All right, good morning. Thank you, everybody, for joining Jefferies Healthcare Conference in London. My name is Clara Dong, one of the biotech analysts here at Jefferies. Here, it's my pleasure to introduce Dr. David Chang, the Chief Executive Officer of Allogene, for giving us this presentation here. For the presentation, we'll do some Q&A as well. Welcome.
Thank you, Clara. Usually, we do fireside chat, but there have been some analyst changes, and we thought it would be best that I do a little presentation and then open up for the Q&A. What I'd like to do is do a little bit of accelerated coverage of corporate tech, so I hope you don't mind. Here is a legal disclaimer. Allogene is really about allogeneic cell company. The company was founded in 2018 at the heels of getting autologous CAR T product approved. At that time, and I think it's still the same, bringing the autologous CAR T therapy to the Allogene egg, we felt that that is one of the biggest challenges, and that's one of the big problems that was worthwhile pursuing.
We have been doing that for a number of years, and now we have three clinical programs at various different stages. The lead program is Cema-Cel. This is a CD19-directed allogeneic CAR T product that we are advancing in Hodgkin's lymphoma, large B-cell lymphoma space. The unique thing about what we are doing with the Cema-Cel is really finding the right clinical setting to advance the Allogene cell therapy. Instead of going after relapse refractory setting or the second line, where the autologous CAR T product is already approved and being used, what we have done is really matching up the recent advances in the detection of high-risk patients. This is a circulating DNA-based MRD approach and selecting those patients and treating them with a single cycle of Cema-Cel. We will go a little bit more about the details of that study.
The second program that we feel very excited about is ALLO-329. This is a program that we are advancing into the autoimmune disease indications. There has been a lot that has been published about what's happening with the CD19-directed B-cell depletion approaches and the benefits that you can derive from eliminating the B-cells. Fundamentally, autoimmune disorders are disorders of both B-cells and T-cells, and we have designed a CAR T program. This is a dual CAR that's directed against CD19 and CD70 with the idea of reducing or lowering the lymphodepletion. This is a number one objective of this program.
The benefit that we are trying to achieve by going after CD70 is addressing the T-cell components of autoimmunity that can open us up for different indications that are not approachable with CD19, and also potentially prolonging the response that you can approach with the B-cell depletion alone. The third program is a solid tumor program. We recently presented the data. This is ALLO-316 that we have been studying in the renal cell cancer setting. We studied patients essentially who have exhausted all treatment options in renal cell, people who have received multiple rounds of the TKI or the checkpoint inhibitors. These are really relapse refractory setting patients. Here, we have seen a response rate in about 1/3 of the patient.
Another thing that's very tantalizing is not only it's the response, the durability of the response that we are seeing in solid tumor is really getting to the level that has been seen in the hematologic malignancy. I think this is really a significant change in terms of what the cell therapy can do, not to mention as an allogeneic cell therapy in solid tumor. Another thing about what we as a company have done is early on, we invested heavily into the manufacturing. What I can say is manufacturing of allogeneic cell therapy products from our company perspective is at the biologic scale as well as cost of goods. We have a dedicated manufacturing facility that can produce up to about 60,000 doses per year. Also, we have brought down the cost of goods manufacturing to the level of the biologics.
We have all the infrastructure to continue supporting not only the pipeline, but eventually, when the product is commercialized, also in the commercial setting. Let's walk through some of the programs in detail. The Cema-Cel, this is our lead program. It is potentially in a registration-enabling study where we are randomizing patients one-to-one in the very unique clinical setting of the frontline consolidation. We believe that this is really the gap in what's happening with the non-Hodgkin's lymphoma, and we are choosing the right patients to treat patients with a Cema-Cel. This is an ongoing study that we expect to have the initial interim analysis in the first half of 2026. More in detail, the recent advances in the non-Hodgkin's lymphoma is really incorporation of the circulating DNA-based MRD testing. What that does is it identifies the risk patients.
As a backdrop, patients with non-Hodgkin's lymphoma, the effective treatment is there. It's R-CHOP based, either R-CHOP or a variant of that that includes the polatuzumab. However, at the end of the six cycles of the treatment, some patients remain MRD positive by ultrasensitive test. What that tells you is that if you're MRD positive, and that's shown on the Kaplan-Meier curve as a red curve, you will experience a disease recurrence, and that will happen relatively quickly. Rather than treating everybody in the frontline setting by adding cell therapy on top of very effective therapy, what we have elected to do is go after the MRD positive patients, patients whose needs are insufficiently addressed with the existing therapy. The attractiveness of this approach is that we are able to capture patients when their disease volume is at the lowest.
