Good morning. Thanks for joining us for another session at the 42nd J.P. Morgan Healthcare Conference. I'm Brian Cheng, one of the senior biotech analysts here at the firm. I'm joined by my associate, Sean Kim, who's in the audience. On stage, we have Allogene CEO, David Chang. I'll pass the mic to David briefly for a short presentation, followed by a live Q&A. If you're joining us live, you can submit the questions for the team through our conference portal. David, the stage is yours.
Hey, Brian, Happy New Year, and thanks for having me on the podium today. For those who are in the audience, thanks for interest in what we are doing at Allogene. You know, legal disclaimer. You know, this is the beginning of the year, and this year, we have made some very important announcement about how we are redirecting our development program..
The four components of the announcements are: one, advancing our lead program, cema-cel, cemacabtagene ansegedleucel, in the first line, large B-cell consolidation. And I'll go a little bit more into the details of how we intend to do that and why this is the right time to do that.
The second announcement is expanding our cema-cel program into leukemia, CLL, where there appears to be a growing unmet medical need in patients who have previously been exposed to BTK inhibitors as well as BCL-2 inhibitors. The third important announcement, and this is a preclinical program that will go into the IND in early 2025, is advancing ALLO-329 into the autoimmune indication.
This is a dual CAR construct that can target CD19 as well as activated T-cells, which we believe will address the, you know, the pathogenic B-cells and T-cells, which are critical components of any autoimmune diseases. And we also provided updates on what we are doing with ALLO-316 in the renal cell cancer, where we are trying to fine-tune the recommended doses that we can advance to the dose expansion as well as potential Phase II indications.
One thing that we also like to emphasize is that, you know, Allogene has made a lot of investment, you know, on the manufacturing infrastructure, and we have a state-of-the-art manufacturing facility, which we call Cell Forge 1. We will continue to focus manufacturing of our product candidates at the Cell Forge 1 , which we believe is a quite distinct strategic advantage as we advance these multiple programs in the clinical setting. So now, let's talk about ALPHA3.
This is a very differentiated approach in how we can advance the development candidate into the frontline large B-cell lymphoma. Just in the setting, you know, everybody who's developing drugs in the large B-cell lymphoma wants to move into the frontline setting. But this is also the indication or the setting where the existing treatment, R-CHOP, Pola-CHOP, you know, is really addressing the need effectively.
But we believe that this is right time to advance our cema-cel program into the front line, having demonstrated complete remission and durable responses in the refractory setting, where, you know, in a much harder to treat refractory setting. And also, we are leveraging with our partner, who is developing a very sensitive and specific diagnostic assay that will identify patients who are destined to progress at the completion of the R-CHOP treatment.
We also believe that this is the right approach, offering, you know, immediately available therapy, and also, we intend to advance this program focusing on clinical trial sites that represents the community cancer centers, which really opens up the use of CAR T that currently is limited to the tertiary centers.
You know, in terms of, you know, the enabling factors is the data that we have generated in the refractory setting. This is a very hard-to-treat patient population, where our studies, including the data that we have presented last year's at ASCO meeting, have shown very convincing complete remission rate.
So what's shown here in the red box is FCA90 Alloy. FCA90 represents the lymphodepletion regimen that we are using. Alloy is the manufacturing process that we, you know, use to manufacture cema-cel in this program. We have shown the overall response rate of 67 and impressive complete remission rate of 58%. And the complete remission is also durable, you know, and at 6 months, 42% of treated patients continued to be in complete remission. Also notable is you know, the adverse event profile.
It's a small, you know, set of data, but cytokine release syndrome and neurotoxicity events, which is well-known adverse events of the CAR T therapy. We haven't seen any grade three events, and also the infection related to the treatment is relatively modest at 8%.... Just for comparison, we have also listed this slide what the autologous CAR T has shown in the similar patient population.
