Welcome to our cell therapy conference, hosted by H.C. Wainwright. I'm Robert Burns, a managing director and senior biotech analyst at H.C. Wainwright. I'm joined today by Zach Roberts, the upcoming CEO of Allogene. Zach, thank you for joining us here today.
It's a pleasure to be here, Rob. Thanks.
Awesome. Allogene has been around for quite some time. For those who may be unfamiliar to the company, could you provide an overview of it, as well as its pipeline?
Sure. Yeah, we were founded in 2018. We've been focused almost exclusively during that time in oncology. We're a cell therapy company. We use healthy donor-derived allogeneic cell therapies to treat patients with relapsed/refractory cancer. We also recently launched an autoimmune program, ALLO-329. Our lead program is a pivotal phase II in first-line consolidation for patients with diffuse large B-cell lymphoma who complete first-line therapy, undergo MRD testing, are found to be MRD positive, and then receive a dose of cema-cel in consolidation or adjuvant. We also have an interesting phase I in metastatic renal cell carcinoma, for which a paper will be released soon.
Okay. Thank you for that overview. Before we dive into the pipeline, given your upcoming appointment to CEO, can you talk a little bit about your strategic vision and priorities for the company, and where they might differ from your predecessor?
Yeah. I joined the company as head of R&D and chief medical officer in 2023. I was tasked at that time with taking a look at our portfolio and our pipeline and really beginning to think strategically about how we could shift the pipeline in its direction to more closely align with the product attributes that we were developing, namely off-the-shelf, immediately available cell therapies for patients who had needs for these advanced products. Really out of that effort came the ALPHA3 design, which was and continues to be a very novel clinical trial strategy, the ALLO-329, world's first dual targeting CD19, CD70 product for patients with autoimmune disease. We continued to push our renal cell carcinoma program forward. You asked how much is going to change.
I will say that we are absolutely focused right now on execution, particularly in that cema-cel first-line pivotal program. That is undoubtedly not going to change one bit. In fact, we're doubling down on that. My vision for any changes as CEO will likely be more subtle, and we'll be looking for opportunities to advance our pipeline. We've recently shared some data on a preclinical program using a BCMA CD70 dual targeting CAR, building out this Dagger platform that really forms the foundation for our pipeline. I think probably the word of the day is continuity here. I've been so tied into the design of our strategy that really my focus is going to be on executing that strategy and then looking for ways to optimize along the way.
Okay, perfect. Why don't we start with cema-cel, since it is your lead asset. Obviously, there's some EFS data that's going to be coming next year. Why don't we first start with the trial design and the powering associated with that trial?
Yeah. The trial design, as I said, is a very innovative design, and I think we're starting to see more examples of this type of a design sort of proliferating across the oncology space. At the core, it's a study that is designed not to treat relapse disease, but actually to prevent relapse from occurring in the first place. What's novel about this design is that we are allowing patients to receive whatever first-line regimen for their lymphoma that their doctor thinks is most appropriate. Most patients will achieve a remission, even to the standard workhorse of the day, which is a regimen called R-CHOP. Most patients, about 90% or so, will achieve a remission to R-CHOP. However, about a third of those patients will eventually progress.
Right now, despite all of our advanced diagnostics, we don't really have a good way of picking out as part of standard of care who is going to relapse and who is going to be cured from their lymphoma. Well, that's all changing now, we've got now this new class of tests called minimal residual disease, which are highly specific blood tests that can pick up tiny traces of residual lymphoma in the patient. If that is detected at the end of first-line treatment, that patient is at extraordinarily high risk of having a relapse, usually within just a few weeks to a few months.
ALPHA3 is the first of its kind in lymphoma, what we're doing is when we're conducting one of these MRD tests for these patients, if it comes back positive, those patients are allowed to come into ALPHA3, then they're randomized to the current standard of care, which is continued watching and waiting, observation. They get a dose of cema-cel, which is our off-the-shelf CD19 CAR. The goal of the CD19 CAR in this context is to mop up or eradicate that residual disease and hopefully cure the patient and prevent that relapse from ever occurring. That's the high-level study design. 220 patients will be randomized, 110 into each arm. It is a pivotal design, discussed with the FDA back in 2023, 2024. We're extremely excited about this.