Their disease volume is essentially at the molecular level. Studies after studies have shown that the cell therapy brings the best value both from the efficacy as well as safety perspective when the disease volume is low. It is really matching the right indication for Cema-Cel. I talked about this. This is really talking about the current standard of care. Patients get treated with R-CHOP-based chemotherapy. At the end of the treatment, most patients would have a very good response. If you follow those patients, about 80%-90% of the patients who have a good response, there is about 1/3 of them who will have a disease recurrence. The whole premise of the ALPHA3 study is that you can identify those patients who will have a disease recurrence with an MRD test, thereby concentrating the treatment effect on only those who need the treatment.
Study design is very straightforward. After selecting patients for MRD positivity, we are randomizing patients one-to-one to either a single cycle of Cema-Cel treatment or observation, which is considered as the standard of care. We expect to enroll approximately 220 patients into the study. The primary endpoint is the event-free survival, and the key secondary endpoint includes progression-free survival as well as overall survival. The beauty of this study is that there is a built-in interim analysis, the first one of which will be happening in the first half of next year. This is looking at the biomarker-based read, essentially how many of the patients become MRD negative after the Cema-Cel treatment. That is the initial interim analysis, and we expect to communicate the MRD conversion rate in the first half of 2026.
Thereafter, we're going into the clinical endpoint, starting with the interim analysis followed by the primary analysis. Another thing that we are trying to address with the ALPHA3 study is really opening the horizon for the cell therapy. Right now, cell therapy is still limited to the certified cell therapy centers, but what we are trying to do is open up where the cell therapy treatment can be given to the community-based cancer centers. This is a very important element in the United States, probably more so than in any other territory where most of the patients are taken care of in the community-based cancer centers for the treatment of the frontline large B-cell lymphoma. By taking the clinical study to the community-based cancer centers, we can capture the patients where they are being treated for rather than waiting for them to be referred to cell therapy centers.
This is one of the very important built-in strategies of the Cema-Cel program. In terms of the market opportunity, currently, the cell therapy is marketed in the relapse refractory setting or the second-line setting. It is probably going to be between $2.5 billion-$3 billion revenue in 2025. When we project out going after frontline consolidation, thereby capturing patients in the frontline setting, we expect the market size to be significantly bigger, thereby really giving us the opportunity to democratize cell therapy, not just in the specialized centers, but in the wider community cancer centers where we can capture more patients. We expect the total addressable market opportunity for the frontline consolidation to be around $5 billion in the U.S. and Europe. Now, let me move to the second program. This is ALLO-329, a dual CD19, CD70 CAR program. We have initiated a clinical study.
We are currently enrolling into a study called Resolution, which is not randomizing, enrolling patients in the dose escalation. One arm is using a low-dose lymphodepletion with cyclophosphamide alone. The second arm is just going after essentially patients without any lymphodepletion. What allowed us to build this idea is really based on all the pre-clinical work as well as our experience that we have generated from our ALLO-316 program, which is a CD70 CAR alone where we have seen remarkable cell expansion. This is really the built-in technology behind CD70-containing CAR. What CD70 is able to do is essentially make the allogeneic CAR T work like autologous CAR T with all the benefits of the off-the-shelf treatment and on-time treatment. In addition, we believe that dagger technology can also further reduce the lymphodepletion.
That is why for the ALLO-329 program, as we take the program into the autoimmune space, we are aiming high. The starting point is low lymphodepletion with cyclophosphamide alone, but we will also be testing no lymphodepletion at all. We expect the initial data, proof of concept data from the 329 program, in the first half of 2026, where we are planning to share a limited number of patient data treated with cyclophosphamide lymphodepletion or no lymphodepletion whatsoever. Now, 316, I covered this program a little bit throughout my short presentation, solid tumor program. Our initial experience is in the CD70 positive renal cell cancer patients where we have seen a 31% response rate. Another thing that is really tantalizing, and some of the graphs can be seen here, is the durability that we are seeing amongst the responders.
Most interesting thing is this is all coming from a single infusion of ALLO-316. Some patients do not get to the complete response, but regardless of how much tumor reduction has occurred, once they get the response, these are all confirmed responses, their responses seem to persist. We have durability of response now going beyond one year in highly refractory renal cell cancer patient population. This is really what we believe as cracking the code of using allogeneic cell therapy in solid tumor. I think it really opens up a variety of opportunities in solid tumor space. Some of the examples of tumor reduction you can see here and also a little bit of patient population of adverse events that we have seen in this study.
I do not want to simplify the adverse event profile, but I would say that what we are seeing from the safety profile is it is highly consistent with any active CAR T. You get some lymphodepletion-related cytopenia, and also you do experience cytokine release syndrome as well as an immune effector cell-mediated hemophagocytic syndrome, IEC-HS, which we have introduced measures to minimize the consequences of IEC-HS, which has worked for us very well. With that, let me just sort of conclude so that we can have more of a Q&A session. Thank you very much for your attention. Clara, you want to do some Q&A here or?