Another thing that's really, you know, very innovative that's allowing us to do that is advancement in the in vitro diagnostic assays. One of the challenges in the frontline large B-cell lymphoma is that the existing standard of care is very effective, and trying to develop a drug on top of an effective treatment is a very challenging situation that sometimes requires very large clinical studies.
What we are leveraging is the beauty of this in vitro diagnostic assay. It's a next-gen sequencing that allows identification of minimal residual disease at the completion of the frontline treatment with the six cycles of R-CHOP. The assay provides about 500-fold increased sensitivity to other currently existing assays, such as ClonoSEQ or CAPP-Seq.
Also impressive is that when the patient who are tested negative by this MRD assay, when you follow those patients, essentially none of those patients have a recurrence. However, if you test positive, those patients, approximately 90% of the patients, do progress within first 3 years of the follow-up. When you look at the red curve, which represents the patients who tested positive to MRD, the rate of recurrence is relatively quick.
You see a very sharp drop in first few months after the completion of the R-CHOP treatment. When we estimate the median time to progression, it's coming to somewhere between 6-12 months. This, you know, what this allows us to do is really relooking at how we can think about the treatment in the frontline setting.
What's shown as a first-line treatment on the left is the current standard of care. Once the diagnosis is made, patient undergoes six cycles of R-CHOP. Majority of these patients have a favorable outcome. There are some patients who, you know, progress through the R-CHOP, and they go straight into the second line. But among those patients who have a favorable response, when you follow them long-term, the outcome is quite different.
Two-thirds of the patients, or 60% of the original patients, continue to have the remission. In essence, they are cured, and they do not need any additional treatment. The other 30%, while, you know, you consider them to be having a complete remission or a very good partial response, when you follow those people, they recur.
And these are the patients that the MRD assay that we are working with our partner, Foresight Diagnostics, is allowing us to, you know, identify. So what really, you know, that results in is focusing the first-line treatment with the cema-cel in this patient population that are destined to have a disease relapse. And the plan is to start enrolling patients in to this potential pivotal study in the middle of 2024. Study activity is already underway.
The initial plan is to randomize patients 1-to-1-to-1 into three different arms. One is the observation. This will be the standard care, which is essentially watch and wait, while you follow the patients with periodic radiographic scans to see how their disease is doing. The other two is a treatment arm.
Two arms are different by the use of different lymphodepletion regimen, but they both get, both arms gets the cema-cel treatment afterwards. We intend to enroll small subset of overall study into this initial, you know, three-arm design, with a plan to select the lymphodepletion, which we project to occur in the first half of 2025. From that point on, the study will proceed as a 1-to-1 randomization into observation and selected lymphodepletion.
The way that we foresee how we're going to select the, lymphodepletion is based on the conversion of MRD positive, which is the enrolling patients and treated patient to MRD negative state, as well as some safety considerations.
The primary, analysis, endpoint that we'll be using at the end of the study is event-free survival by the, blinded independent, central review, as well as using the secondary endpoints of progression-free survival, as well as overall survival. The study, intend to have approximately 110 patients into the key observation and the, in the treatment arm, and, we, you know, will provide further updates, as we start the study in the middle of 2024.
Study is designed as a seamless and very efficient design, which will accelerate both enrollment as well as the data readout. Now, you know, what that's allowing us to do is really looking at the LBCL population and the patients that could be addressable with this approach.
When you look at the U.S., you know, there will be about 34,000 first-line drug-treated patients, and approximately 30% of those patients will progress after the frontline R-CHOP treatment. We believe that patients who will progress can be identified by this MRD assay, and the data supports that assumption. And we estimate that about 75% of the patients will undergo the testing.
That leads to a potential 7,700 patients who could be treated with cema-cel, if pending the data outcome, representing approximately $3 billion of revenue potential. And why does it matter? I mean, this is really, you know, what we see as a paradigm shifting in how we think about development of allogeneic CAR T.
