Thank you, and good morning, and welcome to the next session here at the Jefferies Global Healthcare Conference. I have the pleasure of having the CEO of Allogene Therapeutics, David Chang, up here with us. David, as we were discussing the prior successes of CAR T and all the work you had done at Kite, the point about our discussion was that the prior successes have led to an explosion of interest in CAR T and a lot of great lifesaving drugs.
What's interesting about Allogene is that in the last year or so, you have taken your promising allogeneic CD19 CAR T, which everyone is familiar with, CD19 CAR T, and in your case, allogeneic, but now trying to really open up a new opportunity in what I would call first line, and even in some cases leapfrogging the opportunity of Gilead Yescarta in second line to potentially move in front of that. Can you give the audience an introduction to your product with a specific focus on the design of your pivotal study and why this is particularly unique?
Okay, first of all, Mike, great to have Allogene in your forum. And as usual, you are going with the most important question about exactly what we are doing with the front line consolidation study. So Allogene, we as a company, we are focused on advancing the allogeneic CAR T therapy. CD19 is our lead program, and we spent much of early days at Kite generating the proof of concept data with a CD19, which was then called as ALLO-501A in large B-cell lymphoma in the relapse and refractory setting. Another thing that was always in plan was how to move the CAR T therapy to the earlier line.
Those who are following the large B-cell lymphoma and CAR T, there has been a real explosion of the treatment using CAR T, not only in relapse refractory setting, but also in the second line setting where the CAR T therapy has shown not just the evidence of response and durability, but also the survival benefit in the randomized study. We have been really strategizing about what is the earlier line that we can go into, not just for the demonstration of the efficacy, but also looking at the commercial opportunity that we can create if the study were positive. That has been in works for some time, and it really accelerated in the beginning of 2023. That's when there was a new development in the molecular diagnostic assay to measure the MRD, minimum residual disease in large B-cell lymphoma. This is a circulating DNA-based assay.
And when we saw the data, especially the specificity and sensitivity of that assay together with the outcome difference, this was all retrospective data that showed that MRD positivity after the completion of the front line treatment. It's really telling that those patients will relapse. So with that knowledge, we spent much of 2023 designing and validating a clinical study design with FDA as well as key opinion leaders. And that is really what is ALPHA3 study. So ALPHA3 study, yes, it is a pivot, but not pivot from the product perspective. It is a pivot in the clinical study approach. We had an opportunity to continue both the relapsed/refractory study as well as a front line study, but in the current commercial setting and also in the biotech space, we felt it was prudent to focus our effort on the program that had the greatest value inflection opportunity.
So tell us the design of the study you introduced by explaining your new and earlier lines. There's been a big announcement of data that shows that there's a great test. So tell us about the test and who makes it. That if you are MRD positive coming off of R-CHOP, then you have a high probability of relapse. Therefore, you could prevent that relapse and improve patient outcomes by getting them a CAR T and hope to drive high remission. So describe the design of the study and what you're doing and what the protocol is, because it is unique.
It is unique. So let's take a step back. In the front line study, the mainstay of the treatment is RITUXAN-based chemoimmunotherapy that has been used for the last 30 years, and it works great. Two-thirds of the patients who get the RITUXAN-based chemotherapy, they're essentially cured. You can follow those patients with the radiographic findings for the next two to three years, and their disease doesn't relapse. We don't feel there is a need to add additional treatment for those patients. However, there's the other one-third of the patients, despite having a great initial response at the completion of R-CHOP. When you follow those patients, they relapse. Previously, before the MRD testing, there was no way to tell who will relapse and who will be maintained in the remission-free state.
Right, just to put the framework for people there, when you get basically R-CHOP, 67% of the population gets a really, really good response.
No, actually about 90%.
90% get a CR, but of those, two-thirds are very durable, and one-third of those are going to relapse in a given time. And that has been your opinion is that that's because they're MRD positive. You can find those patients and prevent that relapse.
