Good afternoon. Thanks for joining us for another session at the 43rd JPMorgan Healthcare Conference. I'm Brian Chang. I'm one of the senior biotech analysts here at the firm. I'm joined by my associate, Sean Kim, and Marianne Wacker, who are also in the audience. On stage, we have Allogene Therapeutics. I'll now pass the mic to their CEO, David Chang, for a short presentation, followed by a live audience Q&A. David, the stage is yours. Hey, Brian. Thanks for the introduction, and thanks for hosting Allogene as we kick off 2025. My name is David Chang. I'm Co-founder and CEO of Allogene, which was created with a singular mission of advancing CAR T therapy to what it is now, which is autologous-based treatment to allogeneic, off-the-shelf products, so that this potentially life-saving therapy can be available to all those patients in need. What we have been doing over since the founding of the company is really putting together our knowledge of CAR T, coming from our experiences of advancing autologous CAR T products, as well as a growing data set that we have generated with allogeneic CAR T products, and also combining that with the science to come up with products that could be the best in class for each of the indications that we are pursuing. Currently, excuse me. This study really summarizes in terms of the pipeline that we are advancing in hematologic malignancy indication, as well as in solid tumor. We also have a product that is soon to be introduced into the clinics. This is Allo-329, going into the autoimmune disorder indications. Each of these assets comes with unique differentiating attributes. Semacell is currently in a pivotal phase 2 study in a first-line consolidation setting to maximize the curative potential of CD19 CAR by targeting patients with a minimal residual positive disease. This is really with a goal of improving the cure rate in the large B-cell lymphoma. Allo-316 is being studied in solid tumor, which still remains as one of the elusive indications, despite the great unmet medical need, as CAR T therapy so far has not been so successful. As an allogeneic CAR T, we are beginning to see early signs of efficacy as well as durability. And we believe that this is driven by the Dagger technology that's intrinsic to CD70 CAR, which is part of the Allo-316. And combining these knowledge together, we have designed Allo-329 specifically with the autoimmune indications in mind. And we believe that this product has very unique attributes that address the fundamental biology of autoimmune disorders and becomes the best-in-class product as we expand the program into the autoimmune indications. What all this is bringing together is really the benefits to Allogene's CAR T, scalable manufacturing, and off-the-shelf products that can be readily available to those patients in need, that allows the on-time treatment, logistics, delivery logistics are simple, and this is really a standard pharmaceutical delivery model that allows the product not to only be used in the specialized centers, but potentially also be used in the community-based cancer centers, and the way that we are designing the study, especially going into the front-line consolidation with the Semacell, allows us to leapfrog where other autologous CAR T products are currently being marketed in the third- and second-line setting. And lastly, as we sort of expand the indications into the front-line consolidation as well as autoimmune, it really creates an opportunity for us to continue to develop and expand the potential indications that we are pursuing with these three assets. Another thing that I want to point out, and this is something we have been saying and others in the field are saying, in the cell and gene therapy space, manufacturing process is the product. This is something that we have taken to the heart and invested early on, developing the internal capability for the process development and manufacturing of the product, not only the capability, but also the manufacturing facility that comes with the capacity of producing enough materials to treat upwards of up to 60,000 plus patients on an annualized basis. This is really highlighting the scalability of the Allogene's CAR T manufacturing as we eye the indications such as autoimmune disorders. Let me talk a little bit more about the Semacell program. The strategy behind Alpha3 study, which is the pivotal study that we have initiated last year, and this study is actively enrolling, is bringing together the right product, Semacell, that has shown efficacy in the relapse refractory setting that we believe matches up to what the autologous CD19 CAR T has done to the right patients. These are the MRD positive patients at the end of the front-line chemoimmunotherapy for large B-cell lymphoma. We believe these are the patients who are insufficiently treated with the R-CHOP-based chemoimmunotherapy and need additional treatment, and also at the right time when their disease volume is at the lowest, which benefits the CAR T both in terms of efficacy as well as safety. And let me talk each component of the