Thinking differently, not just following the development of autologous cell therapy, but really re-leveraging the advantages of the allogeneic. What's shown on the left is the growth of autologous cell therapy in the non-Hodgkin's lymphoma. Third line alone had a revenue of about $500 million. When the second line approval came in, there was in a very rapid adoption, but the most of the growth was happening in the second line, and there was no very limited growth in the third line.
We expect that pattern to continue through 2032. When the frontline approval, pending the outcome of the ALPHA3 study, you know, approach of using cema-cel in the consolidation is available, we expect that most of the use of the CAR T in the large B-cell, you know, will occur in the frontline consolidation setting.
Now, let me talk about the second program, CLL. CLL. What happened here? You know, 7-10 years ago, when you know, BTK inhibitors and BCL-2 inhibitors were introduced to the standard of care, that was essentially considered as a cured disease, where there was no development opportunities.
Investigators at the time was advising us to: "You know, CLL, I don't really see a development opportunity, you know, with a CAR T." 10 years later, as these patients who are not cured with a BTK inhibitor or a BCL inhibitor treatment, you know, progress, the same investigators are coming to us saying that there is a need for more effective treatment in CLL patients after BTK inhibitor and after, BCL-2 inhibitor therapy.
So there is a growing need, and we believe that this need can be particularly well addressed with the allogeneic CAR T that does not depend patients on T-cells, which are in a very immuno, suppressed environment. And the studies have shown the patient-derived T-cells from the CLL patients do not function well. Those problems can be addressed by using the allogeneic cell products manufactured from the healthy donors.
The market opportunity in the CLL, you know, we foresee to be, approximately, you know, $3 billion, and I'll go a little bit more into how we come to that, that estimate. The study design, you know, we are also leveraging, you know, our current clinical trial footprint, or the same sites that we are using for the treatment, of non-Hodgkin lymphoma, because the physicians are also treating the CLL patients. We will introduce another arm into our ongoing ALPHA2 study to really, efficiently move into the CLL. Our plan is start enrolling CLL patients in the first quarter of this year, which can potentially lead to the readout of the phase I data by the end of this year.
Pending on the outcome of the data, we plan to advance the program into phase II, which can be a potentially pivotal study. In terms of the patient estimate is listed here, there are approximately 22,000 patients who are treated for CLL in the first-line setting. The second-line number, as well as third-line numbers, are also included here.
The target patient population is third line, who have received both BTK inhibitors and BCL-2 inhibitors, or second-line patients with the high-risk features who have received BTK inhibitors. And that leads to a total of 7,500 addressable patient number per year, leading to a market potential of $3 billion. Now, something that we have been alluding for some time is what we're gonna do in the autoimmune indications.
I think many of you are aware, with the data coming with the CAR T in autoimmune disease indications, which is really tantalizing. The autoimmune drug development has been really driven by, you know, being able to modify the disease and stop the progression of the, of the disease.
What the CAR T has shown is a paradigm shift in how you can manage the patients with autoimmune, not just modifying the disease, but resetting the immune system so that one-time treat can provide a long-term, put the patient into the long-term remission. This is a really tantalizing, and that can really, you know, data that can really, expand the use of CAR T in different indications. We believe that, ALLO-329 provides the right product attributes. As I've said previously, ALLO-329 is a dual CAR targeting CD19 as well as CD70.
which endows the product to go after both pathogenic, B cells as well as T cells. Another unique feature of the ALLO-329, comes from the fact that it has a CD70 component, which has an intrinsic lymphodepleting ability, which allows the allogeneic CAR T cells to expand well, as well as potentially, you know, reducing the lymphodepletion requirement, which we consider to be one of the biggest barrier of advancing the CAR T into the autoimmune indications. So let me talk a little bit about this unique features of, you know, ALLO-329, which comes from our CD19/CD70 program that's already being studied in the renal cell cancer.
