Great. Good morning, everyone. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. Thank you very much for joining TD Cowen's 45th Annual Healthcare Conference. For our next session, I'm very excited to have a hybrid presentation and Q&A fireside chat discussion with Allogene. It's my pleasure to introduce David Chang, the co-founder, President, and CEO of Allogene. David, it's a privilege to have you here. Thank you for joining us. I'll pass it over to you to start the presentation.
Tyler, thank you for that kind introduction, I would say. Thank you very much. I know that this is coming towards the end of the Cowen meeting, and I appreciate your attention to what Allogene is doing. I'm President and co-founder of Allogene, and we have been working on advancing Allogene CAR T therapy. What the Allogene CAR T therapy brings is really an opportunity to expand this potential life-saving therapy across heme malignancies, and now going beyond the heme malignancies into solid tumor, as well as in autoimmune indications. We have three clinical programs at various different stages. The lead program is cema-cel, which is a potential pivotal registrational study in frontline consolidation setting in large B-cell lymphoma. This is a very unique and differentiated approach that we are advancing cema-cel into what we believe is the ideal setting to use the Allogene CAR T therapy.
Another program that we have been working on for a couple of years is ALLO-316 in solid tumor. We recently presented the data supporting its continued advancement, especially highlighting at the recent SITC meeting the response that we have seen with ALLO-316 in patients with advanced renal cell carcinoma. Lastly, we recently announced IND clearance of ALLO-329, which is specifically designed with autoimmune indications in mind. This is a dual CD19, CD70 CAR. Now let me go into each of these programs more in detail. The ALPHA3 study of cema-cel in the frontline consolidation setting is a really unique study. Let me first walk through the clinical setting here. Patients who are newly diagnosed with a large B-cell lymphoma undergo what is known as a rituximab-based chemoimmunotherapy.
It is a highly effective therapy where the majority of the patients after six cycles of R-CHOP continue to stay in remission. However, there is about one-third of patients who do not respond or who progress soon after completing the R-CHOP despite initially achieving a good response. During this period, patients are followed with uncertainty until the disease progresses. What we are trying to do with the ALPHA3 study is identify those patients who are at risk of having a disease relapse and intervening before their recurrence manifests symptomatically. What we believe is essential for this kind of study is the right product, that is cema-cel, and the right patient population, being able to identify those patients who are likely to relapse and doing it at the right time before disease relapse occurs. Let me go into each of these components a little bit more in detail.
We recently published phase 1 data of cema-cel in the JCO, really demonstrating that as Allogene CAR CD19 CAR T, cema-cel brings the efficacy that is comparable to autologous CD19 CAR. Along with that, we also demonstrated the durability of the response in patients who receive cema-cel, as well as a manageable safety profile. Going more into the details, this is the highlights of the JCO paper, starting with the response rate that we have reported with cema-cel in the relapse and recurrent setting, large B-cell lymphoma setting. Response rate of 67%, 58% of CR, and CR rate that is maintained through six months at 42%. We also reported the durability of the response in patients who achieved the response to be 23 months, which is getting to the range of what the autologous CD19 CAR T has shown.
Safety profile, as numerically shown, appears to be comparable or in some categories better than autologous CAR T therapies, as they have reported in their pivotal study, Kymriah, Yescarta, and Breyanzi, each of which carries approval in the relapse recurrent setting. Now, more details on the durability. On the right is the swimmer plot applied to patients who have achieved complete remission, and a majority of the complete responses continue on. The longest follow-up we have at this point is several patients who have passed out in a 48-month follow-up time period. This type of durability is quite reminiscent of what has been seen with autologous CD19 CAR in relapse and recurrent setting in patients. Another important aspect of the study was looking at the sort of subgroup analysis, specifically patients with a low-volume disease where we have seen six out of six complete remission.
This is highly relevant as we think about the ALPHA3 study, and I'll come back to this point in a couple of slides later. Next, how to identify the patient. This has been a somewhat challenging issue. The existing radiological method does not properly identify those patients who are at risk. What we are doing is working together with our diagnostic partner, Foresight Diagnostics, and using their PhasED-Seq to identify MRD in patients after completion of the frontline R-CHOP regimen. What's shown here on the right side is a Kaplan-Meier progression-free survival curve that shows the outcome of patients who are MRD negative, shown in the blue line, and the outcome of patients who are MRD positive. It's a clear separation of Kaplan-Meier curve.
