Everyone, thanks for joining the OpCo Virtual Healthcare Conference. I'm Matt Biegler. I'm the covering analyst for Allogene, which is our next presenting company, and here to tell us more about the story is CEO Dave Chang. It looks like it's setting up to be a really, really important and fun year for the company. Dave, if you want to run through the slides, and maybe we can save some time at the end for questions.
Okay, sounds good. Matt, first of all, thanks for giving us the opportunity to present at your healthcare conference. Hi everybody. My name is David Chang. I'm the President and CEO of Allogene Therapeutics, which has been focusing on advancing the allogeneic CAR-T therapy. A little bit of legal disclaimer here. You know, this slide really highlights, you know, where we are in 2025 with different programs that we are advancing. As we sort of, you know, try to advance this in a very differentiated and unique way, always focusing on the competitive edge, you know, we are really realizing that each of these programs are really, you know, highlighting the AlloCAR T difference, the scalability, on-time treatment, simple logistics, and ability to leapfrog others. Going into the individual programs, our most advanced program is in heme malignancy.
This is cema-cel that's currently conducting a potential pivotal study known as ALPHA 3 study in the frontline consolidation study of large B-cell lymphoma setting. Another program that we recently announced the news of clearing the IND is ALLO-329. This is a next-generation allogeneic CAR-T program. It is a dual CAR targeting CD19 and CD70, and it's designed from the beginning with an autoimmune disease indication in mind. I'll go more into details about why 329 is differentiated in many different aspects. The third program is ALLO-316, somewhat of a legacy program. This is a program that we have been running a study in renal cell cancer for some time. We recently updated the data, and we'll talk about how ALLO-316 is beginning to open the, you know, window to solid tumor, you know, for the CAR-T therapies.
Another thing that I want to highlight, you know, is, you know, where we stand on the manufacturing. Frequently, we say, you know, for cell and gene therapy, the process is the product, and that is so true to it. And this is something that we have taken seriously from the beginning to the point where we invested heavily, not only building the internal capability, but also building the manufacturing facilities that we now estimate that can produce up to 20,000 patient doses per year for cema-cel and, you know, far exceeding that, probably close to 60,000 or more for ALLO-329 in autoimmune indications. And this is a facility that can support not just the clinical studies, but is able to support commercial launch of more than one product. Now, let's go into each of the three programs, starting with the cema-cel.
What we are doing with the cema-cel in the frontline consolidation is really bringing, you know, three rights: the right product. This is a cema-cel that we have shown impressive response rate, as well as durable response in the relapse refractory large B-cell lymphoma setting to the right patient by using MRD assay to identify only the patients who are insufficiently treated with a frontline R-CHOP, which is the regimen that gets used in the large B-cell lymphoma setting. Also at the right time, before their disease manifests itself clinically, and when they're only in the MRD positive setting, intervening at that point to improve overall benefit-risk ratio of using CAR-T for this setting. Ultimately, the goal of ALPHA 3 study is to improve the cure rate of the frontline large B-cell lymphoma in the frontline setting.
A little more details about what we have shown with the cema-cel in the relapse refractory setting is highlighted in this slide. Also, the data were compared on the right side. This is a trial by, you know, a trial comparison, so you have to take it with a grain of salt, but it gives a really good sort of reference point of what our data looks like compared to pre-approved CAR-T products in the large lymphoma setting. What's shown on the top is overall response rate, complete remission rate, as well as complete remission at six months, which is a good surrogate for durable responses.
With a lymphodepletion regimen that is FCA 90 and manufacturing process that we are using for the ALPHA 3 study, what we can see is the response rate of 67%, complete remission rate of 58%, and complete remission at six months of 42%. When you compare these numbers to what autologous CAR-T therapy has done in the same patient population, I would argue that our data stands out and looks very comparable. On the bottom is the summary of the safety, cytokine release syndrome, neuro events, as well as infection, which can be, which are known side effects of the CAR-T therapy. Again, in each of those categories, what we have shown with cema-cel in the relapse refractory setting is that the incidence of these events looks favorable compared to autologous CAR-T therapy.
Also to highlight is that, unlike autologous CAR-T therapy, allogeneic CAR-T, as an off-the-shelf, is able to treat the patient quickly. Time from the enrollment to the treatment was less than three days, and most patients who were enrolled were able to receive the intended products. Now, how do we choose the right patients? This is really highlighting how the MRD test has been, you know, advancing on its own. This is our partner, Foresight Diagnostics, which has advanced a study, a test called a CLARITY assay. This is really detecting the minimal residual disease, which is, you know, harbinger of remnant inner tumors that can manifest clinically in a relatively short period of time. That point is really highlighted on the right side when you look at the progression-free survival of patients who are MRD negative versus MRD positive at the end of frontline treatment.
