Good morning, everyone, and, thank you for joining the 2024 H.C. Wainwright 26th Annual Global Investment Conference. I'm Dr. Jade Montgomery, an associate biotech research analyst at the firm, and I'd like you to please join me in welcoming Dr. Cokey Nguyen, CEO of Atara Biotherapeutics, an allogeneic T-cell immunotherapy company. Cokey?
Thank you. Good morning. Thank you for the opportunity to present our company here at the Wainwright Conference. First, I'd like to start with telling you who we are. We're a biotech company. We're based in Thousand Oaks, California, and we're trying to innovate the space where cell therapy is showing signs of efficacy. And we're doing that with a differentiated approach. I'll talk about that, but key really is if you step back, it's off-the-shelf. We have about 160 employees, and we have the world's first T-cell off-the-shelf program approved. This is approval by the EMA under the commercial name Ebvallo. We've subsequently filed for approval in the United States.
We have a target PDUFA date in January, and really, what I wanna tell you about is how we've taken this robust, commercial GMP phase platform and repurposed it for CAR T- cells, and so if you look over on the other side of this slide, you can see where we're headed, which is our allogeneic CAR-T programs. We have a CD19 CAR-T program that's called ATA3219, and we're going into two indications there, in large B-cell lymphoma as well as lupus, and then I'll tell you about our program that's gonna IND in the second half of next year, ATA3431, so let me tell you what we have and why we think we're differentiated and how this is differentiated compared to what else is out there in the allogeneic off-the-shelf space.
What we do is we, from qualified healthy donors, we extract this memory pool of T- cells that see EBV. The nice thing about this is that most of us are infected with EBV by the time we're 30. This is a repertoire of T- cells that is almost unlimited, as we can get healthy donors all over. And our manufacturing process is that we take these T -cells, there's no gene modification, we expand them. Again, it's a commercial GMP process. And then we use minimal HLA matching. Clinically, this has been shown in over 600 patients in post-transplant lymphoma. We've used this product now in 600 patients, and what's interesting about it is that it's commercially approved.
The second is that it has a therapeutic index, and that it's been efficacious over twenty years with minimal adverse events. That's amazing for an allo off-the-shelf platform, if you think about it. And the next part is we've gotten manufacturing, and I'll hit that in the next slide, to more its biologic-like cost of goods, which we also think is important. Now, what we do on this validated, what we call a T-cell chassis, is then we'll transduce a chimeric antigen receptor, to create the, what we call the next generation of allogeneic CAR-Ts, and that's a bigger problem statement, we think. This retains all the features that we've seen in Tab-cel. Doesn't require gene editing, which we think is important, not only for manufacturing, but also, if you think about it, for regulatory approval.
And I'll walk you through the validated elements we've engineered into this platform. This is what the commercial process looks like. The one thing I would say is if you're used to antibodies, and a lot of our staff come from Amgen in Thousand Oaks, this is about three logs more complex. If you think about the starting materials, sourcing PBMCs, making your drug, which is a living cell, which are the T- cells, expanding them, and then creating your library of product. Now, what we do for the CAR-Ts is the added wrinkle is that we're transducing a chimeric antigen receptor. But where we stand today is we do manufacturing ahead of time. We do partial HLA matching, so we have a library of product ready to infuse to patients within three days, typically.
So that really changes the paradigm, and we'll walk through that, shortly. This is... This slide is really to tee up what the autologous CAR-T patient journey looks like. We know this happens over anywhere from 25-35 days. So if you think about their patient experience, you're doing apheresis, you're asking the patient to then go on bridging therapy after failing three prior lines, so it's a pretty desperate situation. You're asking for two to five weeks to manufacture this autologous cell product, and then you can infuse the patient. And this is what the commercial programs look like. This is Kymriah, Tecartus, Yescarta. What we've shown in our paradigm, at least with our non-gene-edited products, is just a step back. It's a paradigm where we, again, have this library of off-the-shelf T cells, and typically, we're infusing patients within three days.
So again, we're taking healthy donor, EBV-specific T cells, we're not doing lymphodepletion, and then we're going in this five-to-ten-minute infusion. We've shown this in over 600 patients. So this is the paradigm that we're swimming to with our CAR-Ts, and I'll walk you through why we think we can do this. One of the biggest problem statements, we think, is that while autologous CAR-Ts have shown amazing efficacy, it becomes a problem of scale and also the variability of the patient-derived host immune system. So we're taking, in other words, T- cells from very sick cancer patients and asking them to be reinfused and hoping that they have the immune fitness of healthy donor T- cells. I think that's a big question that physicians and patients grapple with. So we know that your conventional alpha/beta CAR-T cell is what works. This is Kymriah and Tecartus.