Patients who are MRD negative continue to enjoy remission, whereas patients who are MRD positive at the end of six cycles of R-CHOP have a disease recurrence, the majority of them, and relatively quickly, with a median time to disease recurrence of probably less than six months. In all, MRD positivity at the end of frontline R-CHOP denotes about a 12-fold increase in the risk of recurrence in patients. Another important point is the relevance of disease volume and the outcome of patients treated with CAR T therapy. What's shown on the left is a probability curve , both in terms of achieving response and experiencing adverse events relative to the disease volume. Patients with low disease volume are more likely to experience durable complete remission, whereas patients with a high volume are more likely to experience more severe adverse events.
As I've shown in a couple of slides before, what we have seen, like other CAR T has shown, is that cema-cel works very well in patients with low-volume disease. This is exactly the indication that we are going after in the frontline consolidation setting. When you look at the disease volume extrapolated by the MRD status, this is done by our partner, Foresight Diagnostics, being able to identify patients who are only MRD positive versus waiting for these patients to have manifestation of the recurrence radiologically. That gives an opportunity to intervene when the disease volume is 200-fold lower than in otherwise patients who will be presenting for the second line treatment after disease recurrence. Now, what we are doing in the ALPHA3 study is depicted in this diagram.
We will be randomizing approximately 240 patients, essentially comparing what is considered to be a standard of care, which is watch and wait, essentially translating to having patients come back to the clinic every three to six months for blood tests and radiographic imaging studies. We will be comparing that to a single infusion of cema-cel. Initially, there will be a run-in phase where we will be comparing two different types of lymphodepletion, FC, which is a standard lymphodepletion that has been used with autologous CAR T, and FCA, which is the lymphodepletion that we have been studying with cema-cel in the relapse recurrent setting. Mid-2024 this year, we expect to carry out the first interim analysis. We will be looking at the futility, as well as looking at the MRD conversion rate to make a determination of the lymphodepletion.
After that point, randomization will continue as a one-to-one with a selected lymphodepletion versus observation. The primary endpoint of this study is event-free survival, with key secondary endpoints of progression-free survival and overall survival. In addition to the mid-2025 first interim analysis, we expect a second interim analysis in the first half of 2026. This interim analysis is statistically powered, and we'll be looking at the event-free survival measures to see whether the statistical boundary has been crossed. Regardless of what happens in the second interim analysis, we expect to have the primary EFS analysis towards the year-end 2026 that could potentially lead to a BLA submission in 2027. Now, let me move to the second program, ALLO-329.
This is a dual CD19, CD70 CAR that is specifically designed for autoimmune indications in mind, with the goal of overcoming rejection, as well as addressing the underlying mechanism of autoimmune disorders with the ability to deplete not only the B-cells, but also CD70 positive activated T-cells. Essentially, the ultimate goal is resetting the immune system while preserving the underlying patient's immune defense mechanism and maintaining the patient in remission for a longer duration. We recently announced the clearance of the IND. We expect to start the Phase 1 study middle of this year with a goal of providing initial prophylaxis based on biomarker data towards the year-end. Now, let me detail about why going with a CD19, CD70 as a dual CAR approach. Autologous CD19 CAR T has shown that depleting B-cells with a CD19 CAR can provide an effective way to reset the immune system.
That's the data coming initially from Erlangen in Germany, as well as having been confirmed by other companies. Another thing that we know from the CD70, which is extrapolation that we have made from the studies that we are doing with ALLO-316, which is a CD70-only CAR T program, is that having a CD70 allows allogeneic CAR T cells to expand and persist much longer. This is an intrinsic ability of CD19 CAR to deplete the patient's whole cells that leads to the rejection of allogeneic CAR T cells. In this diagram, I would say what the CD19 can be done, can do in clinics, and what the CD70 CAR can do to protect the allogeneic CAR T cells, we have clinical evidence coming from our CD19 program and our CD70 programs.