What's shown in blue are the patients with MRD negative, and these patients rarely have a recurrence. Essentially, most of them remain recurrence-free during the follow-up period that extends now to about three years. Whereas if you are MRD positive, you will have a disease relapse, and median time to disease relapse is relatively quick, about four to six months. In ALPHA3 study, our focus is on the MRD positive patients. Now, you know, the fine point about why treating patients who are only MRD positive could be advantageous. What's shown is the relationship between the disease burden and the outcome, both in terms of probability of achieving durable response and probability of having adverse event, highlighting the grade three neuro events on the left side.
What can be seen is when the tumor volume is low, your probability of having durable response is high, and it goes down as the tumor volume increases. Exactly the opposite is true for the adverse event. When the tumor volume is low, the probability of having neuro event is very small. As the tumor volume goes up, the risk of having the neuro events is much higher. This really highlights why it is so advantageous to intervene when the patient is MRD only. Also, on the right side is shown relative disease volume estimate based on the MRD assay. When patients are MRD positive, you know, only at the end of treatment, that's the middle column, compared to a patient who presents with a disease recurrence to start the second line treatment, there is about 200-fold difference in the disease volume.
This is why intervening at the right time, when the disease is only in the minimal residual state, would be advantageous for, you know, with the CAR-T therapy. With those three, you know, key aspects in mind, another thing that we are doing is taking the treatment to the, you know, to the, you know, this clinical setting where the patients are actually being treated. Right now, approved autologous CAR-T products and most of the CAR-T trials are being carried out in special centers or academic centers, whereas the majority of the patients with large B-cell lymphoma are being treated in the community-based cancer centers. With that in mind, what we have done with the ALPHA 3 study is taking the study to where the patients are cared for, to the community-based cancer centers.
Now, the details of what we are doing with the ALPHA 3 study are shown here. It is a randomized study that will compare one-time treatment of cema-cel with a standard pair, which is watch and observation. This study will target to enroll approximately 200 patients who remain MRD positive at the end of frontline chemoimmunotherapy for large B-cell lymphoma, and we are targeting approximately 50 academic and community-based cancer centers in the U.S. Primary endpoint is event-free survival, and key secondary endpoint includes progression-free survival, overall survival, and rate of conversion of MRD positivity to MRD negativity. Initially, patients will be randomized one-to-one-to-one to observation and two different lymphodepletion regimens. One with FCA 90. This is the lymphodepletion regimen that we have been using in the relapse refractory setting.
In this study, we are also testing standard FCA lymphodepletion regimen, recognizing the fact that we are only treating patients with MRD positivity where we do not believe persistence of CAR-T would be important. Our plan is based on a limited number of patients who get treated initially. We will carry out the interim analysis where we will look at the safety, fatality, as well as differences between two lymphodepletion arms to make a determination on which lymphodepletion to move ahead. Afterwards, the study will continue in a seamless fashion, one-to-one, comparing observation to chosen lymphodepletion. This study was initiated in June 2024. Middle of this year, we expect to carry out the first interim analysis where we will make the determination of lymphodepletion. When it comes to 2026, we expect to complete the enrollment and also carry out initial, you know, efficacy-based interim analysis.
The final analysis is expected at the end of 2026, leading to potential BLA submission in 2027. These are the target dates that the entire company at Allogene is working very hard to achieve the target dates. In terms of the opportunity of going into the frontline consolidation is highlighted here. What's shown in the left is the opportunities that exist in the second and the third line setting. What we believe, as we advance the program into the frontline consolidation setting, we can target, you know, more patients creating a, you know, greater commercial opportunity for cema-cel.
Now, let me move into our next important program, which is ALLO-329. As I've said, this is a dual CD19, CD70 CAR that's specifically designed for autoimmune disease indications. We recently announced the clearance of the IND for this program, and we are targeting middle of this year for the phase I trial initiation and potentially generating proof of concept by the year end 2025. Key differentiation we see with the dual targeting is that by adding CD70 CAR, we can overcome rejection, allowing ALLO-329 to expand and carry out elimination of target cells very efficiently. We believe that this also paves a way for reducing or eliminating lymphodepletion, which is one of our key objectives for the program. The second key aspect is by targeting CD70, which is antigen that is upregulated in dysfunctional or activated T cells or immune cells in patients with autoimmune disorders. We believe we can address the fundamental dysfunction in the autoimmune disorders.