What's shown on the left is, you know, I'm a bit of a scientific science geek, so I have to show the flow diagram, but this really illustrates that the CD70 CAR can go after activated T cells. Probably more important is what's shown on the right side, which is looking at the CAR T expansion kinetics.
What's shown in number one and number two is administering ALLO-316 in patients with a renal cell cancer with two different lymphodepletion, both of which gives a much better cell expansion than what we have observed in other allogeneic CAR T. And this is attributed uniquely to the Dagger effect that comes from the CD70.
The kinetics on one and two also shows is that cell expansion is a little bit better, especially when it comes to persistence, when we use the lymphodepletion of FC that contains also ALLO-647. But even without ALLO-647, which is shown as number one, FC lymphodepletion alone, we get very robust cell expansion, couple logs of magnitude better than what we have seen with ALLO-501A, and this is the unique biology of the Dagger technology. So as you know, the autoimmune indications, much of focus is in the lupus nephritis, where, you know, much of the data has become available.
But when you think about autoimmune indications, where autoantibodies play a big, a big role, the indications now starts looking, you know, much broadly, and that includes a myositis, and there's also some CAR T data suggesting that it works in myositis, systemic sclerosis, multiple sclerosis, myasthenia gravis.
What's captured here is the indications that are potentially addressed by, you know, CAR T therapy, whether it's targeting CD19, and probably better when you're targeting both CD19 and CD70. And what we believe the unique attribute that our ALLO-329 can bring is one single infusion that allows the resetting of the immune system that has already been shown with autologous CAR T, and we can make an inference based on what our ALLO-501A program has done in the non-Hodgkin's lymphoma. We believe that we can do the same.
Now, the unique attributes of the allogeneic approach is it's the off-the-shelf, on-demand. We have shown that it provides the scalability and economics, where we can manufacture the cells in large scale and in a much more cost-effective way. It also allows ability to manipulate the genes in a more complex, gene engineering approach, empowering the CAR T cells to do more than one thing, as we have shown with the dual CAR approach.
Probably equally important in this setting is the need to bring the therapy to the outpatient setting, as well as being able to investigate the ability to have the same kind of immune resetting of outcome with a simpler lymphodepletion. And we believe the Dagger component of ALLO-329 brings this possibility.
Our plan is to advance this program, and currently we are involved in the IND-enabling manufacturing process and analytic assay development. We plan to submit for the IND to initiate the clinical study in autoimmune indication in the first half of 2025, and pending the pace of the patient enrollment, potential clinical proof of concept could be available by the year-end 2025.
The last thing that I want to talk about is what we are doing in the renal cell cancer. We have ALLO-316 that we have been studying in renal cell cancer. This is a solid tumor, which remains, you know, one of the, you know, you know, still yet to be untapped area, the opportunities with the CAR T. We believe the time is right.
I think there is a growing evidence that targeting a single, you know, going after a single target with a chimeric antigen receptor approach can provide durable remission in some patients with solid tumors. We also believe that, you know, ALLO-316 program provides a very unique opportunity, as we have shown in the early data, where we have seen approximately 30% response rate in patients with CD70-positive renal cell cancer. And also, as I've shown in the previous slide, with ALLO-316, we can achieve exceptional cell expansion and persistence, which we believe is critical to effectively manage the solid tumor.
So this is a program, you know, ALLO-316 is a very active molecule, and what we are doing is, in a phase I study, continuing to refine the lymphodepletion and cell dose, trying to find the right therapeutic index. And we definitely have seen some hyperinflammatory responses after in patients who received ALLO-316, and we have developed a treatment algorithm that we are currently testing in the clinic.
So, you know, giving some more details about what we have seen in ALLO-316 is on this slide. As I've said, in the CD70-positive tumor, we see approximately 30% response rate in a patient pool of 10 patients. Small number, but very tantalizing data.
