Okay, my name is Ben Burnett, biotech Managing Director & Equity Research Analyst (Biotechnology) at Stifel. We'll go ahead and start our next fireside chat. Happy to be here with Cokey Nguyen, CEO of Atara Biotherapeutics.
Good morning.
Thanks for doing this. Maybe start off just by giving a high-level overview of Atara then we'll get into it.
Yeah, thanks, Ben. Atara is. We've been on the Nasdaq for about a dozen years now and originally spun out of Amgen and we're hitting this amazing year for us. So for the past five to seven years, we've taken this commercial phase allogeneic T-cell asset called Ebvallo. It's approved in Europe and we're in a productive process now with the agency. We're hoping to get approval Q1 in January. So that's our commercial late-stage product. And with this amazing product that's shown this therapeutic efficacy consistently 50% or higher over 20 years, we thought this was the perfect time to take that science and then repurpose these off-the-shelf T-cells and move into the CAR T space.
Fantastic, and actually, so regarding your first off-the-shelf CAR T cell, ATA3219, I guess walk us through, first of all, maybe let's talk about the design of the asset and then we'll get into kind of the clinical programs, but how was this different from other allogeneic CAR Ts?
Yeah, thanks. So we work with a lot of smart people at Atara and we are biology-based. And so that's already going to be bifurcated. In the allogeneic space, there's mainly gene-edited T-cells. And I think when we looked at that, we didn't want to compete in that space, number one. And number two, we wouldn't know which genes to knock out. And I think that's still something the field is figuring out. So we're sticking with the biology that we've seen with Tab-cel, which is what looks the most like an autologous alpha beta T-cell. So that's what EBV T-cells are, in fact. They're alpha beta T-cells from healthy donors, minimal genetic modification. We're literally just putting in the CAR. And then what we engineer is really how you manufacture the T-cells so that they're more pluripotent.
So like what you see in T-Charge, we optimize that into our CAR Ts. And then we use the 1XX signaling domain that was invented by Michel Sadelain, which is pretty amazing also for CAR signaling.
I guess what is unique about the 1XX? I think we're familiar with 4-1BB, CD28, and kind of have sort of, I'm assuming, predisposed expectations for sort of cell kinetics of expansion. But where does sort of 1XX fall?
So I think 1XX, and you see this in the auto space where you saw this the most clearly was TAK-940, which was an autologous CD19 program. And the amazing thing about TAC940 was the RP2D. I believe there it was 12.5 million T-cells. So that speaks to really two things. When you use this unique signaling domain, you have potency and you have this ability to use fewer T-cells. And really what you see in the preclinical data with 1XX, so really it's an attenuated CD3ZA signaling domain with CD28 is what we pair it with. You clearly see that the T-cells in all of our studies clearly are attenuated, so they exhaust less quickly. And we really think that's important in patients.
So for clarification, so TAK-940, I believe that's the Takeda, CD19, it's an autologous CAR T. And it uses the 1XX.
That's right.
Domain. Yeah, okay. So another feature that I think is also unique relative to some of the other allogeneics, you mentioned you don't edit. And I think as a consequence of that, your product has TCR still within the product, whereas others have sort of a modification there. Is that just a different way to get to the same point and avoid GVHD, or is there any benefit of that?
Yeah, so that one of the problems we struggle with in the field is how to address when you take allogeneic T-cells from healthy donors, put them into patients, of course. So because obviously for one production run, you have a thousand doses. So it's a tremendous safety risk if you're not controlling alloreactivity. And now you can approach that genetically and knock out the T-cell receptor. The problem that I see growing up in the field is the T-cell receptor is the single most important protein for T-cells. And when you knock it out, you're knocking out a key survival signal. We use the T-cell receptor to expand our T-cells. And then we also believe because it sees EBV antigens, it sees a very defined antigenic repertoire. And with Tab-cel over 600 patients, it's very safe.
So for us, it's really about persistence and safety, keeping that TCR and then not having to genetically modify it. It also makes our process amazingly efficient. There's inefficiencies associated with gene editing. So again, taking that natural T-cell approach, minimal modification, 12-14-day process, thousands of doses. When we stick close to the biology, what the T-cells look like are really like high quality auto T-cells. They're just coming from healthy donors.