Lastly, you know, CD19 portion will provide depletion of B-cell and potentially resetting the immune system, as others in this field have shown. You know, another key difference that we have done that's on the manufacturing side, we simplified how we manufacture the allogeneic ALLO-329 by using site-specific integration and also being able to introduce both CD19 and CD70 CAR in a single step, which makes the manufacturing process more efficient and robust. Now, let's talk a little bit about, you know, how we envision, you know, CD19, CD70 dual CAR to be working. What's shown is, you know, how the CD70, you know, will go after autoreactive CD19 B-cells, and this is something that the field has already demonstrated. When it comes to CD70, the first thing is addressing the autoreactive CD70 positive T cells that contribute to early rejection of allogeneic CAR-T cells.
Having the CD70 CAR, which we also call as a Dagger technology, allows the allogeneic CAR-T cells to overcome the early rejection issues. Very important for allogeneic CAR-T programs. The added advantage of having CD70 CAR is it has the opportunity to eliminate autoreactive CD70 positive T cells, as well as activated antigen-presenting cells such as dendritic cells or APCs, as well as eliminating dysfunctional Tr egs, which can contribute to the immune activation. This is a bit of a, you know, dense data slice, but it really highlights what we can show with ALLO-329 in available preclinical programs, and it plays out exactly as we have envisioned. What was done here is immune reconstituting mice with a PBMC, peripheral mononuclear cells derived from the lupus patients.
Shown on the left is how the immune reconstitution and the CAR-T administration is done in terms of time points and how ALLO-329 can efficiently deplete the B-cells, and in a way, you know, very similar to what CD19 CAR alone will do. What's also shown is because we use the, you know, the blood cells from the lupus patients, we can also, you know, follow double-stranded DNA antibodies, which these cells start producing. Here, what we are seeing is ALLO-329 is more effective than CD19 CAR alone in terms of reducing the double-stranded antibody titer. On the left is, you know, demonstrating that these cells, CAR-T cells, expand well, and also expression of the CD19 as well as CD70 CAR in ALLO-329 is very homogeneous. Now, with that, you know, let's talk a little bit about the opportunities that are ahead with the, in the autoimmune space.
The way we think about this space is looking into different therapeutic areas and indications within that therapeutic areas, starting with rheumatology, lupus, systemic sclerosis, myositis. These are the three initial indications that we will be enrolling patients into the phase I study, and then moving to neurology, multiple sclerosis, myasthenia gravis, as well as some other variants of multiple sclerosis. The opportunity also extends into nephrology, hematology, and potentially gastrointestinal inflammatory diseases such as ulcerative colitis and Crohn's disease. Many of these indications, there is already proof of concept existing coming from the B-cell depletion approach that has been done with the CD19 CAR-T. When we look at this, the addressable patient population in autoimmune disease indications far exceeds the global addressable patient population in heme-only indication, which we estimate to be about 300,000. When you go into the autoimmune, the numbers are significantly higher.
Now, let me sort of wrap up my presentation talking about ALLO-316. This is a CD70-only CAR that we have been studying in the renal cell, and I will go straight into the data that we have recently updated. In this phase I study, we tested both different lymphodepletion as well as cell doses, and we have decided to advance lymphodepletion and FCA 500 with 80 million cells, which is the phase I- B cohort that we are currently enrolling. What's shown on the right is when you look at the, you know, the volume change in tumor across different patients who have been enrolled in the study, there is one very consistent finding. If you have a CD70 positive renal cell cancer, those are the patients who have the tumor reduction.
In fact, in this cohort, we have seen a confirmed response rate of 33% in patients with high CD70 expression in their renal cell tumors. Not only that, we can also show that CAR-T cells, not only in the blood, but also in the tumor biopsy. On the left is a matched blood and tumor biopsy that we have done in 12 patients, and what we are seeing consistently is that ALLO-316 migrates into the tumor and expands as one would want to see when you are treating solid tumors. Also, when it comes to CD, you know, the kinetics of the expansion, the expansion of the ALLO-316 that we see in renal cell cancer patients is very robust and is almost at the level, sometimes exceeding what you can achieve with CAR-T cells or autologous CAR-T cells in hematologic cancers.
This is a very potent product that's showing promising early efficacy, and we are continuing to enroll patients in the phase I- B dose cohort with plans to update the data later this year. With that, let me sort of conclude the presentation, you know, with where Allogene stands. Our last disclosed, you know, cash position is over $400 million, which gives our runway to way into the second half of 2026. This year, we are looking to update you with a cema-cel lymphodepletion, as I've talked about, also generating the initial proof of concept with the ALLO-329 in autoimmune indications and updating ALLO-316 phase I- B result later this year. Each of these indications, you know, brings a very attractive market opportunity.
