Good morning, everyone. My name is Biren Amin. I'm one of the managing directors here at Piper Sandler. I'd like to welcome everyone to Piper Sandler's annual healthcare conference. And I'd like to introduce our first company for day one. We have Allogene Therapeutics with Founder, President, CEO David Chang, as well as their CFO, Geoff Parker. So welcome, gentlemen. Great to have you guys here. You know, maybe, you know, let's start off, David. You have, I think, several programs in the clinic. Maybe if you could provide us with an overview of where you are with cema-cel, as well as, you know, with some of the other programs.
Yeah. Yeah, Biren, first of all, great seeing you. And thanks for having Allogene on your panel. It's great to kick off a conference. And, you know, Allogene, for those who are following us, we are focusing on advancing allogeneic CAR T therapy. And the past 12 months has been a very exciting time for Allogene as we positioned our lead program, cema-cel, into a very innovative clinical development path, going after a new indication, called first-line consolidation. So cema-cel is a CD19 allogeneic CAR T program that we have generated very compelling data in the relapse refractory setting. And we always have been looking into moving that program into the earlier line.
When we came across a very novel way of identifying patients who are at risk of relapsing after completing the front-line treatment, we came up with a clinical study design that will allow us to leapfrog cema-cel ahead of all the other autologous CD19 CAR T programs into the front-line consolidation study setting. That study has been ongoing since June of this year. Right now, we have activated more than 50% of the clinical sites. We're continuing to activate study sites at a rapid pace. We are, you know, continuing to, you know, guide that by mid-2025. That's probably, you know, you know, next year, you know, not too far from now, that we will make the first announcement on the progress of the study by selecting the lymphodepletion that we'll move forward with.
We are also very excited about the second program, which is ALLO-329. This is a very differentiated approach of advancing CAR T into the autoimmune space. I think everybody nowadays has been very familiarized with the fact that the immune system can be reset by deep depletion of the B cells. That's the data coming from the CD19 CAR T program. See, ALLO-329 is a next-generation CD19, CD70 dual CAR with a purpose of addressing not just the B cells, but other lymphocytes that contribute to the autoimmune disorders, as well as paving a path for reducing or eliminating the lymphodepletion, which I think will open up the use of CAR T in the autoimmune space to not only people with a severe disease, but also with a moderate disease. And our third program is ALLO-316, CD70 CAR T program that we have been studying in renal cell cancer.
We recently updated the data in the study where we have seen upwards about 30% of the confirmed responses. That program is continuing. We're continuing to enroll into the phase I-B portion of the study. We expect to update the data mid-2025.
Great. So I guess next year with the interim update on cema-cel, you know, that's the next catalyst for the company as far as, you know, its programs. And maybe I wanna, I guess, focus on that a little bit. You know, how should we think about, you know, that interim analysis? You're clearly, you know, gonna make a decision on a lymphodepletion regimen, based on MRD conversion. So what are you looking for in terms of making that decision of which, you know, regimen to move forward with?
Yeah. In 2025 for Allogene, there will be a catalyst-rich year. It's not just the cema-cel. I mean, there will be a significant update on our autoimmune program as well as renal cell cancer program. But the, you know, front-line consolidation is our primary focus. And the study design that we are currently conducting right now, it is a 1:1:1 randomization. You know, patients who are MRD positive at the end of front-line R-CHOP regimen, they would be randomized to control arms, which would be observation alone, or two cema-cel arms. One with a lymphodepletion that would be considered as a standard FC lymphodepletion. And another, where we are randomizing patients to FCA, which is the lymphodepletion that we have been using in the relapse refractory setting.
Planned update, mid-2025 is when we make the selection between FC and FCA and choose one lymphodepletion to complete the rest of the study. From that point on, study will be instead of 1:1:1 randomization, it'll be 1:1 randomization. The basis with which we will make the determination, you know, starts with one, we like to see more MRD conversion, which I mean is patients who are enrolled are all MRD positive. We wanna see them converting to MRD negative. There is enough data that will suggest that once patient converts to MRD negativity, their chance of disease relapse goes down significantly. That's a pretty, you know, good way to assess the efficacy of the cema-cel in this setting. You know, one is you know we wanna see more conversion in a cema-cel arm than the control observation arm.
And the second one that we are trying to do is between FC and FCA, which one works better. And that's the, you know, the selection of lymphodepletion that we will announce. So, we will not provide details of, you know, what, you know, number of patients who converted to MRD, you know, negativity. But, the inferred message in that announcement would be, you know, one, there are more conversion, with a cema-cel treatment. And at least one of the lymphodepletion is good enough for us to move forward.