And then the last point I want to touch on, so your partial HLA matching. I guess the critique would be that's complicated. Is it, I guess?
It's interesting, right? Because we've spoken, it's a very small field and we get a lot of questions from gene-edited allo T-cell companies asking, well, Caribou is going to partial HLA matching. So what are we doing all this gene editing for? And then partial HLA matching. So we're saying, well, we're not really sure, but what we can say from our experience, partial HLA matching looks like it works, Ben. And again, it's principles of transplantation. So you're trying to match up the recipient immune system with the donor T-cells. It's worked in Tab-cel. Again, it's consistent efficacy again over 20 years. And that's really where we hang our hat, looking at those data and saying, hey, this might work for CAR Ts.
Yep. And I guess do you have sort of a sense of what the kind of cell bank that you would need to maintain for a CAR T program?
Yeah. So for Tab-cel, where the activity is through the T-cell receptor, right? Because it's EBV specific T-cells, that's about 20 banks of T-cells. Now for the CAR T programs where the activity is through the chimeric antigen receptor, it's really about four. And that's for lymphoma. When you go into autoimmunity, because the genetic background is different in a lot of autoimmune patients, it could be six banks. But we think about this whole process as it's remarkably efficient and it's easy because there's two things, right? There's innovation and then there's thinking about pivotal registrational path. And so we're trying to bake that into the CAR Ts early.
Okay. Very good. Let's move to, so I think the first data we're expecting from ATA3219 in one Q of next year in Non-Hodgkin's lymphoma. What do you expect to learn from those data?
Yeah, thanks. So we think we'll have our dose level one cohort of patients. And this is dependent on recruitment, obviously, which is ongoing. But we want to see safety, obviously. That's the whole point of a phase one trial. We want to see PKPD and then obviously efficacy. We know what good looks like from the autologous field. We know what an overall response rate looks like. We know what a complete response rate should look like at six months. We want to see that nice T-cell expansion and then the B-cell aplasia because we think obviously that correlates one to one with what we hope to see in autoimmunity.
Great. You know, when we think back to some of the early autologous CAR T data sets, so Gilead, Kite, that patient population that Axi-cel was developed in kind of doesn't exist anymore, right? I mean, I think we've seen some other CAR T data sets evolve post Axi-cel, post some of these other CAR Ts. And we're seeing, I think maybe a more eclectic mix of lymphoma patients. We're also seeing some patients that are CD19 exposed, some of those are not. I mean, do you expect kind of a mix of patients as well? And kind of what's your efficacy threshold that you'd want to see in sort of CAR T naive patients versus CAR T experienced patients?
I think to your point, we're seeing exactly that. You're going into space where there's approved auto CAR Ts, and so it does change the patient population. The standard of care is just revolutionized in such a short period of time. What I would say though, and this is interesting in our clinical experience, as a lot of companies are pivoting in autoimmunity, we're actually seeing more lymphoma patients present, which is surprising to us. To your point, we intend to treat CAR naive as well as CAR experienced patients. And I think the one question, again, this is drilling down into the details, but when you think about autologous CAR T, you're taking T-cells from a cancer patient. They're typically older. They've seen a lot of other treatments.
We don't know sometimes if the complete response is because the CAR T didn't work or the patient's immune fitness was not high enough. So we still think there's unmet need to go into that space with higher quality T-cells and try to hit a complete response rate that is competitive with auto. And so to answer your question, to continue development, we want to see complete response rates at six months that are higher than the 40% you see now with Breyanzi and Tecartus.
Okay. And you kind of touched on this a minute ago, but should we kind of look at this to inform sort of the autoimmune pursuit that's coming thereafter?
Yeah. There's two advantages. Again, I think we as scientists, also as investors and also as partners, we know what good looks like, and so you have to establish in a known therapeutic disease area how this therapy should look like. Obviously, you want to see B-cell aplasia, but there's also safety. I think what you're seeing with auto CAR T is some safety signals and that comes with how you make auto CAR Ts, Ben, and allo, the advantage, at least our advantages, we're tuning out all reactivity. We're tuning T-cell reactivity with 1XX. We really think we have a reduced inflammatory signature. You kind of see this. It comes with auto CAR T. It just comes with how they make the T-cells.