right product, right patients, and right time more in detail. The efficacy of Semacell has been extensively investigated in the third-line large B-cell lymphoma setting. Shown here is the response rate, including CR, as well as durable CR. With the lymphodepletion and cell dose that we are moving forward in the front-line consolidation, we have shown the response rate of 67%, complete remission rate of 58%, and 42% durable remission as measured by the complete remission at month six. When you compare these numbers to the numbers that were generated with the currently approved large B-cell CAR T products, autologous CAR T products, Kymriah, Yescarta, and Breyanzi, I would argue the numbers match up to the efficacy that has been demonstrated with the CD19 autologous CAR T products. When it comes to the adverse event profile, numerically, cytokine release syndrome and neurotoxicity appears to look favorable, and also, some of the concerns that have been raised about the infection risks, especially with the lymphodepletion regimen that we are using, which includes anti-CD52 antibody, grade 3 infection rate, if anything, trends lower than what has been reported with autologous CAR T products, so we believe we have the right product. Now, let's talk about the right patient. This is really where the lymphoma field is going, using the MRD to assess the disease burden as well as to measure the treatment outcome. What is shown here is the outcome of the patients based on their MRD status at the end of front-line chemoimmunotherapy, the R-CHOP-based chemotherapy. On the right panel is progression-free survival shown by the Kaplan-Meier curve. If you are MRD positive, which is shown in the red line, the majority of those patients relapse, and the relapse occurs very quickly with a median time of four to six months. So these are really the patient population whose need is insufficiently addressed with R-CHOP and requires additional treatment. Whereas if you are MRD negative, you do extremely well. This is shown in the blue line, patients relatively free of the recurrence during the follow-up of up to three years. So, where we are focusing here with the understanding that MRD positivity, those patients who are MRD positive are 12 times more likely to relapse, is identifying the patients using the CLARITY assay, which is developed by our diagnostic partner, Foresight Diagnostics, to choose the right patients to treat the patient with a Semacell. The argument about the right time really is summarized in this study. Study after study with a CAR T has shown that the patients with a low disease volume fare better. Their efficacy looks better, and the safety profile appears to be better. What's shown on the left is the probability curve based on disease burden. When you look at the response, durable response probability, it is higher when the disease volume is lower. On the other hand, when you look at the adverse event profile, specifically the neurotoxicity event, it trends the other way. When the disease volume is lower, they do not experience many neurotoxicity. Now, let's put this in the context of MRD positivity in the front-line consolidation setting. We estimate, based on quantitative measures using the MRD assay, patients who are treated at the MRD positive state, this is essentially when the smoke appears to be appearing before fire, it becomes evident, their disease burden is about 200-fold lower. So this is what we mean by applying the right treatment to the right patients at the right time when their disease burden is the lowest. Another important aspect of the design of the ALPHA3 study is, with all the benefits of the Allogene's CAR T treatment, we are moving the treatment from specialized cell therapy centers, which is where the autologous CAR T therapy is administered, to the community-based cancer centers. The fact Semacell comes with very simple logistics and without any kind of infrastructure requirement for the administration allows us to easily move into the community-based cancer centers. As we are conducting the ALPHA3 study, at this point, more than half the sites that are currently active and enrolling are the community-based cancer centers. Now, some details about the ALPHA3 study. This is a randomized study that will compare the outcome of the patients treated with Semacell to the observation, which is watch and wait, the current standard of care. Initially, patients will be randomized through three different arms, two arms that contain a Semacell treatment, but using two different lymphodepletion regimens, FC and FCA, and a third arm, which is a control arm, watch and wait. Mid this year, 2025, we will carry out the first interim analysis and make a determination on which lymphodepletion to continue. And thereafter, the study will be randomizing patients one-to-one to Semacell with a chosen lymphodepletion versus control. We expect to enroll approximately 240 patients. This study is using event-free survival as the primary endpoint, and the key secondary endpoint includes progression-free survival, overall survival, and