This is a blockbuster drug. They, they're probably gonna gross over $2 billion forthwith, and then with Carvykti, it's supposed to gross over $5 billion. But really, the fundamental issue is manufacturing. So if you have, for example, 30,000 patients, and you can, you're limited to 5,000-10,000 starts, that's huge unmet need, and you also have high cost of goods. So, so us in the allogeneic field are really grappling with these challenges to get off-the-shelf CAR T- cells into these patients. As you can imagine, there's many challenges, and we're outlining them here. There's graft versus host disease, which can happen. There's allorejection, so the patient rejecting the allo T cells. There's actually, obviously, we see this exhaustion and diminished persistence of not only the auto CAR Ts, but also with the allo, for sure.
You have the inflammatory responses. A few weeks back, there was a lot of negative reaction to what we expect, low-level CRS in patients getting these CAR T- cells in autoimmune patients. But this is expected. The question is: Can you engineer these things out and also provide an off-the-shelf CAR T- cell solution to patients? This is how we think about it. Again, using the tab-cel chassis, we're retaining that T- cell receptor. We have a clonal pool of EBV-specific T cells, which we think is part of the safety profile because these T cells are very specific for EBV antigens with a very low preponderance to cause alloreactivity, and this has been proven over twenty years. We're maintaining the MHC, so again, no gene editing.
The MHC we're maintaining because we use the principles of transplantation. In other words, a priori, instead of gene editing the T cells and saying, "We're smart enough to know which genes to knock out," we're just saying, "Let's take the principles of transplantation that worked for us for 20 years and then just create a CAR T-cell." The next two components we've engineered into this, that we've designed is, we have a next generation costimulatory domain, and this has been clinically validated, and I'll walk you through that in the next slide. We also, because of our manufacturing, have a less differentiated phenotype. One of the things we know about T cells is, no matter what you do, they're always going to exhaust. That is evolution. Otherwise, we'd all die of autoimmunity.
But what 1XX does is pretty amazing, and I'll walk you through those data, as well as a less differentiated phenotype, and I think that's important because what you see in a less differentiated phenotype is you see less cytokine burst. And again, that's been shown in the clinic for programs that focus on this also. So we just talked about these clinically validated components, but I wanted to call them out for you, why we think there's a basis in the data. The first is that EBV CAR T-cells have been in patients. This has been studied at Memorial with Dr. Kevin Curran. He basically took tab-cel and then just transduced the CAR T. So this is sort of a first-generation product. There wasn't any optimization, but what Dr.
Curran was able to show an 83% complete response rate that sustained beyond two years, and he didn't see alloreactivity, graft versus host. The data were pretty amazing for a small cohort. The second thing I would say is, with Novartis, they've validated this less differentiated phenotype. This is their YTB turbocharged product. So in other words, it's exactly like Kymriah, but then they have a two-day manufacturing process. And the difference is, astounding in the sense that instead of infusing 250 million CAR T-cells, their RP2D now, or recommended phase II dose, is 12.5. So you can see it's about a 20-fold less T cells. So this is, maintaining the efficacy for the patient, but also reducing the adverse events.
So what Novartis and Takeda have shown is lower levels of ICANS, which is this deadly neurotoxicity issue often associated with CAR Ts. They've reported out, and their complete response rate for Novartis is 73%, which again, beats the canonical autologous CAR Ts. We think this is an important element in our product. The second thing I'd say is people always ask about 1XX, and what is that? This is a signaling domain in the chimeric antigen receptor. This was validated by Takeda and TAK-940. They also saw pretty astounding data in the sense that the complete response rate was quite high, 75% overall response rate, close to 90%. Similarly, notable is that their RP2D was, again, one-tenth of sort of normal, so 25 million CAR T-cells.
So really, when you think about it, we're trying to engineer not only this premier, preferred, off-the-shelf, validated approach, which is EBV CAR T-cells, and then have a memory-like phenotype, and then also this next gen chimeric antigen receptor. That's 3219 . Now, here's the problem statement as we see it, and at least as it presents to the autologous companies. This has been well delineated by Allogene, for example, who are leader, like, leaders in the space in terms of the first entry. There's access challenges, and we know, for example, that unless you live within 50 miles of a major clinical center, you won't get treated, and then you know that sometimes there's manufacturing failures. So overall, net net of the 30,000 addressable patients, you can see that most people say only about 20%-40% can be treated.