What is also tantalizing about being able to deplete CD70 positive cells is the role of CD70 in immune response. CD70 positive autoreactive T-cells have been attributed as an underlying pathophysiological mechanism leading to autoimmune disorders. Also, CD70 positive dendritic cells or antigen presenting cells that have been reported to be upregulated in patients with autoimmune disorders. We believe being able to deplete the CD70 positive immune cells would lead to a much better reset of the immune system, potentially leading to a much longer duration of the remission that one can achieve with a chimeric antigen receptor that is directed only against CD19. We recently presented the IND enabling data of ALLO-329. In this study, we made a direct comparison of what ALLO-329 can do versus CD19-only CAR. What can be shown in the left upper panel is that both products can deplete the B-cells effectively.
Also, when you look at the cell expansion, both products seem to have expanded a little bit better. If anything, ALLO-329 expands much better in one of the experiments. What is also tantalizing is when you look at the autoantibodies. ALLO-329 is a lot more effective in reducing the titer of autoimmune antibodies in this experimental model. Lastly, when you look at the persistence of CAR T cells, not only in the circulating blood, but in tissue, ALLO-329 persists much longer in tissue, namely in the spleen, which is shown on the right lower panel. The potential of autoimmune indications that can be addressed with CAR T programs is listed here. It ranges from rheumatologic indications to neurology, nephrology, hematology, and potentially GI indications. In the initial study, we will be focusing on patients with lupus, systemic sclerosis, as well as inflammatory myositis.
This will be proceeding as a basket study. From the beginning, we will be studying both reduced lymphodepletion, which utilizes cyclophosphamide alone without the fludarabine. In parallel, we will be investigating without lymphodepletion whether ALLO-329 can lead to the B-cell depletion and reset of the immune system. Lastly, let me talk a little bit about ALLO-316. This is a renal cell cancer program that we recently updated the clinical data. CD70 is an antigen that is upregulated in immune cells, as I have just talked about, but it is also significantly upregulated in the majority of the patients with a clear cell renal cell carcinoma. What we have been shown in the 316 study is ALLO-316, which is directed against CD70 antigen, is highly effective in demonstrating meaningful anti-tumor activity in CD70 positive renal cell carcinoma.
Going a little bit more into details, in the Phase 1 study, we tested different lymphodepletion as well as different cell dose to come to a conclusion that the ideal cell dose and lymphodepletion is cell dose of 80 million cells, and lymphodepletion then consists of standard Flu/Cy lymphodepletion, which is highlighted in the orange box on the left side. What we have seen in this subset of patients is that the response rate in the high tumor positive score, so these are the patients who express high levels of CD70, can be as high as 50% and confirmed response rate being as high as 33%. This is based on a relatively small number of patients. What we are doing is continuing to enroll additional patients into this Phase 1b cohort. We expect to update the data based on approximately 20 patients by mid-2025.
Lastly, let me conclude by sort of highlighting where we stand as a company. The last reported cash position at Allogene is $403 million, which will give us a cash runway into the second half of 2026. We have three active programs in hematologic malignancies, solid tumor, and soon to be in autoimmune indications. Key data readout is listed here, cema-cel lymphodepletion selection, mid-2025, ALLO-329 clinical prophylaxis based on the biomarker data towards the year-end 2025, and also ALLO-316 Phase 1 update in renal cell carcinoma mid-2025. Each of the indications that we are pursuing, frontline consolidation, autoimmune indications, and renal cell carcinoma comes with total market opportunities that are highly attractive. Let me conclude my presentation, and thank you for your attention.
Great. Thank you very much for that presentation, David. We're going to kick off Q&A, but we are also joined here by Zach Roberts, Executive Vice President, Head of R&D, and Chief Medical Officer at Allogene. We had a panel this morning where cema-cel showed quite favorably. It was picked as a favorite among the allogeneic therapies in development. Not surprised, just like both you were pioneering at Kite, you guys are pioneering a new approach here in frontline lymphoma. I want to ask a couple of follow-ups on that JCO publication that you reviewed. Obviously, this doc had a pretty significant reaction as people caught on to that. Six out of six responses in patients with low disease burden is obviously great, right? 100%.
As you think about the low volume of disease burden in those patients and compare that to what you're enrolling in ALPHA3 in the frontline post-R-CHOP, can you elaborate on what the difference in disease burden is, or if it's very similar to what you're enrolling and how that may translate to probability of success?