the translational analysis of rate of MRD conversion, meaning how many patients convert to MRD negativity after the Semacell treatment. The study was initiated in 2024. The first important milestone, and this is a significant de-risking information that we will generate, is the interim analysis that's planned for mid-2025, where we will select a lymphodepletion regimen. The study will continue leading to the first interim efficacy analysis of primary endpoint event-free survival in the first half of 2026, followed by the primary analysis towards the end of 2026. If the study is positive, the study program will be moving into potential BLA stage in 2027. So why the study design is so important to maximize the potential of the Semacell is illustrated in this slide. Currently, the second- and third-line is where autologous CAR T therapy is approved and marketed. By going after first-line consolidation setting, we are leapfrogging where autologous CAR T therapy is and putting the Semacell ahead of the currently approved CD19 CAR T products. This comes with the benefit of a much larger addressable patient population as well as much greater commercial opportunity. Now, looking at the future of Semacell, the idea of treating patients at the MRD-only stage becomes a very attractive proposition. And the same concept can be applied to other CD19 malignancies, including acute lymphoblastic leukemia, follicular lymphoma, mantle cell lymphoma, as well as other CD19-positive B-cell malignancies. This is a potential future of the Semacell program, depending on the outcome of the first study that we are currently conducting. I'll now move into the second program that we are very excited about. This is Allo-329. This is a CAR that's targeting dual targets, CD19 and CD70. This product was really designed from the beginning with the autoimmune disease indication as the primary goal, and we optimized every aspect of the CAR, including the targets that we are going into, with the idea of one as an allogeneic product, you have to overcome rejection. We believe we have sufficiently addressed that important issue, and also that allows us to consider potentially lowering and eliminating lymphodepletion requirement, which can greatly increase the use of Allo-329 in patients with autoimmune disorders. Allo-329, as I previously alluded to, goes after the fundamental mechanism of autoimmune disorder, not addressing only the CD19 B-cells, but also CD70 positive lymphocytes, including CD70 T-cells. And I'll come back to this particular aspect on the next slide. And the real excitement of using CAR T for the treatment of autoimmune disorders is this is really a paradigm-shifting approach to managing autoimmune disorders from chronic lifelong treatment to one-time CAR T infusion that can provide prolonged drug-free, symptom-free remission. This is really the future that we would like to see as we advance Allo-329. So the most important thing, what are we exactly doing by targeting CD19 and CD70? What's shown here is CAR T with a CD19 CAR and CD70 CAR. Being able to go after CD19 positive cells will allow us to deplete the B-cells. Being able to go after CD70-positive T-cells allows us to overcome immune rejection, and we have clinical data coming out from different programs that substantiate this important biology of CD70, which is now a proprietary technology known as Dagger technology that we are using for Allogene's products that is in development. The other one is that CD70 is an antigen that is upregulated in activated T-cells, dendritic cells, and other lymphocytes that contribute to the maturation and activation of B and T-cells. We believe targeting those CD70-positive cells is an important aspect to holistically go after the autoimmune disorders. Now, a little bit of preclinical data, but this is very informative preclinical data that we have generated. What was done is using blood cells coming from the lupus patient, and we used two different donors and reconstituting mouse with human blood cells. And then we tested two different CARs, CD19 CAR and Allo-329, which is a dual CD19, CD70. As expected, both products very efficiently deplete the B cells. However, when you start looking at other parameters of efficacy, such as controlling production of autoantibodies, it appears Allo-329 in this experiment is far superior to CD19 alone, chimeric antigen receptor. Another important thing is shown on the right lower panel, and this is not just looking at the persistence of CAR T cells in the blood, but the persistence of CAR T cells in the tissue, particularly in spleen. At the termination of this animal study, CD19 CAR has all but disappeared, whereas Allo-329 continues to be present in the spleen. So Allo329 appears to be able to infiltrate into tissue much better than CD19 and also be able to persist much longer, which I think is a very important attribute as we think about autoimmune disorders. Now, the potential opportunity here. When you think about the number of patients afflicted with autoimmune disorders in rheumatology indications, neurology, here