Also impressive is what is shown on the bottom, a radiographic image of a patient with a large renal cell tumor that's shown as a bright irregular-shaped spot on the primary tumor on the left side of the kidney. I don't know whether I have a pointer. And the subsequent radiographic imaging done on day 28 and day 56 shows that significant reduction in the size of that tumor.
I just want to highlight, you know, this particular case, because in renal cell cancer, you know, most checkpoint inhibitors do not give, you know, that kind of dramatic tumor reduction in the primary tumor. And I think this really highlights the potential of what we can do with ALLO-316 in CD70-positive renal cell cancer.
So next step for the TRAVERSE step is, we will be updating, you know, what the safety algorithm that we have introduced to the, to the ongoing study, in the second quarter of this year. And towards the year-end, we will provide more comprehensive updates on the phase I study, and hopefully by then, we expect that the lymphodepletion and cell dose to be more finely refined.
The manufacturing facility, I think this is some of the key differentiation for any company that's in the CAR T space or cell therapy space. We have the state-of-the-art manufacturing facility that is fully operational. Not only that, we have a team of manufacturing operators that can do the process development as well as analytic assay development, which is key to advancing the programs into the clinics.
We will continue to leverage this, our unique, you know, ability to do all that, plus having our own manufacturing facility, as we expand our clinical programs. I have sort of talked about a lot of different events that is to occur throughout the year, but this slide really summarizes, you know, the data flow throughout 2024 and extending into 2025. Most important activity for us in 2024 is starting an ALPHA3 study, enrolling the patients, which we expect to occur in the mid-year, middle of this year.
Also at the same time, as I've talked about, we will be initiating enrollment of cema-cel into the CLL patients in the first quarter, with the expected data read out from the phase I study by the year-end. Also at the year-end, we'll be providing update on our solid tumor program of ALLO-316.
And 2025 gets even more exciting as we will provide more updates on what's happening with ALPHA3, which will include a selection of the lymphodepletion, as well as advancing our autoimmune program, ALLO-329, into the clinics. So with that, I very much appreciate your attention to the presentation, and I'm going to invite our head of R&D, Zach Roberts, to the front to answer any questions that you may have.
Great. We'll begin the Q&A session. For those of you who are, who are in the audience, if you have any questions, you can raise your hands. We have runner on the floor. For those joining us virtually, you can submit questions on the portal. So I'll kick off with a couple of questions. Just the last couple of days, you had really significant changes across your R&D portfolio.
Maybe just one is, you know, when you think about the... How long has it been, you know, when you, when you start thinking about this pivot to the frontline consolidation setting? I know that you have started the ALPHA2 in the third line for quite some time, I think in back in late 2022. What really drove that strategy change? I guess, why does it make sense to do it now?
Yeah, you know, I can answer that question, and I'm going to also ask Zach to further expand on that. You know, he really has been the mastermind behind the frontline strategy. When we started the third line study, we are already thinking about what is our path to the earlier line large B-cell lymphoma, and that thinking process has been going on for some time.
What's really enabling us to do that, you know, such a bold move, is really, you know, many different things coming in together... you know, our, you know, continued, you know, following of the patients who are treated in the refractory setting, and seeing the durability of response that we are seeing, and growing confidence that allogeneic CAR T works just as well as autologous CAR T in the refractory setting. That's number one.
Number two is really, you know, the development of, and essentially, the availability of the MRD assay. 'Cause our strategy is really centered on, you know, offering the cell treatment to only those patients who needs the treatment, and that MRD assay allows to do that. And with that, you know, we formulate, you know, different options and consider pros and cons, and come to our, you know, study design.
And throughout that, we were constantly getting inputs from the KOLs. Not just the KOLs from the tertiary centers, where the CAR T therapy is given, but also the clinical investigators and clinicians who take care of the patients in the community-based cancer treatment centers. And then last thing that we had to at least get some feedback was the regulatory interaction with FDA. Zach, do you wanna sort of add to that?
