the lymphodepletion, you know, using 647 or not, I guess, what is kind of the rationale for you know, maybe not needing it earlier in lines of therapy where it was so crucial in later stage? Yeah, so this is a very interesting scientific question that the field has been grappling with for some time, which is, you know, what is the role that LD plays in cell therapy? And I think this is going to be a key area of focus in the AID space. But even in oncology, if I'm being honest, it still is a bit of a black box. And so we know that, you know, every cell therapy, whether auto or allo, needs some measure of lymphodepletion to affect, you know, the efficacy outcomes that you desire. When the bar is quite high in somebody with bulky disease after multiple rounds of therapy, you need to give your cells as much of a support, a leg up, if you will, to be able to expand and eradicate all of those tumor cells And so the main tool that you lean on there is lymphodepletion. And the deeper the lymphodepletion, the more effective the CAR T cells are. And we see this. This is a tenet of cell therapy that goes back to bone marrow transplants and TIL therapy at the NCI. So we knew that, you know, in later line therapies, we needed that extra push. In the early line study, when you only have molecularly detectable disease, so in maybe a few million tumor cells left in the body, it is actually a really interesting scientific question: Do you need the same depth of LD or do you not? Mm. Now, so, you know, we're running that from a scientific perspective, but also, you know, to appease the FDA, who, you know, we had a, a long back and forth with on the expand study. They wanted us to run that study to really generate the data that would allow them to approve ALLO-647- Mm-hmm. in the eventual case that we approved it, that ALLO-501A was approved. So what we've done is kind of condensed those two programs into a single sort of seamless and efficient design, which allows us to generate the data that will be used to establish the contribution of effective ALLO-647 in the event that we carry forward with that arm. Mm-hmm. So that when we get to the end, we'll, we'll have a data package that will support registration of both cema-cel and ALLO-647. It may be that in this unique and novel clinical trial setting, we don't need ALLO-647, in which case, you know, we- Mm-hmm. We walk away from the whole endeavor. Got it. Okay, that is really interesting. Maybe shifting to CLL, I guess maybe kind of walk us through what we've learned to date from CAR T and CLL and why cema-cel may be better positioned in this indication versus, you know, like a liso-cel or something like that. Yeah. So CLL has been an interesting story- Mm. you know, those of you who have been following this field as long as some of us have, will remember that the very first splash that CAR T-cells made in the clinic were in patients with relapsed/refractory CLL. Three patients treated at University of Pennsylvania, published in the New England Journal in 2011, is really what started this whole field. Mm. I would say from that sort of high watermark on day one, CLLs had kind of a difficult path, and that's been for a few reasons. Number one, it was around that very time that BTK inhibitors, and then shortly thereafter, venetoclax, a BCL-2 inhibitor, were approved. And so when I was at Kite, you know, we clearly were interested in CLL because of the proof of concept that was out there, and we were going to KOLs, and they were saying: "This is, you know, not worth your time. There's not really an opportunity here. Everybody's just getting put on these oral therapies." And that was sort of the case for a while. Now, there were some programs that were sort of nursed along, and the liso-cel data is, you know, speaks for itself, that there was an unmet need in these, you know, dual relapse/refractory BTK, BCL-2 relapse patients. What we're now hearing is two things: First, the unmet need is now growing again because all of those patients are now coming off of their BCL-2 and BTK inhibitors, so they're needing additional therapies. The patients who achieve CRs with liso-cel do extremely well with, you know, years of follow-up with no evidence of relapse following a single treatment. So the, you know, the promise of cell therapy is now being realized by patients with relapse/refractory CLL. So this is a very exciting... Those very same KOLs now are coming back to us saying, "Please run this study." And then to your specific question around allo versus auto, another key point of excitement for these KOLs is the fact that one of the reasons that people believe that CLL has not been a home run for auto CARs, as it has been for LBCL, is because of the intrinsic T cell dysfunction that is well described. Mm In patients with CLL. It's a very famously an immunosuppressive malignancy. And furthermore, these patients can have, you know, millions and millions of circulating leukemic cells. So actually extracting T cells from that, you know, immunosuppressive milieu, manufacturing products from them, and then expecting those T cells to eradicate cancer is kind of a lot to ask. Mm-hmm. We're coming forward with healthy donor-derived