I guess when you think about comparing FC versus FCA in an earlier line setting, such as post-consolidation, you know, how do you, what's the determinants in terms of, you know, cell kinetics in early line setting versus a refractory setting?
Yeah. So that's a great question. And one may also ask, well, why are you even studying, you know, FC regimen when all your data is based on FCA? And by the way, in the relapse refractory setting, we have treated, you know, a fair number of patients with FCA lymphodepletion followed by single cycle of cema-cel, where we have seen in patients with bulky disease complete response rate above 50%. And more than one-third of the patients were having a durable response, a complete remission lasting more than six months. So cema-cel with FCA in the relapse refractory setting works very well, almost, you know, equivalent to what autologous CD19 CAR T has shown in the relapse refractory lymphoma setting. The reason that we are studying FC, which does not have anti-CD52 antibody, is, you know, we are factoring in the indication difference.
We are going from bulky relapse refractory setting to MRD-only disease where disease volume is probably at the lowest it can be. And so here, we don't expect the long persistence to be critical. We just want the cells to expand and wipe out the remaining cells that is giving the MRD positivity. So that's why we are testing FC in addition to the FCA. And as you have sort of indicated, we are not expecting the long persistence of the CAR T-cells to be necessary to carry out the elimination of, you know, residual lymphoma cells that's contributing to the MRD positivity.
You're feeling pretty good about the FCA, FC, issue.
I think it's a really, you know, great scientific, you know, question, and I think there's a pretty good chance FC could work as well as FCA, but we will find out, and we'll make the determination based on the clinical data.
Yeah. I think it's fair to say we have different regimens. On the one hand, FC is the standard. It'd be a simpler approval path. But FCA with the anti-CD52 antibody provides a proprietary nature to the therapy. But it adds one more step in the regulatory process to get a portion of the regimen approved. We don't think that'd be a big hurdle. But in that sense, we're sort of indifferent between which one will work.
You know, you are enrolling patients in an outpatient or community setting, correct? Like, what's the receptivity of FC versus FCA in the community setting? Is there a preference on lymphodepletion regimen?
I mean, so far, the investigators are very excited about the study. They like the study design. And they also like the fact that we are, you know, testing two different lymphodepletion. In terms of, you know, the preference, they haven't really indicated any preference. I mean, that's probably not the right thing to do when you are actually testing it. I mean, we should make the determination based on the data. So, you know, yes, the investigators are very excited about the study. And screening of MRD has been pretty active for some time. So, you know, but there has not been any stated indication on FC versus FCA.
Got it. Okay, and I guess in terms of the trial, there's also a second interim on event-free survival that's expected in the first half of 2026.
Yeah.
Can you just tell us a little bit about that in terms of what are the thresholds in terms of, you know, stopping rules and such around that analysis?
Okay. So, you know, 2025, you know, the lymphodepletion selection mid-2025, that's the pretty significant, you know, the catalyst, you know, in, in our view. And when the next year in 2026, that's when we expect to complete the enrollment in the first half of 2026. And also, around that time, you know, we expect to carry out efficacy, clinical efficacy-based interim analysis. So this is statistically powered and has a chance of, declaring that the study is a win if, if the statistical significance has been demonstrated. So we will be looking event-free survival, which is a primary endpoint at that interim analysis. So, and then, another thing that I should add is, you know, towards the end of 2026, that's when we expect to carry out the primary analysis of the ALPHA3 study. So 2026 is, when a lot of things will happen.
What would be considered clinically meaningful?
Clinically meaningful, so without going too much into the statistical assumptions that we have used in this, by the way, you know, we have not gone into that kind of details of how study is powered. But this is a 240-page study. So you can assume that the hazard ratio is pretty aggressive. But I would say the study is very well powered on various different, you know, assumptions that we have made, you know, for the study. In terms of the more important question of, you know, what is clinically meaningful, you know, the best one, you know, source of that information is what the clinicians have been telling us about what would make them change their practice and how they would sort of adopt this, study.
Probably the best one that I can quote is, you know, one investigator telling us that if about a quarter of your patients, you know, who are treated, do not experience disease recurrence, this study will be, you know, a home run. And they will change the practice pattern.
So a quarter of patients do not experience disease recurrence. So that would be over the control arm, is what you would be looking for.
How does that translate into, like, event-free survival as an endpoint?