The study, as you asked, is powered to detect a 50% reduction in the risk of event-free survival events, which is the primary endpoint of the study.
All right, perfect. Obviously this is a pretty unique population. You guys sort of pioneered this sort of trial design here. Given the uniqueness of it, can you discuss the current rate and trends of MRD testing within the market broadly, both in an academic and community setting context? How should an investor be thinking about this market opportunity?
Yeah. What I think we're seeing right now, which is what we hoped would occur and what we believed would occur when we launched the clinical trial two years ago. Some argue internally that maybe we were ahead of our time, and of course, I accept that accusation. I think we were ahead of our time just by a little bit. Right now we're seeing really an explosion of MRD utilization across the board, both in the context of clinical trials, but also just for routine monitoring of patients. The additional prognostic information that these tests offer to patients and doctors is quite an advance in the field. It's much better than any imaging test that we can use. Patients are requesting this increasingly. We're seeing explosive growth in the lymphoma market right now for the currently available commercial tests.
Quarter-over-quarter, significant growth, 10%, 20%, 30% sometimes quarter-over-quarter. We're also seeing the rest of the world sort of adapting to this. Just last month, actually, we saw the world's first drug approval for atezolizumab or TECENTRIQ in the context of MRD positive muscle-invasive bladder cancer after definitive first-line therapy, which in that context, of course, is surgery. That was based on the IMvigor011 trial, which read out last year as very positive for both disease-free survival and overall survival. Just this week, the NCCN guidelines were updated to offer a Category 1 recommendation to test for MRD in muscle-invasive bladder cancer. Similarly, we've got a Category 2B to use ultra-sensitive MRD tests in diffuse large B-cell lymphoma in the context of an ambiguous PET scan at the end of first-line therapy.
We are seeing now evidence across the board of utilization and uptake of minimal residual disease testing as part of everyday care. The second part of that question is about the market opportunity. This is a market that is growing rapidly, and the vision of the ALPHA3 study was actually to position access to these life-saving medicines, this modality, CAR T cells, to patients who needed them as early as we could and wherever they received treatment, and that second part is really critical. 80% of patients in the U.S. receive their first-line care in community oncology practices. Those patients generally do not have access to autologous CAR T if and when they relapse. In the ALPHA3 study, we are finding these patients in the community or in academics, wherever they happen to get their first-line care, but the majority are in the community setting.
We're finding these patients, we're running this MRD test, we're identifying these ultra-high-risk patients, in ALPHA3 because we have this off-the-shelf product, we can actually bring that product to the patient in their community practices without the need for referral. Our vision for the market opportunity here is fairly large. We will be able to capture a substantially larger percentage of patients who will eventually need second-line treatment well ahead of the currently available second-line salvage regimens. In our estimates, based on our commercial analysis, which included feedback from both academicians and community oncologists, that this opportunity would be about $2.5 billion-$3.5 billion between the U.S. and the EU Five. A fairly sizable opportunity here.
Yeah. No, that sounds great. Not too long ago, you released interim futility data from the ALPHA3 trial. Can you walk us through that data as well as its potential read-through to the interim EFS analysis that is expected in 2027?
Yeah. We were really excited about this interim data. The study was prospectively designed to have an early look using MRD clearance as a surrogate endpoint for efficacy. We wanted to ask the question, does a consolidation dose of cema-cel for these patients with MRD-only disease, does it bring value? Does it actually put them into that lower risk category of an MRD negative patient? Of course, we wanted to also understand the safety. That was really what this futility analysis was designed to check. We looked at 12 patients in each of the two arms, cema-cel versus observation. What we found was that in the treatment arm, the patients who received cema-cel, and these were all very high-risk patients by all the traditional measures by which we assess risk in diffuse large B-cell lymphoma. These were real lymphoma patients.
We saw a 58.3% clearance of MRD. Seven out of 12 patients cleared their MRD. Almost all of them did so by the very first time point that we looked at the MRD clearance, which was day 45 post-randomization. In contrast, the patients in the observation arm, only two out of 12 of those patients cleared their MRD, which is about what we expected to happen. We do expect some rate of natural clearance of this. That was 16.7%. By the day 45 time point in those patients, we were already seeing evidence of molecular disease progression. As expected, these patients, if they're left alone, by and large, will proceed towards a disease progression or a relapse event. Equally as exciting to the efficacy data was the safety data.