Thanks, Tyler, and thanks for the invitation to participate in the Q&A here. Great question. ALPHA3 is different from the ALPHA and ALPHA2 programs that were presented in the JCO paper in that all patients are going to be coming into the trial with very, very low disease burden. By design, this study will have really the lowest disease burden that's ever been studied in a prospective clinical trial ever. We're already sort of putting ourselves in a great position because these patients really have very few cancer cells left in their body, relatively speaking. What was so exciting to us about that subgroup analysis that David presented was that even in patients who still have visible disease radiographically but have a low disease burden, that's where we saw the greatest concentration of efficacy.
By extrapolation, when you're treating patients with even less disease that's only molecularly detectable by this MRD test, we strongly believe that the efficacy may even improve further over what we were able to show in the relapse refractory setting.
That's great. Can you talk more about how enrollment is progressing in the ALPHA3 trial? How many sites are active, and what's been the reception by KOLs and physicians in the academic and community settings?
Yeah, I think it's consistent with the poll that you cited just a moment ago. We have really been warmly welcomed by the investigator community, the KOLs who strongly believe that this is a study that is really going to change practice. It's a paradigm-shifting idea of bringing CAR T cells to patients at the time when they're most likely to derive benefit from CAR T. That spirit and support has really been quite strongly reflected as we've rolled the study out. We are on our way, somewhere between 30-40 sites activated so far. We're going to activate approximately 50 in the United States. Initially, we had primarily community centers that were activating because they tend to have a little bit less red tape than the academic centers. As time has gone on, we've seen more academic centers activate.
It is roughly 50-50 at this point, community versus academic. We are seeing tremendous enthusiasm for the study. Patients are actively being screened and enrolled. As we have repeated, and David just did, our guidance towards our first major milestone in the program in the middle of this year is we announce the selection of the lymphodepletion regimen, at which point we will go from a three-way randomization down to a two-way randomization in complete enrollment.
Let me just. Another element of the ALPHA3 study is one of the limitations of the current use of approved autologous CAR T is the treatment is right now more or less centered in the academic centers or so-called cell therapy centers, whereas the majority of the large B-cell lymphoma, especially the frontline treatment, is done in the community-based cancer centers. What we are doing with the ALPHA3 study, and this is really, I believe, essential to continue to expand the use of the chimeric antigen receptor therapy, is placing the trial where the patients are cared for in the community-based cancer centers, not only in the tertiary centers.
Essentially, the outcome, if this study is successful, I believe would allow the use of allogeneic CAR T, cema-cel, in the community-based cancer centers, which I believe will significantly increase the adoption as well as utilization of the cema-cel in the frontline consolidation setting.
As you know, Kite Gilead's been focusing on trying to expand into the community centers, but it's been slow and it's early inning. The uptake that you guys have seen is quite encouraging. As we think about the upcoming lymphodepletion decision this half, obviously, a less intensive lymphodepletion regimen would be great. The safety that you guys have observed with cema-cel has been encouraging and should get better in patients with lower disease burden. What will you share with us when you make that decision? What can we look forward to?
As we've pointed out, this is a seamless design. From the very beginning of enrollment, all of those patients are counting towards our overall sample size for the clinical trial. When we do this interim analysis to select the lymphodepletion, at which point we're going to be looking at efficacy using a biomarker, and that's looking specifically at MRD conversion. Everybody who comes into the study is MRD positive to start with. If they become MRD negative, we know that's a very strong prognostic indicator of durable disease control. We'll also, of course, be looking at efficacy. However, that is going to be an internal analysis because these patients will count towards that overall sample. We will announce that we have selected a lymphodepletion regimen. We will also be performing a futility analysis at the same time.
If we make that announcement that we've seen evidence of activity, we've selected a lymphodepletion regimen, and the study is on track to complete its goals, that will be the extent of the detail that we share because anything further would jeopardize the trial integrity by giving detailed response rates, for example.
I guess just to follow up, clearly, based upon those metrics, including MRD conversion from positive to negative, you're just looking for if you were to make that decision to go to the less intensive regimen of just FC instead of FCA, you would look for them to essentially be similar, similar results.
Correct.