You know, cema-cel, you know, over $5 billion in the U.S. and EU5, ALLO-329 potential to treat a larger, you know, number of patients far exceeding what you can do in hematologic or hematologic indications, and ALLO-316 in renal cell cancer that we can project up to over $3 billion global revenue. With that, let me end my presentation and pass to Matt for any Q&A.
Thanks, David. Appreciate that rundown. I want to start maybe just asking about the planned mid-year update, and obviously, I know how important it is in the grand context of things in terms of selecting the lymphodepletion that you're going to use and whether you need alemtuzumab or not. In terms of the actual data that we're going to see, can you kind of just set our expectations for what that's going to look like, or is it just going to be a straight-up announcement, we've chosen this versus that type of deal?
Yeah, as I've talked about in that interim analysis, like any other early interim analysis, we'll be looking at the overall safety across three different arms and also confirm that the efficacy is there. And efficacy, we're using the MRD conversion, you know, that, you know, you know, as a measure of, you know, whether the cema-cel treatment is different than the control arm. The last component of that is, you know, once the efficacy expectation is met, you know, we will compare the two different lymphodepletion and make the selection of that. From the internal perspective, this is a very significant de-risking event. In terms of, you know, communicating the result to the to the public, because this is an ongoing study, we will be very cautious in saying anything about the efficacy.
You know, we will, you know, share about the expectation that the safety, you know, there are no surprising findings, and the efficacy is meeting some of the expectations, and we have chosen the lymphodepletion. The reason that, you know, we will not be able to share too much details about the efficacy is the enrollment will be ongoing at the time when we make this determination and make the announcement. We, and because of that reason, we do not jeopardize, you know, so-called the clinical equipoise that, you know, we like to preserve as we are continuing to enroll the patients. That's the reason that we will not be sharing too much about the efficacy result.
That makes sense. In terms of efficacy for ALLO- 329, though, this is, we're probably looking at a few patients treated at active doses with lupus.
It could be, you know, any of the three indications. It could be myositis, or it could be systemic sclerosis. So any of those indications, the main things that we'll be looking for is, you know, allogeneic CAR-T showing the expansion at reduced lymphodepletion, and also in that setting, you know, demonstrating that we can accomplish B-cell depletion. And, you know, hopefully in some of the patients who had a longer opportunity to follow up recovery of the B-cells, which we have shown in the preclinical models, but we would love to see that in the clinical setting as well.
I apologize if I missed this, but are you completely eradicating Flu/ Cy, or is it just a lower dose of either fludarabine or cytarabine?
In the phase I study, our plan is to test two different lymphodepletion. One is Cy alone. Already, even with the lymphodepletion arm, we took out the fludarabine. The second cohort that we will be testing is one that does not have any lymphodepletion. Obviously, that cohort will lag a little bit behind. You know, initial data in a communication will be very much, you know, on the one that has a Cy cyclophosphamide alone as a lymphodepletion.
Understood. A question from the audience. Are you also investigating ctDNA as a potential surrogate endpoint in the LBCL trial?
We are collecting the samples to generate the data. I think, you know, one has to generate the data, you know, to really elevate, you know, using the MRD as a surrogate endpoint for large B-cell lymphoma. By the way, in multiple myeloma, you know, last year, there was all that discussion talking about MRD as a potential, you know, you know, regulatory endpoints, and the board was unanimously, you know, positive, you know, for for using MRD as a surrogate endpoint. We are hoping that with the data that we generate from our study, we can add, you know, another indication in large B-cell lymphoma as an indication that can leverage MRD as a surrogate endpoint.
If the effect size with this interim update this year is so large that potentially the statistics make sense, could you possibly file for accelerated approval just based on that interim?
You know, I will not rule out that possibility altogether. I mean, we will have to look at the data, but, you know, the overall number of patients that we would have treated will be somewhat limited. On the other hand, early 2026, you know, we are carrying out the first, you know, event-free survival interim analysis. You know, at that point, you know, there is some possibility that we would have crossed the statistical boundary, and if that's the case, we will definitely have a discussion with FDA.
Got it. That'd be really, really great to see. The other questions I'm getting are really just on the leanness of the company. If there's any ways that you can extend that $400 million in cash, given kind of how tricky markets are right now.
You know, any suggestions that I, you know, that, you know, the questioner had, I would gladly take. We are doing everything possible, you know, in terms of focusing our programs to the most critical ones and, you know, trying to operate the company as lean as possible. I mean, that's, you know, something that I believe that any biotech company has to be, you know, doing right now, and we are certainly doing that. At the same time, we are looking, you know, to extend the cash runway by potentially partnering one of the programs.
Makes sense. All right. Shaping up for an exciting year. Thanks, David, for letting us know what's new.
Great seeing you, and thanks for having us on your healthcare conference.
Thanks, everyone.