It's more than my opinion, the actual data. Yes, it is a retrospective sample analysis. So the study that supports the value of this MRD assay, which is developed by a small company called Foresight Diagnostics, is that they looked at blood samples of patients at the completion of the R-CHOP treatment. So these are essentially patients in a CR looking at the blood samples by the MRD assay. About, I think, close to about 70% of the samples were MRD negative. And when you follow those patients, they do not have a disease recurrence. We don't feel that we need to do anything for those patients. The other 25 to about one-third of the patients are MRD positive. And when you follow them for two to three years, most of them relapse within that time period, and median time to relapse is less than six months.
Think about that. 25%-30% of those people in that large sample were MRD positive, and the Kaplan-Meier shows that a significant portion of them are going to relapse within six to twelve months, and you have basically found the marker to predict that that's going to happen.
Correct.
And so then the question is, if you're going to enroll all these MRD positive patients, A, why should someone enroll these patients? Because current standard of care is to do nothing, watch and wait. And B, if you do give them this product, what is the reason to explain to them and the investigators why they should get the product? Because what are we going to show?
Yeah, so let me answer the second part of the question, so you identify the patient population with the MRD assay.
So this Foresight test.
Yes. And we have the data that we have generated from the relapsed/refractory setting that cema-cel works very well. The data that we have on about 33 patients in relapsed/refractory setting is one-time infusion of cema-cel can provide overall response rate in about two-thirds of the patients and about 50% of them having a complete response. So that is the efficacy portion.
Potent and effective CAR T that in all intents and purposes clearly looks similar to autologous, a very powerful drug. So if we're going to give that to them in their MRD positive, what's going to happen?
At a minimum, we expect the bulk of the patients will convert from MRD positive to MRD negative. The important clinical point in this setting is something known as event-free survival. When does their disease recur, or do they need any other anti-cancer treatment for lymphoma? That is the primary endpoint of the ALPHA3 study that we're using.
So how many patients are you enrolling? Where are you in enrollment? How is that going? And how is the adoption and interest level in getting these patients? Because it's, again, really kind of untapped territory. No one's been doing this. This is before Gilead's second-line therapy.
It is definitely before the Gilead second line therapy. It is almost front line, but it is really right after the front line. That is why we also call this study as a front line consolidation. Let the patient complete six cycles of R-CHOP, and then we will add one more cycle, and that one more cycle is the one-time infusion of cema-cel. That is the essence of the study, and another thing that is really we felt important, and this is we learned while we are conducting our relapsed/refractory study, and also other companies in this space are also saying the same thing.
The fact that the majority of the lymphoma patients cared for in the community cancer centers, when the cell therapy is only available in certified centers, that is a barrier where the patient has to be referred from the community-based cancer centers to the specialized centers to receive the treatment. The logistics of that, including insurance and all that, becomes a very challenging issue, so when we started this study, we started initial conversation with the community-based cancer centers to see whether we can place the centers, and the receptivity of the community-based cancer centers were extremely high.
Why would that be? Because let me insert this. These are the challenges, I would say. These are the things we're going through to get this going to make sure we enroll on time so that we can get the data. And part of the things that people are trying to figure out is, is this actually logistically feasible? One of the things I actually heard last night at dinner with Gilead is that the reason why Yescarta has slowed down is because they've tapped out a significant majority of use at major centers, obviously. Future growth, particularly in second line, but in general, is that there are DLBCL patients, but they're in the community center and they don't actually want to give up the patient and send them over to get a CAR T.
And Gilead's like, yeah, we're trying to convince people that these doctors have to give the patient up for very effective therapy. So given that a lot of these patients are in the community, why would they want to do that?
Yeah, I mean, first of all, the fact that Kite, Gilead is recognizing this issue and trying to move into the community-based cancer centers, it's actually helping ALPHA3 study because we are already trying to do the clinical study there. From the community-based physicians, this is really a U.S.-specific topic that we're discussing. One of the reasons that we were told that they did not embrace the autologous CAR T therapy was, when it was approved, the logistics. Logistics of following the patients and making sure that leukapheresis, which is a collection of the T cells to make the CAR T product, had to be coordinated with the manufacturing slot. That is a complexity, a very complex process. The option that we are offering to them is you do not have to worry about those logistics.