We expected treating patients with low disease burden would lead to better safety outcomes than traditionally as seen with CAR T. Even we were surprised at how well-tolerated it was in this first group of patients. We saw zero cases of any grade CRS, zero cases of any grade ICANS. We had no high-grade infections. No patients needed toci. No patients needed steroids either before or after treatment. Critically, there were no patients who needed any hospital stay for any treatment-related adverse events. This really does illustrate the utility of treating patients at the right moment, before they have a disease relapse, and then in the right place. That's the last piece that I'll share on this interim data. As I mentioned, we've got community practices open in the study right now. About half of our clinical trial sites are community practices.
Fully a third of the infusions of cema-cel in this interim analysis were conducted in community oncology practices, including in some centers who had never given a dose of CAR T in their history.
We are validating the vision here of bringing access to CAR T to patients in the community, doing so safely, and hopefully with an ability to improve their prognosis, and ideally cure their disease.
No, I must say, when I saw that data, I was really happy for patients. The option that cema-cel will actually provide to these patients. It really does clear that 25%-30% benchmark where you start to see this really significant EFS trend, at least based on historical studies. It seems like that cema-cel is going to clear that by leaps and bounds.
Yes, absolutely. Thank you for mentioning the 25%-30%. As we were heading into that analysis, we sort of had to pull together what is the I mean, obviously, we had some benchmarks in the protocol itself.
Yeah.
That was really more oriented towards futility. We really wanted to see beyond that. We arrived at this 25%-30% based on a broad array of the MRD data and how it correlates to long-term disease outcomes. When we saw that delta of 42%, you're absolutely correct, that really did fill us with confidence that we're on the right track here.
Yeah, no, I completely agree with you there. I know the interim futility data analysis is going to occur in 2027. Any more clarity as to when in 2027? I know it's an event-driven.
Yes.
Endpoint, so kind of hard to pin down exactly when. Do you think it's first half, second half, middle of the year?
Yeah. We've been saying middle of 2027, I'll reiterate that here. I do want to also add that this is an ongoing pivotal study, our first and most important goal here is to make sure that we don't do something that is going to jeopardize the approvability of this package. We really do see this as a practice-changing opportunity. As that date approaches, we will be extremely mindful about what we can share from that data set.
Okay. Obviously, ASCO and EHA just wrapped up not too long ago. Coming out of those conferences, I want to get your thoughts on a few topics. Obviously, the frontline opportunity in LBCL, how it might evolve over time, given the data that we saw from rapcabtagene autoleucel, the CD25 specifics, as well as the Frontline trial.
Yeah. It's an exciting moment for lymphoma. I think there's a lot of new novel therapies that are coming to the fore. You certainly mentioned several. I think the second-line products are quite compelling. Watching that space develop, of course, we would slot in ahead of second line. The question really is about first line, as you asked. Frontline was the first real pivotal readout that we'd seen from a number of ongoing phase III's in that space. My takeaway was that it looked like it could be beneficial for a certain subgroup of patients. However, similar to a lot of those other frontline therapies, including those that are based on the T-cell engagers, the toxicity profile, I think, did turn a few heads. That is probably not going to be appropriate for all patients in all centers.
This probably goes for the T-cell engager-based regimens as well. Maybe in academic centers, maybe in patients that are really, really high risk, there may be an opportunity to treat some patients with a significantly more complex and toxic upfront regimen. For the most part, most of these patients get treated in the community. Most community doctors don't want to deal with the hassle and the toxicity of having to admit a patient in the middle of a busy clinic day. They're going to continue to use the two available regimens now, R-CHOP and Pola-R-CHP, by and large. We expect.
Yeah.
those MRD rates to be roughly consistent between now and the years to come, which means that our market opportunity here will be quite preserved. Furthermore, we have a nice moat around this opportunity, too, because it's really hard to replicate what we can do with an off-the-shelf CD19 CAR with a bispecific, with an autologous product. I think we're pretty well-positioned here, even with that sort of advances in the first line.