The same thing for bispecifics. For bispecifics, we know that dosing is a problem. So you're taking a biologic. You're hoping that the pharmacology of a biologic systemically will get to the site of action. While they tend to work, they come with higher adverse events. We know that for sure, and then, for other allo programs before us, we know that persistence and durability has been an issue. Now, this is where the rubber meets the road. This is the first data slide, but this is really demonstrates our core belief, so whenever we make CAR T-cells in the lab, we make autologous, and then we'll make an EBV set of T cells, and this is really head-to-head in a pretty challenging model that everyone uses, which is called Nalm-6.
It's a leukemic model, and what you see on the far right typically is that all the mice in the cohort succumb by 20-25 days. What we were noticing is that you could take the auto CAR T benchmark, which is Tecartus-like. And these can show anti-tumor activity through 30-40 days, and then there's an aggressive drop-off as the Nalm-6 outgrow the T cells in this model. What we were starting to notice, and that was amazing to us, was that ATA3219 T cells were not only showing greater persistence, which is in the middle, but also better overall survival. And for me, this is pretty remarkable. So throughout my 20-25-year career, auto CAR T has always been the benchmark.
And if you could beat that with T cell engagers or even small molecules, that is in fact amazing, and it's very difficult to do. So when we started to see this with our off-the-shelf platform, we felt more confident about moving forward into the clinic. So I talked about large B-cell, and let's talk about lupus. This really is where there's a lot of excitement now. There was this initial study by Georg Schett in Erlangen, where they had a small cohort of patients, under a dozen, and they showed 100% response rates, 100% amelioration of disease, and this is beyond two years now. And what's amazing about this is that in especially lupus nephritis, there have not been a lot of agents which show this remarkable response.
You've only seen it from autologous CAR T agents, and it is a high unmet need. When you think about it, what we're trying to accomplish, and this is what good looks like, is B-cell depletion, what we think is an immune reset, and then this sustained remission. And to be honest, physicians that we talk to all over the country haven't seen this with T-cell engagers, Rituxan, Ocrevus, corticosteroids. It's only with cell therapy. But now, we talked about the problems in manufacturing, which is if you're limited to 5,000 , 10,000 starts, how do you address an unmet need of 200,000 ? It's a big problem. And so this is exactly where allo CAR Ts, we think, are going to be most impactful.
This immune reset, but off-the-shelf, no need to apheresis, no need to ask a patient to go off of immunosuppressant drugs for a month so that you can apheresis and then make them wait another thirty days for infusion. The paradigm we're moving toward is, again, infusing within three days. Why we think that, again, is that we have a differentiated T-cell platform. There's a lot of different cell types people are trying. This reminds me of back early in the antibody days, and I'm aging myself, where people tried different antibody formats, but 20 years later, we're still using the IgG format predominantly. We're trying the same thing. We're trying to understand, is it an NK cell? Is it gamma delta? Really, the data say it's the alpha-beta T -cells that work, okay?
The only data we have are from autologous alpha-beta T -cells. Again, that's where we think we have this ability to impact patients in a positive sense. Alpha-beta T -cells, they look very much like autologous. They come from healthy donors, and they have all the advantages of allogeneic. In addition, what I'm going to tell you is the way because of the 1XX and the memory phenotype, we have a lower cytokine burst, and this is consistent through manufacturing. It's consistent with 1XX. It's consistent with the central memory phenotype. In other words, every time we make T cells from a given donor, and we make auto CAR Ts or allo, we see a reduced cytokine burst for interferon-gamma, TNF alpha, and IL-6.
We think this is even more important for the autoimmune patient, which is not going to tolerate the same level of adverse events that oncology patients tend to tolerate. Just to highlight that, here's another slide again to look at the data. We maintain the same level of efficient cytolysis, killing target cells. But again, you can see very clearly in the cytokine release on the bottom, what's remarkable to us, and we hope so to prove in the clinic, is these T cells really don't have the same level of interferon-gamma, TNF-alpha, IL-6. These are really the danger signals, and this is problematic for autologous CAR T that many patients are in fact hospitalized long term for. Now, we're going to take this one click deeper. If you index on lupus, we're now going to say we have two cohorts.