Okay. All right. Okay. What are your expectations for what the control arm of observation in this study should do as we think about the final readout?
Our assumption is basically what the Kaplan-Meier curve that David showed a moment ago. The patients who are MRD positive, arguably, given what we know about this test and about outcomes in large B-cell lymphoma, retaining residual disease at the end of frontline treatment is arguably one of the strongest negative prognostic features that you can have about your disease. That red curve on the KM curve, which showed a median time to progression of less than six months for patients who retain MRD at the end of frontline. That is what we've used to model the ALPHA3 study. We expect these patients to be progressing fairly quickly. That is really what's driving the relatively rapid series of milestones in this trial with interim analysis first half of next year and then primary analysis by the end of next year.
Great. Let's move to autoimmune. You discussed the dual CD19, CD70 mechanism of action very well during the presentation. With the initial Phase 1 data potentially by the end of this year, what do you think you need to show, or what do you hope to show to achieve clinical proof of concept?
Obviously, one thing with the chimeric antigen receptor approach, and especially with the CD19 CAR, is the depletion of B cells. In some autoimmune indications that are known to be associated with autoantibodies, autologous CAR T has also shown that along with the depletion of B cells, the antibody titer can go down. I think those are very good indicators. Also, as an allogeneic program where we are testing with a different lymphodepletion, we would also like to see the cell expansion. Here, I think this is a very unique situation. We do not believe the persistence is required in the autoimmune indication. The CAR T cells need to go away relatively quickly for the immune reconstitution to occur after depleting B cells and CD70 positive T cells.
We just want to see a nice peak of CAR T expansion and following contraction and disappearance, and along with that, recovery of the patient's endogenous B cells and T cells. Probably the most important thing early on is the expansion, depletion of B cells, and possibly reduction of autoantibody titers.
Do you think you'll have enough data then to decide whether to reduce or potentially remove lymphodepletion?
Let's go step by step. We have very set objectives in this Phase 1 study, and we will be reviewing the data very carefully. The way we view it is with a cyclophosphamide-alone lymphodepletion, that already gives you a lot of opportunity with patients with autoimmune disorders. If you can do this without any depletion, that opportunity expands greatly to patients with moderate severity autoimmune disorders, which is essentially all the patients who get treated for the autoimmune disorders. This is a product that can bring a great opportunity for patients.
Great. Obviously, you've incorporated the Dagger technology there, which I continue to be semi-infatuated with. I think it's a super cool technology. I don't think folks appreciate it, and this early data will be exciting to see. With ALLO-316, again, encouraging late-stage data in relapse refractory renal cell, we're going to get data later this year. What are your thoughts on moving that forward in development? How do you prioritize that versus the two programs we just discussed?
Yeah. First of all, I think we have to recognize that the evidence that the chimeric antigen receptor approach can work in solid tumor is growing. Most of them are coming from autologous CAR T targeting CLDN18.2 or GPC3 for hepatocellular carcinoma. What is remarkable about the Phase 1 data of 316 is, as an allogeneic CAR T, this matches up with what the autologous CAR T has shown with different targets in different solid tumors. This is very exciting. As you sort of have asked, this is, I think, what the Dagger technology is allowing us to do. The second question about what are you going to do, what is the development plan? Obviously, this is something that we're thinking very carefully about. Renal cell cancer brings a lot of opportunity. CD70 is also antigen that's known to be upregulated in a number of other cancers.
There are different ways to think about it. First of all, we want to get to the proof of concept that gives us the confidence that we will move forward and there is an opportunity to go forward. The response rate that we have reported, I think, gets us there. What we are waiting for is the durability that is associated with those responses. That is why we are treating more patients and following them longer to look at that important element.
Great. Makes sense. I believe it's lunchtime, but to wrap up the conversation, I'd like to ask you what you believe is the most underappreciated aspect of the Allogene story by investors right now.
That's a loaded question, and I can give you many different reasons. What I would say is, I think we are ever so close to realizing the potential of allogeneic CAR T therapy. This is happening not only in hematologic indications, but also in solid tumor. Now, as we're moving forward in autoimmune indications. When we look at 2025, I think this is really the year that we can highlight all the benefits that the allogeneic CAR T therapy can bring across many different indications.
Wonderful. David, Zach, thank you very much for your time.