T cells that are manufactured, you know, easily and well ahead of time. It's sort of a fundamental shift in the biology of these products, and the fact that we can deliver these overnight to patients and not have to, you know, experience manufacturing failures, et cetera, is another compelling opportunity. Got it. I guess maybe how should we think about the efficacy benchmark for CAR T in CLL? Is the strategy longer term to move up the lines of therapy and compete with the, you know, BTKs and BCL-2s, or is it- is kind of post refractory to both kind of the, the, the end game? So we're starting in the refractory population. Mm. It's a little bit of nuance there. So in CLL, as in other heme malignancies, you can actually risk stratify patients at the time of diagnosis based on genomic or molecular features of their tumor. Mm. And so there are patients who are classified as high-risk CLL patients. They tend to not do as well with BCL-2 inhibitors as they do with BTKs. So for that subset of patients, they just need to have failed BTK inhibitors only. They don't need the- Okay ... BCL-2 inhibitor failure as well. For all the standard and low-risk patients, they do need to see both. So we are going into that sort of area of highest unmet medical need right now. Mm-hmm. We think the efficacy bar there is actually on the low side, and you know, look at the liso-cel data, which was awarded priority review by the FDA. They had a sub-20% complete remission rate and an overall response rate of under 50%. Mm. -in a subset of patients that was 49, was it 49 patients? And that is the pivotal data set that's in front of the FDA right now. So in terms of, you know, single arm, very small study- Mm-hmm. Very low efficacy bar, we do think that there is quite an opportunity here for us to show comparability or even superiority, of course, cross-trial comparison caveats apply. Mm. to the liso-cel cell data. Yeah. Okay, that's great. Shifting now to ALLO-329, your, your program at autoimmune, I guess, how was this program designed? How is it differentiated from the other CAR T approaches, like you, you mentioned in the intro? Yeah. So, we took kind of everything that we knew from our existing platforms for CD19 and CD70 and designed a product that kind of pulled the best parts of each of those programs together- Mm. -really with a view towards treating a patient population, which is something that most CAR T cell companies have never treated- Mm. A group of patients that have never been treated. These patients typically are young, they're otherwise healthy, you know, they're, most cases, not staring down imminent death like you are in relapsed refractory cancer. So, you know, through conversations with rheumatologists, et cetera, we knew that we needed to have something that was going to be differentiated, and we chose to differentiate in two main ways. The first is we wanted a multi-targeting CAR, so one that wasn't simply focused on B cells- Mm-hmm. because we do think that you know, while the proof of concept does support that in lupus, there are hundreds, probably different diseases in the class. Mm. classification of type I, type I and II, and many of them actually have a strong T cell component to them. And so we really wanted to bring T cell targeting to this platform, and that's where we leaned on the CD70 experience that we have. So in our ALLO-316 program in renal cell carcinoma, that's a CD70-directed CAR, and we know from the translational data as well as, you know, well-published sort of data on CD70 expression, that CD70 is turned on in activated T cells. Mm-hmm. We see that in our patients, and we see that in the literature. So we know that we'll be able to address the pathogenic T cells with the CD70 targeting CAR products. We've got B cells through CD19, T cells through CD70. And then the last piece is, again, unique to the AID population. These patients and doctors are going to be a little bit worried about giving large doses of Cy/Flu. Mm-hmm. What we've learned from our renal cell carcinoma program is that the CD70 CARs actually bring an element of lymphodepletion along with them through what we call the Dagger effect. Mm. In a nutshell, the way that works is when a T cell becomes activated, it turns on CD70, which then allows it to be eradicated by the CAR T cell. And so when you're using an HLA unmatched product like ours, you have an alloreactive effect, and our CAR T cells are actually able to prevent that- Mm. alloreaction through that, that sort of anti-T cell targeting. So we actually have been able to deintensify our LD regimen in our renal cell carcinoma program using this Dagger biology, and so we see that as a path to deintensification of lymphodepletion in this sort of unique patient population with AID. So really, those two components, B and T cell targeting and a plausible path to LD deintensification, is what went into the design of 329. Mm-hmm. Yeah, no, that's great. And, maybe just remind us the status and the timing of this program, and then what indications of interest do you have kind of near and longer term? I know our panelists mentioned, you know, there are some diseases that this would be particularly interesting