Okay. Excellent. And I guess, so if all goes to plan, just sticking with lymphoma still, the data sort of unfold the way you want them to, what is sort of the development path from here?
So we would be very data driven. We want to be capital efficient for our investors as well as our employees. If we saw complete response rates that were competitive or better, which again is at six months, typically 30%-40% is what autologous CAR Ts present with. If we could supersede those data, I believe our management team would move forward to think about a development path. As it is right now, we would probably partner. We're very open to partnering to be capital efficient in the pivotal space. As a small company, we're really about innovating.
Excellent. And then maybe just last question on this program that I don't want to get into the autoimmune pursuit, but just, so you mentioned four lines, four cell lines as a bank, a lot smaller than what we saw with Tab-cel, possibly a little bit more with autoimmune disease. But walk us through just logistically from watching Tab-cel and now going through this lymphoma program in the phase 1, what are the logistics involved that a physician has to go through to match that patient?
We learned from Tab-cel so Tab-cel, the paradigm is the patients get the meds in three to five days in the U.S. or Europe. Now it takes a little bit longer in the United States, especially in our lymphoma trial right now. What we do is patients present, we check state of disease, is it serious enough to be treated? and then we do the high resolution HLA genotyping and then immediately goes into our bank and matching. From our data, from the patients that present, we're still matching about 90% and then we package and label the T-cells, they get shipped and the patient's treated within days.
Excellent. Okay, so let's move to the autoimmune program. I think we're going to see some data coming up mid next year. I want to start. We've seen, of course, academic data for autologous programs. We're seeing some academic data for company sponsored programs as well. We have seen some allogeneic CAR T, one actually this morning from a competitor, but there was also some data over the summer from BRL Medicine's study in China. We thought that did look pretty good, but that asset contained a number of different sort of edits and modifications. I guess question number one, what do you think of those data? And then how does the technology that you're implementing sort of compare relative to that?
So we were really excited about those data. Obviously gene-edited, I think there were five edits that are knocking out HLA A, B, beta 2M, TCR, PD1, heavily edited. However, like you said, in the three patients that presented, amazing data. One was necrotizing myopathy. The other two were systemic sclerosis, clearly reducing the auto antibody burden. Patients were resolving. We got excited. You saw PKPD. The one thing though, and this might indict the field, I don't know, it's too early, but the 1%-4% translocation rate, it's going to be worrisome when you go into pivotal. When you go to the agency, the agency is incredibly sophisticated now. They're going to question, how do you make the T-cells? And if you see a 4%, even higher percent translocation rate because you're doing so many gene edits, how do you know?
It's going to be a high hurdle, and I think this is the thing right now, the field is in this early innovation space. We are also in the innovation space, but we're also again thinking about what is pivotal, what is going to be approved, and that's why I think one of the advantages of what we're doing is simple, sticking to the natural biology of a T-cell. It could be simpler if we show the same or better activity, and then you say, oh, we know how to get this through the regulatory agencies.
Translocations aside, which I totally agree that was notable. In fact, I think they even mentioned that some of the off-target editing may have actually led to a third HLA being knocked down.
Yeah, that's right.
But I guess just like from a high level, so it feels like they were trying to increase persistence by reducing HLA. Do you think that's necessary? Do we know that yet?
I don't think we know that yet. I would say the data are still out there and we're going to learn a lot from the people who are slightly ahead of us. We just don't know what persistence is required. You could imagine B-cell aplasia and otherwise normal autoimmune patients is a bad idea, and so there's this sweet spot where maybe you don't want these CAR Ts to persist, so for fundamental reasons, auto CAR T is not the best idea. It's great for POC, but you don't want this long-term persisting CAR T, and the second thing is making enough is very hard, as you know. Maybe allo is the answer.
Let's talk about, so you have two autoimmune cohorts. You have a lupus nephritis cohort. You have another just lupus SLE cohort without kidney involvement. First data of mid 2025, is that right?
Yeah.
Okay. What should we expect in terms of sort of number of patients and follow-up time?