You're talking about community centers for sure.
Yeah. So as an allogeneic, it's a drug in a vial. When the treatment decision is made that they want to participate in this study, we can just send out the vial. That made the proposition of doing the clinical study with the Allogene CAR T very attractive to the community-based cancer centers. So I think that is really built into the strategy of the ALPHA3 is moving to a very unique indication with a very differentiated clinical approach and also at the same time address one of the biggest barriers of expansion of CAR T, which is moving the therapy into a wider use in the community-based cancer centers. And now back to your first question about, okay, MRD positive patients, why would they go on the study? Right now, the treatment option here is essentially watch and observation.
There's no drug that is approved for the MRD positivity after the front line treatment unless their disease relapse, and the second, to our best knowledge, there isn't any clinical trial that has yet started targeting the same patient population, so in a way, by going early, we are differentiated from the patient population that we're trying to capture as well as the lead time that we have on this study.
So the question that we've gotten and have actually spoken with some sites, and I hope to maybe hear that we don't see this, is that some centers, and this is published. Sylvester, University of Miami says, "We don't really do that because standard of care is watch and wait. And why do that? If they do relapse, we give them another therapy. We can give them the CAR T then, give them the CAR T when they relapse, or we can give them other therapy. So why are we doing that and doing all this testing? We just watch and wait." And your answer is you've gone out to centers and sites. Sure, maybe Sylvester does that. Maybe they'll change, but other centers and other sites do not. They say, "No, why would you not want to find them and catch them earlier?
Yeah. First of all, I mean, I know the hematologists, oncologists at the Sylvester Cancer Center pretty well. I do not agree with what they're saying. I mean, if you look at what's happening both from the FDA and regulation, there's a FrontR unner Project. For those who do not know what that is, it is push from the FDA to move the anti-cancer treatment to the earlier line quicker than later. And on the CBER side, which governs the regulation and approval of the CAR T, they have been pushing. When you have a curative therapy like CAR T, the maximum benefit that you can achieve is by moving into the earlier line as quickly as possible. And we're doing exactly that, trying to catch the patients before their disease is blown out of control, which is exactly when the second line study would start, second line treatment start.
We are capturing this patient at a very unique place in a minimal residual disease state where there's ample evidence that suggests that CAR T therapy works better when the disease volume is low and we're going after that.
Yeah, I mean, to summarize, I would say, look, yes, current practice is watch and wait. Fine. That's done for many reasons, but partly because there wasn't a therapy necessarily to induce any change. And why would one not want to find patients earlier with a test, put those patients at another level up on the Kaplan-Meier curve that would induce potentially a long, durable cure? That's a positive. You're saying that actually there's insights at the FDA, including CBER, Peter Marks and others that are suggesting that there's a push to get cancer therapies earlier. And that's why they've talked with you. They're in alignment on this protocol. Obviously, you spoke with the FDA about this. And you have buy-in and they say they're excited about and interested in this design.
Probably this is one of the investigators in our study have sort of described this situation. He is sort of drawing an analogy to a fire. If you see a smoke in a house, would you intervene, and most people would say yes before it gets blown out and you see the red flames and house burning down, which would essentially when the disease is fully blown and manifests itself as a recurrence. What we are trying to do is put out the flame or put out the fire when it's in the early stage where you're just seeing the smoke.
And so tell us about enrollment again. So now that we've agreed, yes, people should do this. There's incentivization to do this. You have found plenty of sites and you have strong confidence you will be able to enroll 100 patients on time and get this done. Tell us about that.
Yeah. So it comes from one, the level of investigator enthusiasm. And some of the things that we have heard and we have heard repeatedly even outside the investigator pool is this is an innovative design. This is exactly the kind of study that is needed for the large B-cell lymphoma. And if this study is positive, it will be paradigm shifting. It will change the clinical practice. So there is a high recognition of the value of this study.