multiple sclerosis, as well as myasthenia gravis, nephrology, and hematology, the number of patients far exceeds the total addressable patient population in hematologic malignancy. This is a much greater market opportunity that I think is very worthwhile for us to investigate with a chimeric antigen receptor approach. I'm going to conclude my presentation with our last, but also very important program, Allo316. This is going after solid tumor, renal cell cancer specifically. The patient population that we have studied with Allo-316 is renal cell cancer patients whose disease is not controlled by TKI and checkpoint inhibitor, which is the current standard of care for the treatment of renal cell cancer. What we have recently presented last year is the efficacy data coming from this study. We have seen an overall response rate of 50% and a confirmed response rate of 33%. It also appears that confirmed responses are very deep and durable. Shown on the right is the disease control rate with a CD19 CAR in patients with CD70 positive renal cell cancer. Also, as a little background, the fact that Allo-316 only works on patients with CD70 positive renal cell cancer really tells exactly what this CAR is supposed to be doing. This is targeting CD70. We did not expect CD70 negative renal cell cancer to respond, and that's exactly what we are seeing. And the disease control rate in the CD70 positive patient is currently tracking close above 92%. Now, some of the translational data coming from the 316 program is equally tantalizing. We see the CAR cell expansion, which is a prerequisite to see any kind of having a pharmacodynamic effect such as response. With the 316, we are able to get the cell expansion and persistence that matches up to what autologous CAR T has shown in heme malignancy. Not only that, when you look at the tissue biopsy, tumor biopsy after the treatment, we see homing and trafficking of the CAR T cells to the tumor. And this is something that people have been asking about, whether CAR T can traffic into the tumor. I would argue that we have answered that important question coming from this TRAVERSE study of Allo-316. Next slide summarizes the adverse event profile of Allo-316. Currently, it tracks and appears to be consistent with the CAR T treatment and appears to be manageable. As we start 2025, we have a strong financial cash position that will carry us through the second half of 2026 as we pursue very important market opportunities, frontline consolidation with Semacell, autoimmune indications with Allo-329, and renal cell indication with Allo-316. As for the important milestone events this year, it is the first interim analysis of the Semacell program where we will determine the lymphodepletion and advancing Allo-329 to the clinic and generating proof of concept data by the year end and updating Allo-316 phase 1B data mid-2025. So with that, I thank you for your attention, and I look forward to 2025 as we deliver on these key important programs throughout the year. Thank you very much. Great. Let's begin the Q&A. Before the Q&A, can I invite our head of R&D, Zach Roberts, to help me respond to some of the questions that you? Of course. Of Of course. So let's begin with the Q&A. I'm joined by David Chang and also Zach Roberts from Allogene. For those of you who are in the audience, if you have any questions, you can raise your hand, and we do have a runner on the floor. For those joining us virtually, you can also submit questions on the conference portal. So maybe we'll address the upcoming major milestone for the Semacell first. How much can we, from the public side, how much can we get a sense on just, especially on the event-free survival, right, on Semacell at the interim readout? I think in one of your slides, you pointed out that there is futility and also LD selection off the back of that milestone. So how much will we be able to tell what the Semacell benefits will be in this frontline setting? So let's talk about a little bit of details of the first interim analysis, which is slated for mid-2025. So this will be in the initial phase where we are randomizing patients one to one to one into three different arms, two with a cema-cel, one with observation. We will be looking at a predefined number of patients who have received the treatment. And we will be looking at the MRD conversion rate as a primary sort of translational endpoint for the efficacy. And the comparison will initially be done with the cema-cel treated arm versus the control arm, where we expect the most conversion to be occurring in the cema-cel treatment arm. In a way, this is akin to futility analysis. The second phase of the interim analysis is comparing two different lymphodepletion arms to make the determination. And of course, we will be looking at the safety, but with a specific question about how much read can we have on the event-free survival endpoint, which is the primary endpoint of the study. I would say that this is a little bit too early, and the number of patients would not be sufficient to get a good read. But the MRD conversion