So what we're expecting, and again, this is based on recruitment and number of sites activated, is initial data from dose level one in both cohorts. So just to reiterate what the cohorts are, the first to your point is lupus nephritis. It phenocopies what the Schett lab has done. So there's lymphodepletion, which is pretty standard, and then a standard dose escalation with our EBV CAR T cells. The second cohort is in moderate to severe lupus, so-called extrarenal lupus without lymphodepletion. And they're recruiting concurrently. And what we've heard from KOLs, you know I know there was a study today where a female patient went on to have a baby. And I think the field had a sigh of relief, but we shouldn't have to worry like that. When we talk to KOLs, they say these are young patients in their prime.
They do not want to take genotoxic drugs, alkylating agents, which de facto is what lymphodepletion is. They want to know they can just take this med. It's a 15-minute infusion and then their symptoms go away. So we think that's really differentiating. We're obviously pursuing the lupus nephritis. It's a very competitive space, but this space, if you don't need lymphodepletion, Ben, clinicians are really excited.
Absolutely, and that study you were talking about, I think this is the Bristol CAR T data that you were referencing?
Yeah.
Yeah, where there was a pregnancy.
Yeah.
Yeah. Okay. So excellent. I think we learned different things based off the follow-up time. Obviously, we ultimately want to know what is the durability, what is the ultimate efficacy, are we curing patients? But at the first update, presumably follow-up time will be less mature there. So should we focus on things like SLEDI, proteinuria? What are the endpoints that I think are going to be informative here?
Well, you know the clinicians are a lot smarter than me, so they'll inform us. The first thing obviously is safety, but the clinical symptoms to your point, improvement quality of life, which is SLEDI, the composite scores. But I think more specifically, our KOLs tell us to look very carefully at reduction in that autoantibody titer in the patient. The immune reset, I think you and I talk about that, but we really need to see it. And not every modality might show that immune reset. I think that maybe that's a term we invented for the field, but I think it's super important and you can see that in the data. So again, it's your biomarkers, it's your clinical diagnosis, symptom-free patient.
Will patients have the opportunity to drop their background lupus medications?
Yeah, so that's one of the things on our, for example, our non-lymphodepletion cohort. We're starting out with a bolus of steroids before infusion, and that's really just to level set the patient. The steroids quickly taper, and then if necessary, the patients can go back on, but really, obviously what you expect is no.
Yeah. So I think the value proposition of not having lymphodepletions is pretty clear, but I guess the concern is, does that negatively impact the CAR T's ability to work? I guess what gives you the confidence that that could work with that lymphodepletion?
Sometimes you have to be lucky, my friend. And back when Tab-cel was developed, there was no such thing as CAR T. They didn't know to do lymphodepletion. They were responding to a need, which was post-transplant lymphoma, patients dying within 30 to 40 days. And so they said, holy mackerel, we need to get these healthy donor T-cells into the patient. And remarkably, that's Tab-cel. There's no lymphodepletion. It's infused week one, week two, week three. We've looked for immunogenicity and anti-HLA antibodies de novo. We're not seeing them. So that's with 600 patients. And this is an old school process that was developed in Memorial. We really haven't changed it. When you have this ability to engineer in potency with 1XX and a central memory phenotype, these T-cells obviously are going to expand better. They're going to be more potent. And that's why we're confident.
So the base build for the science is already there. And we're saying we're actually making the T-cells better. So that's why we're confident.
Okay, okay, and maybe this kind of gets to this question, but what is the biggest challenge to implementing CAR T therapy in a disease like lupus?
I think one of the biggest things is safety. This is why one of the surprising features of the EBV T cell, the EBV CAR T cell is we're seeing less cytokine burst. Now, I think endemic to the way you make autologous CAR T is you're activating in a polyclonal fashion every T-cell in that patient's body. If this is an autoimmune patient, not sure that's a good idea. In other words, you're saying if you have any autoreactive T-cells, we're going to activate all of them regardless, put CAR into them, put them back into the patient. What we're saying is maybe that's not good. Maybe allo has an advantage because you can curate and refine and choose your donor T-cells for the right profile to address that safety issue. I think honestly it's two things. It's safety for the patient.
It's efficacy, of course, and then obviously accessibility. If this disease indication is 300,000 or a million, if you go into all B-cell mediated diseases, auto can't do enough starts. Allo will figure that out.