Okay. We've seen a lot of enthusiasm around in vivo CAR T as well, and we started to see some data from Kelonia over at ASCO. Obviously we saw the data from LB2501, CD19, CD20 in vivo CAR T. Wanting to get your thoughts on that data set specifically, how you view this novel technology as a competitive threat, and where does allogeneic CAR T sort of fit into the treatment paradigm if in vivo CAR T proves successful?
Yeah. We were watching the in vivo space very closely, and I think we've got a long way to go there. I think most folks that I talk to, no matter their background, whether they're coming from academia, whether they're coming from big pharma, most of us acknowledge that this is going to be a five-plus year journey before we start to see some of these products get approved. There's still lots of questions around safety, particularly in the viral-based in vivo, both of which of the products you just mentioned are LVV based. We haven't seen any really bad outcomes yet, and I hope for patients' sake that we never do. Knowing, as I do, these vectors, they can integrate all throughout the genome, and depending on where they land, that can cause problems.
With respect to specifically ALPHA3, our analysis is, and based on extensive conversations, is that this is probably never going to be a product that is used in a patient who's in remission. Right? The patients that we're treating right now are in remission. They're MRD positive. They're relatively lymphodeplete, having just completed 6 cycles of combination chemoimmunotherapy, so they don't have a lot of T cells to transduce if you were to give an in vivo.
Yeah.
CAR T. Furthermore, the risk tolerance here is very low. These patients are in remission.
Yeah.
Getting admitted for an infusion-related reaction, or God forbid, you end up with a secondary malignancy, this is not something that's compatible with somebody who has been told that they were likely to be cured with frontline R-CHOP. They're going to want something that they can get outpatient, they can go home, they can be reassured that they're not going to be admitted to the hospital, and that they can receive in the community. I just do not see a world in which community oncologists are regularly giving in vivo CAR T. The safety risk there is just not compatible with a busy oncology practice.
Okay. No, that's a great analysis, and I completely agree with you. The lentiviral-based vectors, they definitely have that risk of secondary malignancy. I think that obviously we've seen a shift for a lot of cell therapy players into the autoimmune space. I don't think in vivo we'll see in vivo CAR T in that space either, at least if it's lentiviral-based.
Yes, I agree.
Given that massive shift for a lot of cell therapy players, why don't we shift gears now to ALLO-329, and what advantages this agent possesses against other cell therapies that are being evaluated in that setting, and more importantly, the other allogeneic cell therapies that are being developed there?
Yeah, thanks for the distinction there. Right out of the gate, I think allogeneic cell therapies have an advantage in this context in autoimmune patients. These patients across the board, of course, are on everyday immunosuppressive regimens, quite powerful ones, and there are risks with taking those patients off those regimens, and what you need to do in order to collect cells to manufacture an autologous product. They have to go back on their therapies, and they have to taper back off in time for infusion. Not having to do that with an off-the-shelf product I think is a huge benefit to patients. I totally agree that allogeneic is the ideal product profile for autoimmune patients. What makes ours stand out? First and foremost, we are the first dual-targeting CD19/CD70 CAR.
We have both the CD19, which of course, is there to modulate the B-cell compartment, but the CD70 is there for two reasons. First is that CD70 is upregulated, is expressed on both B and T cells that cause autoimmune disease. It's known that patients with treatment-resistant lupus and scleroderma have a much higher fraction of CD70-positive T cells in their body. Those ones are likely the ones driving the pathogenesis there. We're the only CAR T, auto or alo, that actually has a path to eradicating pathogenic T cells. That's the first reason why we included CD70. The second reason, which I think is even more exciting, is that it brings this Dagger technology to the product. By Dagger technology, what I mean is, we know that allogeneic cells like ours stimulate an immune response in the patient who receives the CAR T cells.
They're recognized as foreign, and that's by design. We want the patient's immune system to reject these cells eventually. Once the job is done, you don't want any CAR T cells in your body. This is a feature, not a bug. However, we need them to persist for long enough to do the job. When the patient responds to the CAR T cells with an immune response, those T cells also turn on CD70. When they do that, our product is able to recognize those cells as targets. They kill the patient's T cells that are trying to reject the CAR T cells, and thereby they give a growth stimulus to the CAR T cells.