rate is very important, and in my view, I think that will directly translate to the event-free survival endpoint. Okay. Maybe just as a background behind the correlation of event-free survival to MRD conversion, right? Because there's a lot to hang on the MRD conversion, and as you think about, there's also variability in it too, where you're also trying to understand whether you have powered the study enough, so can you give us a sense of what data is out there that can give you a sense of the correlation of MRD conversion, especially when patients are treated with R-CHOP or Polivy plus R-CHP to the event-free survival rate? Yeah. So the Kaplan-Meier curve that David showed, by the way, thanks for the invitation up to the stage, David. Nice to see you, Brian. Oh, welcome. Happy to be here. This Kaplan-Meier curve, as David rightly pointed out, is an aggregate of patients after treatment with frontline. Clearly, this is predictive in that case. I will say that there's also a growing abundance of data in the post-autologous CAR T setting, both in third line, which has been published, as well as post-second line, which has now been presented twice at ASH in 2023 and 2024, using this very same assay. In all of those cases, this assay is very predictive of durable disease control, in this case, looking for the likelihood of relapse post-CAR T infusion. We think this is a very validated biomarker post-CAR T, now in multiple clinical settings, and therefore have selected it as a reliable biomarker to predict durable disease control in ALPHA3. Any questions from the audience? So at ASH. We had one. Oh, we do. Okay. Could you share any, you talked about your strategic investment that you've made on manufacturing and continue to make that. Are there any key milestones in 2025 that you wish to talk about that's going to enhance not slipping up on any scale-up or supply issues that you worked diligently over the last few years? Yeah. I would say that manufacturing facility is fully operational, and in fact, all the clinical trials that we are conducting now, the clinical supply is coming from Cell Forge 1, which is our manufacturing facility. If I think about the next milestone event for the manufacturing facility, that will occur when we file the BLA. At ASH, that felt like a year ago, but at ASH just. Oh, that was only three weeks ago. That's a couple of weeks ago. I had the opportunity to meet with the CEO of Foresight, and we talked about how he is thinking about the MRD testing, the application of MRD testing in the LBCL. And I guess after I walked out of the meeting, I thought about just how it's very disruptive, potentially disruptive. If you are able to show that if patients do get conversion, if you treat them early, then you increase survival. But what is going to stop other CAR T therapy companies or even other modalities to come in to capture this space? Because part of it also is that, do you think that competitors are just kind of waiting to see how this plays out? And if so, how are you trying to kind of bolster your leading position in this MRD setting? I mean, you are absolutely right. I mean, the most KOLs in the non-adjuvant pharma space view the MRD as the future. And in fact, recently, there was an update to the NCCN guidelines, which now starts talking about using MRD as a treatment assessment at the end of the frontline R-CHOP treatment. So this is the future that we started journeying much ahead of others. There's definitely the lead time advantage that we will maintain. And the second thing is really what the product brings. Certainly, other autologous CAR T therapy can consider a similar approach. But on the other hand, whereas Semacell will be readily available immediately at the conclusion of R-CHOP treatment as a consolidation, one-time consolidation treatment, autologous CAR T requires leukapheresis and manufacturing. They do not have that kind of immediacy in terms of how the treatment can be delivered. Another very attractive proposition of the Semacell consolidation is consolidation, as the term denotes. It's a one-time treatment. It ends the frontline treatment, whereas if you sort of start bringing up bispecific antibodies, which some carry approval in the large B-cell lymphoma, that we don't view as something that can be only given one time to get the same kind of benefit that the Semacell will bring. The value proposition that comes, that's intrinsic to the allogeneic Semacell, as well as the time advantage, I mean, I think that it plays in our favor. Another thing that we don't talk about is the current study that we are doing is a randomized control study. Ultimately, the outcome will determine the regulatory approval status, but usually, randomized control study leads to the full approval. If it is fully approved with the kind of benefit that we foresee, the future entrant in this space would have to compare themselves against Semacell. I think there are many sort of facets, but our focus is executing the study and maintaining the lead time advantage. Can I just add one additional point? So as