Okay. Fantastic. I guess if the data are good and everything sort of works as planned, what do you envision the regulatory kind of path being? I know that's just an impossible question to answer without seeing and having kind of efficacy data to sort of inform that. But kind of your expectations now, what is the path forward and could that be different in the various sort of lupus cohorts that you're testing?
I think it'll be different from oncology because what we're talking about is not a life-threatening situation. So I think the bar in oncology, and I say this not in a cavalier way, could be lower because you're talking survival. When you're talking about the quality of life of a patient, I think physicians and patients and payers are going to look very carefully at efficacy, cost of goods, and then lack of side effects. And so that might really require a smarter way to develop these drugs in pivotal. They might ask you to go against physician's choice, whereas pivotal CAR T is really kind of an open phase 2. So I think it's going to be much more complex.
Okay. If there's any questions in the room, jump in any time. But in the last few minutes, I want to move over to one of your pipeline assets, ATA3431. Talk about that asset.
So 3431 is a dual CAR. It sees CD20 and CD19. What we've seen as the base build in auto is it's broken through the ceiling of efficacy that you see with CD19. Early data, at least from AbelZeta, says 90% response rate, 73%-75% complete response rate. It's amazing. It's going to be game changing. We think that this could possibly supplant the CD19 CAR Ts because you're seeing both antigens. You're not going to see antigen escape. However, then you circle back to, oh my goodness, how do you make enough T-cells? That's why I think it's awesome that there's autologous data, but then it raises the question, how do you get this drug to patients? I still think it's allogeneic. I think it's a cost of goods.
I think instead of scaling in a linear fashion, you're saying, no, no, no, we're going to reset this paradigm. Instead of the space shuttle, which is $2 billion per launch, right? You're going to go like SpaceX, eight launches in six months. It's a very different business model.
Fantastic. And just for context, AbelZeta is a Chinese company, right?
Yeah.
This is CD20, CD19, autologous CAR T.
That's right.
We've seen data from myeloma, lymphoma. They actually are, I think, are positioned to have lupus data next year. So we're looking forward to that. What are your plans for this asset? Do you have a sense yet or do you want to see the first asset, kind of what those data look like? But is this going to be an oncology asset?
We think that it makes the most sense in oncology. And I talked to the management team, Eric, our COO. We're thinking if we could partner, we could accelerate development. We don't want to do linear. I think if we do parallel, it could be really differentiated.
Okay. Fantastic. So Atara is probably best known for successfully developing Tab-cel. You mentioned Tab-cel earlier. Maybe talk about your current partnership and kind of the structure of that partnership with Pierre Fabre.
Fabre has been an amazing partner, so they're our partner of choice to commercialize in Europe, and they're our commercial partner in the United States. They're headed by a talented person named Adriana Herrera, who's the commercial franchise leader for Kite. So at BLA approval, we're transferring this program to Pierre Fabre to bring to patients in post-transplant lymphoma in the United States. What that helps us with is all these associated costs for a small company, all these commercial GMP levels of activity, these large expensive contracts. We are going to work with Pierre Fabre to transfer this to them, and then we pivot to become a CAR T company.
So this is really the transition of Atara saying, we brought this to patients, this amazing journey, the world's first allogeneic T-cell therapy, amazing safety profile, no really adverse events that we know are associated with the product, works more than half of the time. And now we can take this base build and now move into CAR T.
Okay. Fantastic. And would there be like a milestone payment or any kind of financial implications of a U.S. approval?
Yeah. So there's a milestone at approval, and there's certainly sales milestones and royalties associated. Yeah, and so we want them to be successful. We're working with them very closely, so it's a successful launch.
Yep. Yep. Okay. And then I guess assuming that, what is sort of the kind of cash runway that you're projecting?
So we're projecting two years of cash after the BLA approval. And we think that that's important for a small company. It gives you time to get your data and then have financial stability to make decisions to your point. Do you partner? How do you develop? How do you keep innovating?
So that gets you past the NHL readout, the lupus nephritis readout, the SLE non-lymphodepletion readout as well.
Yeah. Yeah. Into 2027.
Into '27.
That's the guidance.
Great. Okay. Any further questions? Well, it's been a great conversation. Thank you.
Thanks, Ben.