The first is lupus nephritis, where the autologous CAR Ts have shown efficacy. We're going to go into that space with lymphodepletion. The next click is we are now enrolling patients for no lymphodepletion, in an extrarenal, lupus cohort. Again, these patients have severe or moderate lupus. They don't have lupus nephritis, but we're not going to subject them to lymphodepletion, and we think this is important for patients, since a lot of these patients tend to be female, they're young, they're in childbearing ages. They don't want to be exposed to the genotoxic stress of lymphodepletion, and again, we're trying to take that advantage that you see with, the alpha/beta autologous CAR T-cells, all of those notable features off the shelf, partially HLA matching, no lymphodepletion, and we really think this could change the paradigm.
The last thing I'll say is, in addition to ATA3219, which, as you can see now, is pivoting into autoimmune space, we ourselves have a CD19/CD20 dual CAR program, and what's notable here, again, is I think the data will be coming forthwith. What you're going to see probably is the CD19-20 programs could surpass CD19 CAR T programs for efficacy. We think what we're starting to see emerge, and this is in the data from other auto programs, is they're breaking through this glass ceiling of complete response. Typically, autologous CD19 CAR Ts are really about a 40% complete response rate at six months. What you're seeing with the dual CAR Ts is something much higher, and we think you're going to see that data at ASH.
Toward that, we have our internal program. It's off the shelf, ready for IND second half next year. Just as a teaser, this is a pretty challenging model. It's called Raji. If you put a CD 19 into this model, it looks pretty terrible. The mice succumb. But what we started to notice, again, going head-to-head with an autologous benchmark, is that the 34 31 EBV CAR T-cells perform remarkably well, not only for tumor growth inhibition, but overall survival. Again, this is why we're planning on an IND second half next year. This is where we stand today. We have a differentiated pipeline of EBV T cells with the milestones.
I think the big one for us in the short term is getting tab-cel to the finish line with the FDA. Again, that target PDUFA date is in January, where we'd be very excited to then have approval in the EU and the United States for tab-cel with our corporate partner, Pierre Fabre. Then we have right behind that our phase I programs for CD19 and then CD19/20. I would be remiss if I didn't mention our corporate partnership with Pierre Fabre. They're an amazing corporate partner for us. They've commercialized tab-cel in the EU. Here on this slide, we just delineated the milestones that we've disclosed. Pierre Fabre is also working with us through the BLA process with the agency, as well as commercializing in the United States. So we're very excited for the next 12 months.
This is just to bring you up to speed. It's been a long journey for the company to get here, but again, we'd be very excited to reach the finish line with this program. So again, this would be the first allogeneic T-cell therapy approved in the United States. So that's 20 minutes on that time. Thank you for your attention.
Thank you so much, Cokey. It's very exciting stuff, and I know it can't be easy joining us from California at this hour, so yeah, I'd just like to thank you again, and if anyone has any questions, Cokey and his team are here, and you can also ask questions online.
So there are a few parts of the cell therapy for the particular indication. Where do you see Atara's biggest impact? What indication? Is it autoimmune? Is it multiple sclerosis? Is it maybe intersection with oncology, lupus? What do you feel would be the, you know, the prime goal?
That's a great question. We think about it in probably three ways. We think that there's still unmet need in large B-cell, in the sense that, allogeneic T-cell therapeutics, at least in the first wave, haven't really accomplished what auto have. And so that's why we're going into that indication, to see if we can recapitulate what good looks like. To your point, next, in autoimmunity, I think not having lymphodepletion, if we could see that to completion, would be amazing for patients. It would be amazing for docs. If you think about the paradigm right now, you, in autoimmunity, you have to have hemonc and rheum and an ICU all lined up to treat patients, and it's incredibly clunky, and it's incredibly expensive.
So we think if we could change that paradigm, you could move away from these massive clinical centers, even to the community setting. And then, obviously, the third piece is if CD19/ 20 looks as good as we think it's going to look with the J&J program that they in-licensed from AbelZeta, you're going to want an allo program. And it's not trivial to do an allo program. What we've heard is there could be, it could be difficulties incorporating that bigger cistron of the dual CARs into by gene editing. And when we've talked to other companies, they've actually expressed that difficulty in getting all the gene edits plus this larger gene cassette into their T cells. So we think there's opportunity there also.