David pointed out in his presentation, a big strategic objective of this trial is to bring CAR T cells to community practices where autologous CAR Ts have famously struggled to penetrate. So even if we get to a place where there are additional modalities or products that are usable in an MRD setting, they're going to be geographically restricted in the way that we will not be. So that is going to be a built-in advantage that we are going to press. Can we just, building on your point about the importance of community center in the LBCL disease indications, right? This trial, ALPHA3, I think you're giving options to treat patients, outpatient and inpatient, right? How should we think about the mix of outpatient versus inpatient experience? Because I think earlier during the, in your preparatory remarks, you said that more than 50% of the sites are community-based. So are you actively trying to advocate for outpatient and maybe also some color on their readiness to apply Semacell as an outpatient treatment? Zach? Sure. So we leave this up to the decision of the investigator. I will say that we have fairly extensive experience in administering Semacell in the outpatient, including in our phase one program in the relapsed refractory setting. So we anticipate that a substantial number of these patients will be treated fully as an outpatient. We'll have to wait until the end of the trial to disclose the exact mix. But there is nothing in the protocol and nothing according to the safety profile that you've seen here in this presentation that would dictate an inpatient administration. So we expect a large number of these patients to be managed in outpatient. That itself is also hugely attractive because they have just finished six cycles of outpatient treatment. So this is yet another opportunity for them to stay out of the hospital, consolidate their remission, and hopefully never hear from their disease again. Let's not forget about the disease volume of the patient population, the MRD positive. This is the lowest disease volume that one can think about. All the available data would indicate the safety profile, if anything, will be much better in the MRD-only setting. That's one thing that we are counting on. Certainly, data will tell us how that factors in terms of the treatment administration and follow-up. So on your autoimmune program, what's your criteria in selecting which rheumatology indication to move into? Zach, so obviously, we're watching this field very, very closely, and I think there's a lot of progress and new case reports and small case series now publishing what feels like every month with new indications under study. Just last week, there was a publication in The Lancet of a patient with refractory ITP who was treated successfully with CAR T cells, and that led to a resolution of his thrombocytopenia, so that's obviously not rheumatology, but I raise that point to suggest that the list of indications where proof of concept has been established is already long and growing, and so we are looking at this. We want to choose an indication or a set of indications where there is a good balance of proof of concept and yet not an overwhelmingly daunting competitive landscape. Yeah. And I would also make kind of the very sort of interesting observation. When the autologous CAR T data came out in the autoimmune indication, investors were getting excited, whereas the rheumatologists and KOLs were on the sideline. Now, about 12 months later, there's a little bit of investor fatigue and confusion about what's going to happen. But at the same time, the rheumatologists and KOLs are getting extremely engaged and excited about the prospect of using CAR T to treat autoimmune disorders. And at the end, in any drug development, the investigator and KOL interest will drive in more than anything else. I think, I mean, I cover this space extensively. I guess one of the feedback had always been the data have been very great from coming out of the academic institutions. But then when you look at the companies that are spearheading, investors are more confused about just the regulatory path there, right? And are you, because there's also the question of, well, when you look at lupus nephritis, and it may appear to be very difficult for some. So I mean, how are you trying, how are you going to get credit for this program? Just kind of thinking about these potential pushback that you might hear as you launch this asset into the clinic. I mean, the fact that you cover the space and helped us quite a bit to understand what's going on. In the end, having been in drug development as long as I have, I believe when you are developing drugs, do it in the right way. Don't try to jump the gun. Get the basics done. Phase one study is a proof of concept, and one of the important proof of concept that we will try to generate is whether we can get the benefit of CAR T without lymphodepletion requirement, and once that is done, I believe that we can rapidly move into the other indications without needing the lymphodepletion off the shelf one-time treatment.