Yeah. So, you know, event-free survival, you know, that's, you know, the endpoint that we use in the randomized study. So one way to look at it is a median difference in the, you know, event-free survival. I mean, that's one way to look at it. Another way, especially with the immunotherapy, is really looking at where the plateau occurs. And if you recall, the reason that a CD19 CAR T is adopted so quickly in the relapse refractory setting is it changed the plateau where patients instead of, you know, having a relapse or having a, you know, dying from the disease, and the curve plateauing at, you know, 20%, with a CAR T treatment, the plateau went up to, you know, around 40%. So that is the plateau difference.
So here, you know, we would expect that most patients who are MRD positive, you know, about 85% or 90% of the patients will relapse. But we are trying to, you know, to raise the plateau, where patients do not experience the relapse.
Got it.
Biren, I would add that another exciting part of the ALPHA3 study is the opportunity for community oncologists to have access to CAR T therapy. So as many people know who follow the autologous CAR T world, one of the big impediments to the growth of that market has been moving from the academic centers into the community oncology centers because of the need for the leukapheresis and other supportive elements and logistics having to do with autologous CAR T. So one estimate by one of the major players in that space is they have about 80% of their patients they can't access because they originate in the community oncologists. And then they're never referred to the academic centers for a variety of reasons. Some of them are logistical. Some of them are coverage, and so they don't have access to CAR T.
In the case of cema-cel as an allogeneic option, we don't have the leukapheresis step. It's off the shelf, and so we can deliver cema-cel to the community oncologists, which makes our study that much more compelling and the indication that much more compelling.
You add to that the speed at which you can deliver the therapy being off the shelf. You can save six, eight, 12 weeks of time, to get the therapy on board, which in the case of an MRD positive post-R-CHOP cancer patient is a critical time point. We estimate that somewhere between 25%-33% of patients will relapse within that first six months or so. So getting them on therapy early without the leukapheresis step makes this a very important application of CAR T therapy that to date has not been thoroughly explored. So that makes this study that much more important, to all the oncologists.
We're seeing interest both at the academic centers because of the novel nature of the study, combining it, you know, with the Foresight MRD test, which is something that is quite important to all of the oncologists and then to the community oncologists in particular, given that they haven't had access to autologous CAR T in the past.
I guess talk a little bit about, you know, patient management, in the community setting, as far as outpatient. They're able to manage around CRS and ICANS. What's the experience been in the study?
Yeah. You know, I think, you know, you know, this is also, a lot has to do with the timing. When you look at the last three to four years bispecific T cell engagers, you know, that have moved into the, you know, the lymphoma setting that has been studied in the community cancer centers. So in a way, taking a CAR T, which has a similar spectrum of adverse events and, you know, requiring the attention, the community-based cancer center, you know, physicians are very familiar with the concept of cytokine release syndrome and ICANS. So that also makes this study much easier. And, you know, frankly, I think their experience also, you know, made them think, "You know what? We gotta have the CAR T in addition to the T cell engagers for our patients.
So you talk about T cell engagers. I do want to pivot to the autoimmune side of things.
We're developing ALLO-329, CD19, CD70. So it's a differentiated program. It's dual targeting.
You know, I guess, what's the rationale in terms of targeting CD70? No one's really gone after that as a target for autoimmune.
Yeah, so CD70 is an antigen that is upregulated when the lymphocytes are activated. You know, we don't talk about B cells, but CD70 is upregulating B cells. CD70 is upregulating T cells as well as dendritic cells. So and also there is a lot of interplay between B cells and T cells, B cells and dendritic cells that leads to the, you know, the autoimmunity. So rather than just going after the B cell, we designed the program to really address the fundamental, dysregulated immune system of the autoimmunity. So we are going after all, you know, immune components that contribute to the autoimmunity. So, you know, you know, from the MOA perspective, that is very differentiated. That's something that you cannot do with a CD19-directed therapy or BCMA-directed therapy or combined CD19-BCMA-directed therapy. So that is one very differentiated attribute of our product.
The second one is, when we were looking into the autoimmune space with a CAR T, you know, the one conclusion that we immediately draw is this is space that is really primed for the allogeneic cell approach. And the second one that we begin to think very seriously is that for the CAR T therapy to have an effective, you know, you know, use in the autoimmune space, you got to address the lymphodepleting chemotherapy that is commonly used or I would say universally used before the CAR T therapy. Having the CD70 components gives us a mechanism-based way to eliminate the lymphodepletion. So, the goal of the, you know, program is really, you know, make an allogeneic cell therapy, that can be used as a one-time and be-done treatment, with minimum or no lymphodepletion. And that is the goal.