In a manner of speaking, these cells bring with them the lymphodepletion that cell therapies need, that gives us a path to eliminating or reducing the chemotherapy-based lymphodepletion, which is almost across the board, part and parcel with CAR T cells. We knew ahead of time that we needed a product that was going to be easily available, off the shelf, and was not going to require high-intensity chemotherapy, which these patients and doctors just flatly will not use on a regular basis. We stand out in quite a number of ways with ALLO-329.
Perfect. When we think about the allogeneic space, in particular with regard to I&I, we've seen some data come out of Fate, right? They've got the sword and shield technology. They're also going with a less intensive lymphodepletion regimen. They also have the opportunity to potentially go lymphodepletion free. I'm sort of curious how you view them as a competitor.
We're seeing Fate tinker with the lymphodepletion regimen, which I give them a ton of credit for. We're also seeing some other peer companies, including some autologous companies, that are just dropping the lymphodepletion and giving the CAR T cells and seeing what happens. I think that that is validation of our original view when we set out on this path two years ago that chemotherapy lymphodepletion is a problem. What's different about what we did, a path we took, was that we engineered our product with a specific mechanism of action to alleviate the dependency on lymphodepletion, whereas these others don't have that. Maybe Fate, as you mentioned, their sword and shield, maybe there's some angle there.
Setting all that aside, I will say that I'm actually fairly encouraged that some of the long-term disease control that we're seeing, at least for the first few months, in patients without lymphodepletion is possible.
Yeah.
Even if you don't include something like the Dagger technology. I think that bodes very well for our product as we continue to do our dose escalation study here.
I completely agree with you. I know that we're expecting update from that dose escalation portion in the fourth quarter of this year. Can you help frame investor expectations around that data set?
We mentioned at our last quarterly that we have been enrolling this program extraordinarily quickly. We had dosed, at the time of the call, nine patients, and that was after our first patient was infused in November of last year. Nine patients in just under six months of enrollment, we are extraordinarily pleased with how well this enrollment is going. We are very much excited about this Q4 update. We should have, of course, those nine patients. We also had disclosed that we started our dose escalation at 20 million flat dose CAR T cells. Again, this is a low dose, very low dose compared to our peer companies, and that's because of this Dagger technology driving the intrinsic lymphodepletion and in vivo expansion.
We've gone to 40 million, now we're at 80 million, and we've got some room to go still on the dose escalation. We'll be sharing all the patients that we've treated up to the date when we release the data in Q4, clinical efficacy, clinical safety, and then of course, a fairly robust translational package, looking at things like B cell depletion or suppression, CAR T cell PK and so forth.
Okay. No, that's perfect. You did also release earlier this year some preclinical data for a BCMA CD70 targeted agent. Obviously you've got CD19, CD70, ALLO329. When we think about the future development paths of these two agents, where do you see the differentiation from an I&I perspective? Obviously BCMA is also a validated target to go after certain autoimmune indications. I want to get your thoughts there.
Yeah. It's a great question, I think the field is still sorting out which diseases are better treated with a CD19 targeting agent versus a BCMA CD19 or BCMA targeting agent. We have been working on this because number onee, it's a clearly validated target.
Yeah.
There is now growing evidence that in certain very strongly antibody-driven diseases like myasthenia gravis, for example, that targeting the antibody-producing plasma cells is a very rational strategy. However, I think that there's still quite a lot to learn about the overlap or lack thereof of CD19 and BCMA. It was very prudent to us to have both tools in our toolbox as we continue to move forward in this new and massive opportunity at autoimmune disease. Once we've established proof of concept with the LO329 product, that would, I think, give us some strong justification to move forward in additional indications, both with that product, but also potentially advance the BCMA CAR into yet additional opportunities.
Perfect. I guess last question from me. Can you remind us what your cash was on hand as of end one Q, what the operational runway it provides?
Yeah. We have a cash runway now into 2029. As you know, we also just recently raised about $200 million on the back of the interim futility data.
Yeah.
This will give us enough data to move all the way through these upcoming catalysts.
Awesome, Zach. I really appreciate you taking the time today. Can't wait to see the dose escalation data for 329 later this year, and then the EFS analysis potentially in the middle of next year. Great stuff coming out of Allogene, I must say.
Thanks, Rob.
All right. Awesome. I'll talk to you soon.
Okay. Take care.