Sure. So maybe.
Let me also introduce our Head of R&D, Zach Roberts, who can help me answer more tough questions.
Maybe I just want to talk a little bit more on the ALPHA3 enrollment and how's the enrollment progressing so far and how many sites have you activated and started actively enrolling patients so far?
Yeah. We have over 50 sites that are active right now in North America. It is roughly 50/50 between academic and community-based centers. The points that David was making about bringing CAR T into the community is something that we are employing in the context of the trial. I would say that enrollment, as expected, has continued to build since we opened the study and is enrolling nicely now.
Great. In terms of the fertility analysis we are expecting next year, maybe just frame the expectation a little for us, the audience as well. What should we expect to see? Is there any good proxy rate in terms of MRD conversion, maybe from historical studies or from literature, we should use as a good benchmark?
Yeah, it's a great question and one we get asked a lot. We believe that a 25%-30% improvement in MRD conversion between treatment and observation would represent a major breakthrough potentially for these patients who are all going to relapse. Just to kind of put some of this in context, recently we saw the first frontline approval in diffuse large B-cell lymphoma in 25 years with the POLARIX regimen or the polituzumab-based regimen. That was only a 7% improvement in PFS over R-CHOP.
That has been a transformative approval with now about 30% of the market share going to that. In the second line, we see CAR T cells rapidly taking over that salvage space over transplant. That was based on roughly a 30% improvement in complete remission rate in the CAR T versus auto transplant space. We think that this would be an absolute breakthrough for these patients in consolidation.
How do you see this MRD negativity translating into kind of long-term survival outcome in DLBCL patients?
Another great question. We know a lot about this test, but there are some things we still are learning about this test. No test in medicine is perfect. There is a small false positive rate, there is a false negative rate. As you see from that Kaplan-Meier curve, this is a highly accurate test. We believe that that will likely be the case as we do this futility test.
I will point to another data set that has recently come out in bladder cancer, a very similar study to ALPHA3, but in bladder cancer where MRD positive patients were randomized to either a checkpoint blocker or placebo. In that clinical trial, they saw an 11% improvement in the MRD conversion between placebo and atezolizumab, yet that was a very positive final outcome of disease-free survival and overall survival. That highlights how the MRD test can somewhat undercall the eventual primary endpoint.
Maybe if you could just talk about general feedback you've received from physicians, KOLs, and payers in terms of using off-the-shelf CAR T therapy in frontline consolidation, like what's the value proposition?
Yeah. Since we first started talking about ALPHA3 with both KOLs as well as community oncologists, the study design has been overwhelmingly positively received. Many doctors recognize that once a patient relapses with DLBCL, even if they're in a position to have access to CAR T, often the patients simply can't either don't have coverage for it or their disease is progressing too rapidly that they can't actually get the CAR T. Being able to identify patients who are at extreme high risk of relapse and treat them at the moment when the CAR T cells are most likely to have a beneficial impact and a positive safety profile is extremely attractive.
To be able to do this right at the end of our R-CHOP, largely as outpatients, so these patients can just come in and get what we call sometimes the seventh cycle of treatment, it is a very attractive change to the current standard of care.
Maybe just talk about your interaction with the regulatory agency in terms of the endpoint for the clinical study using MRD negativity and what's the path forward here.
Just to clarify, MRD negativity is not the primary endpoint of ALPHA3. It's event-free survival, which is a very validated endpoint in CAR T studies. All of the second-line CAR Ts used EFS as the primary endpoint. That was the conversation that we had with regulators who accepted the EFS as an endpoint there. MRD is only being used in this futility analysis as a proxy for efficacy.
Got it. In terms of the autoimmune data we are expecting to see, maybe just kind of level set the expectation here. What kind of data do you think you need to see in terms of both efficacy and safety for you to push the program fast forward?
Yeah. David did a very nice job outlining the design of the phase I study. We're going to be testing this idea of whether low or no lymphodepletion will allow treatment of these patients. We should be able to get that information relatively quickly. If we are seeing B-cell depletion and seeing good CAR T cell kinetics as we expect to see, I think that would be a strong signal for us to begin to aggressively expand into other therapeutic indications.
Great. Anything else you would like to highlight?
Yeah. I think the questions are really centering on the most important thing. I think the main thing is first half 2026 where we expect to communicate both the futility analysis for Cema-Cel as well as the initial proof of concept data coming from the autoimmune studies. We really look forward to the first half of next year.
I'm really looking forward to it. That concludes our discussion here. Thank you very much, Mark, sorry, David, and Zach for joining us here today. Thank you to all the audience for joining us in person and online. Enjoy the rest of the conference.