And so you're entering phase I next year, right, with data, by year-end 2025. Will we have read-through on, you know, which direction you're going in, in terms of lymphodepletion by the end of 2025?
Yeah. That's what we are hoping for. So we, you know, plan to file IND in the first quarter of next year, start the trial in mid-2025. And in this setting, you know, you need a limited number of patient data to understand whether the B cell depletion or the cell depletion and resetting of the immune system, you know, that is evident. So hopefully by year-end, we will know that. And in addition, we will have insight into, you know, which direction that we, you know, we are moving.
Sorry, Geoff, let me go.
I was just gonna say that, our third program, the solid tumor program, with 316, which is a CD70 CAR, that is the program that has given us the evidence that the combination of a CD19, CD70 may have an opportunity, to be applied without lymphodepletion or with very low lymphodepletion.
Because that CAR has shown an amazing ability to expand in the body with, you know, very light lymphodepletion.
That's part of the translational medicine that we're very excited about.
Yeah. Well, you know, what really gets us excited about our, you know, the autoimmune program, ALLO-329, is, you know, what we have generated, you know, preclinical data. And all this is presented at a recent ACR. Our website has the, you know, the poster presentation. I mean, it works well in all the models that we have tested as we have designed. And also, we have moved away from lentivirus to site-specific integration using AAV. And that also made the manufacturing a lot more efficient and scalable. And you know, lastly is not only, you know, our sort of, you know, belief in, you know, this product is coming from the preclinical data.
There's a lot of inference that we can make from two separate programs, CD19 allogeneic CAR T that's a cema-cel and CD70 program in solid tumor, which actually is put together for the autoimmune, you know, construct.
I mean, Jeff, you raised an important point with ALLO-316 as the read-through into ALLO-329. Can you talk a little bit about, you know, the data there? I think you had looked at on DL2 specifically FC500 as a regimen within, you know, the ALLO-316 program. What's the read-through on the autoimmune by choosing that as, as a lymphodepletion regimen?
Yeah. So, you know, first of all, you know, the most important readout is how the CD70 works to allow the allogeneic CAR T-cells to expand robustly. I mean, you know, to the point that this has a implication in how we think about the next generation of allogeneic platform. And we even named the whole, you know, you know, the mechanism as Dagger technology. So, what we have seen with CD70 in renal cell cancer is that with the standard lymphodepletion that is used in the, you know, autologous CAR T, ALLO-316 works as well. And this is an allogeneic CAR T. So the fact that allogeneic CAR T-cells works with a standard lymphodepletion is saying a lot.
I mean, the biggest challenge of the allogeneic CAR T is how to prevent the rejection of the you know allogeneic CAR T-cells and having CD70 address that very fundamental question, so this is really gonna open up how we think about the allogeneic CAR T, not only in solid tumors, in other indications as well, and certainly the read-through to the autoimmune program is pretty significant.
I know we've got maybe the last few seconds on 316 specifically, I guess. So what's the next data set that would come out of that program?
We are enrolling patients into the phase I-B where we have, you know, we're using 80 million cells with a lymphodepletion FC500. We are targeting to treat about 20 patients. You know, enrollment is ongoing. It'll probably end pretty soon. We'll follow those patients enough to evaluate for efficacy and update the data mid-2025.
Great. Thanks. I think that's about all the time we have. Really appreciate you guys coming and attending the Piper Sandler Healthcare Conference. Thank you.
Thank you.
Thank you, Biren.
Right on time. So, thank you very much. I'm the analyst here, in diagnostics, Dave Westenberg. I'm here with Guardant Health, AmirAli, and Mike Bell. And, you know, we'll kick it off here. So I'll just get on the topical news from last week. You know, you won a $300 million false advertising claim against Natera. Does this have any benefits from a sales and marketing perspective? And when can you expect the payment? And what are kind of the ranges of fines that it could be?
Sorry.
I think so. Yeah, we are pleased with the way that verdict went, which I think justice worked. And I think it's a good kind of a verification of the performance of Reveal and the reality of the strength and the technology and the products that we have developed. It's one of the biggest and largest kind of verdicts in this field of misleading advertisement. And we believe just oncologists deserve better, like, you know, sharing the right information when you're talking about the performance of tests, especially by another manufacturer, really makes sense. So we are excited about it. Still, it's a long journey. You know, we expect that probably this is most probably or certainly, but it's gonna go to appeal process. And maybe in terms of timeline, you can add more, Mike?
Yeah. I think, you know, it's the post-trial motions that are coming up soon.