for, Yes. Thank you for asking that question. Yeah. So we haven't come out and declared what indications we'll be pursuing from the get-go. I think obviously we're going to have to consider lupus and lupus nephritis, given that's where the POC is. Yeah. But, you know, we really are quite eager to road test this T cell targeting- Mm ... end of things. And so as we get a little bit closer to the IND, more color will be provided there. As far as the program status, this is still a preclinical program of ours. We are working furiously at this point to get the IND ready to go. A lot of that at this point is sort of just gathering the kind of, you know, turning the crank on an IND preparation. Mm-hmm. The candidate itself is defined. We, you know, we published some preclinical data late last year on it. So, you know, the construct is set. Now, it's just a matter of, you know, generating the package that's required for the IND. So we expect to have that first half of next year, and be in the clinic shortly thereafter. Yeah, great. Well, we look forward to it. I guess shifting now to ALLO-316, and the TRAVERSE trial, maybe just remind us of the opportunity in CD70-positive RCC, and the benchmark, you know, how we should think about the benchmark. Yeah. So this is quite a large opportunity in terms of unmet need. You know, 12,000+ patients in the U.S. alone have relapsed refractory third-line RCC, which is where we're studying ALLO-316 at the moment. And I think, given that there's two drugs approved specifically in this line, tivozanib- Mm-hmm ... which is a TKI, and then belzutifan, which was a very recent approval, both of them showing sort of 20-ish% response rate in less than six months PFS. Mm. This is really a pretty awful prognosis for these patients. So we think the bar is actually still quite low- Mm ... even with the new entrant into this market. And we bring the benefit of CAR T, which is a one and done opportunity, right? These patients, the ones who have derived benefit in our study get their treatment and, you know, are able to kind of go for several months without seeing another drop of therapy and, you know, seeing significant improvements in their day-to-day life. So we think that this in a, in a true kind of relapse refractory cancer setting, the bar is very low for us to make a substantial improvement here. Got it. Maybe just remind us the status and when we'll see the next data cut there and what to expect. Yeah. So, you know, as we've announced earlier this year, you know, we had to slow the study down a little bit, in the second half of 2023 as we encountered some adverse events that were related to hyperinflammatory syndromes that we were observing in some of these patients at the highest end of the dosing intensity spectrum. We were able to successfully navigate those, that toxicity profile through the development of a diagnostic and treatment algorithm. All right. And so, you know, the study enrollment is ongoing under an amended protocol, which incorporates this algorithm. So looking forward to catalysts in 2024, in this program specifically, we are looking to have a fairly near-term deep dive on this hyperinflammatory syndrome that we observed- Mm. as well as its diagnosis and management, so detailing this algorithm. You know, that will likely rely heavily on some translational data, maybe a patient or two worth of clinical outcomes to really highlight this. Mm. And then later in the year, as we've sort of built some more experience under this new protocol, and then with enrollment, kind of a more complete update in terms of safety and efficacy across the, the program in, in general. Okay, got it. That's great. And I know we're running up on time, so maybe just quickly to end off- Okay. cash runway, catalyst lineup for 2024. Yeah, on the cash runway, we've been very public that we have cash into 2026. Yep. So this full year, next full year into 2026, and Zach hit on some of the catalysts this year. But I think the key catalyst for us, starting with ALPHA3, first patient dosed will be- Mm -mid-year this year. And I do think momentum in ALPHA3 is gonna drive a lot of interest in, in the company, because that opportunity is so well understood now. Just seeing momentum in that trial will be, confidence building. Then the CLL data, we hope to have end of this year- Mm. RCC data end of this year. And then beginning of next year, we'll have the IND on 329. Right. We'll also have a point in time in the first half of next year, where we'll signal that we've picked a lymphodepletion arm in the ALPHA3 study. Mm. That study will go from 3 arms, 2 lymphodepletion regimens, and observation to 1 lymphodepletion regimen and observation. Mm. At that point, I think we'll be able to communicate some confidence in understanding how the trial's going. Probably not data, not specific data- Mm -on that because we don't want to screw up with the statistics on the study. But the simple act of picking a, a- Yeah ... picking an arm will, I think, be very, confidence building again in ALPHA-3 in, the first half of 2025. Got it. Okay, great. Thank you so much for joining us. And, with that, we will move on to the next session. Thanks. Thanks, Kelsey. Thank you.