Might I just add, I would think, but I'm just an analyst, if this works, then you're telling me that you've shown a statistically significant huge improvement on event-free survival in first-line consolidation. And you have prevented, I'll pick a number, 50% improvement in relapse. Then, in other words, basically induced a cure in 50% of these people and saved half those people. Doesn't that mean less people that would go to second line and therefore, because you're curing more people, therefore that actually the market shrinks after you?
I think that would be a good thing.
That is a good thing. That's not a good thing for Gilead. That's a good thing.
That is a good thing.
That is a good thing for you. I'm saying that you are moving in front and therefore you believe that you could induce a significant more number of cures.
And back to your question, I don't want to evade the question. We had earnings call. Site activation has been going very briskly. We announced that we're targeting about 50 sites in the U.S. We have more than 50% of the sites already activated. And we have also said that MRD screening.
This is all in the U.S.?
We believe that 50 sites in the U.S. will be sufficient, but we are always looking for additional opportunity.
Okay. Because we'd like to treat patients also outside the U.S., but also, again, you think that you can get this done in the U.S.?
Yes.
Okay, and what is the timeline? Sorry.
So in terms of the study itself, we're not going to provide details, play-by-play description of how many patients that we have enrolled, but we have publicly said that MRD testing has been very active and we are enrolling patients into the study. And as for the study itself, we are expecting to complete the enrollment in the first half of 2026, leading to the primary analysis. This is looking at the clinical outcome at the year end 2026. But what will happen before that is one, there's one interim analysis that's planned for the beginning in the first half of 2026. Okay. And in addition, one thing that we didn't talk about, the study design itself, but in the beginning, we are testing two different lymphodepletions. And based on a certain number of patients' data, we plan to determine which lymphodepletion to carry through and complete the enrollment.
We will announce which lymphodepletion is chosen.
Sorry, what are the choices and what would happen?
This goes back to the history of how we have been developing the cema-cel, especially with the allogeneic. We use a lymphodepletion regimen called FCA. This is standard for fludarabine cyclophosphamide plus ALLO-647, which is anti-CD52 antibody. We have data from using that regimen in the relapse and refractory setting. Okay. Obviously we're going to continue that initially. But given that we are going after minimum residual disease, lowest disease volume that one can think about, we decided that it is worthwhile to test more standard lymphodepletion of FC, which is used by the autologous CAR T therapy in this particular indication. In the initial phase, we are comparing how FCA versus FC plays out. And we will choose one and carry on the rest of the study.
So, sorry, but obviously in more traditional relapsed/refractory, there's disease burden. We want to obviously clear that out and give FCA, Cy-Flu that is not a particularly easy to tolerate regimen. And if you have a low disease burden, which is basically MRD, so barely evidence of early cancer, then you would not really want to have FCA because you wouldn't want to give those patients that.
Yeah. I mean, the whole idea is in the relapsed/refractory setting, we're trying to push the maximum that we can get out of the CAR T. We do not feel that is necessary in the MRD-positive setting. That's why we're backing off on the lymphodepletion, which could even be more well adapted by the community-based cancer physicians.
So the idea is that you would likely have your antibody as the conditioning regimen. Is that correct? That's a base case?
That's a base case based on the relapsed/refractory setting, but we are also testing that may not be the case in the MRD-positive setting.
Got it. Okay. So that announcement would likely come in 2025?
Mid '25.
Mid 2025, and then we will get a completion enrollment first half 2026, and then we will have potential readout second half 2026.
Yeah, year-end 2026.
Fantastic. Thank you very much, David, for the update. I appreciate it and look forward to execution this year.
Okay. Fantastic. I love the questions that you're asking. Very direct and also impersonalized.
I didn't even ask about autoimmune and the whole thing.
We ran out of time, but autoimmune is another one that we should really talk about. Very exciting program.
Thank you very much, guys. Appreciate it.
All right.
Thank you.
Thank you.