Yeah, I'll just add a couple of points. And, you know, at the beginning of this conversation, as we first were beginning to understand this new MRD test and speaking with those KOLs about what kind of an impact that test alone could have on the practice of care for these LBCL patients, it became quite obvious to us that this would open an opportunity for us to run a clinical study.
Again, focusing specifically on those patients who need additional care, because right now, we, you know, there's no way for us to know which patients are going to need more care and which are not. So what this test is allowing us to do is essentially see into the future and really focus that consolidation strategy on those patients.
So as that concept began to take shape in our minds and through conversations with regulators, it became quite, quite obvious that this is going to be a potentially practice-changing opportunity for us, and so, we really just, you know, took the idea and continued to push it, and here we are.
Yeah.
Any questions?
Almost uniform feedback from the KOLs and every clinicians that we have spoken with said, "This is the right study, and this is the right approach with the allogeneic CAR T." So, stay tuned.
Any questions from the audience? I guess conceptually, when you think about the first line, I think that there are two parts in it, that I think. How are you thinking about the receptivity around? You know, you're asking patients who are in complete remission after R-CHOP, 6 cycles of R-CHOP, to go on Cy/Flu, and also, well, plus 647, and then also 501A.
How receptive are they, are KOLs in terms of getting that piece in? 'Cause today, doctors are, you know, somewhat hand-waving around testing MRD after patients are in remission in R-CHOP. So can you kind of address those two points?
Yeah, I mean, great question. I mean, you have spoken, Zach. I'm gonna ask Zach to respond to both of those questions. I mean, I have to say that I've been involved in the clinical development for many years, but I have never encountered this kind of positive interactions with the investigators, where they're just as eager as we are to be involved in this study and really, you know, in a way, you know, take the whole management of the frontline Large B-Cell Lymphoma in a different direction.
Yeah, so again, the test allows us to foretell the future relapse. And so as you see those curves, the way that they are, a negative test means you're cured. You know, that means that likely you won't need to be followed as closely, fewer scans, et cetera. And if you're positive, it almost, it certainly means that you're gonna need an additional line of therapy.
So it takes the uncertainty out of that period between completion of R-CHOP and the initiation of second-line treatment. And furthermore, knowing that these patients really are teetering on the edge of cure, I mean, they're in a radiographic CR, but we know that they're going to progress, creates an opportunity to really push them into that complete remission using a seventh cycle of therapy. So yes, it is a shift in strategy.
We're not giving another dose of R-CHOP, but leveraging all of the experience in CAR T in chemo-refractory patients, which these patients are, and giving them an option at cure without ever having to experience a disease relapse event. This is a paradigm-shifting opportunity, and every KOL and every community oncologist is eager to implement this strategy.
So let's turn to autoimmune. I think over the past couple of weeks, we saw quite a few companies switching-
Mm
... into some shape or form of, you know, targeting CD19 into autoimmune disease. I think we saw Schett's data at ASH, more supportive for CD19 to go into this space. You're also heading into CD70 into that space as well. But the way you're shaping it, it seems to be more of a bispecific approach, CD19 and CD70. So, you know, you have that slide on persistent and expansion.
How important is expansion in your view, right? Given your platform here using the Dagger. You know, just based on what we saw with Schett's data, that's one. Lastly, of course, you know, the breadth of autoimmune is so wide, how do you kind of pick and choose which one to go for first?
Yeah, I mean, first of all, you know, I think, you know, that all these companies that's going into the autoimmune really highlights, you know, what a great opportunity this represent for the entire cell therapy. I mean, cell therapy so far has been, you know, limited to very refractory setting in oncology, you know, with you know, the large B-cell lymphoma and multiple myeloma.
But when you are, you know, sort of talking about expanding that opportunity in a very meaningful way, I mean, you are not just, you know, talking about another disease-modifying approach. You're talking about immune resetting. Any clinician who's sort of thinking about this will see this is, this is a worthwhile journey. So I, you know, I, you know, and so applaud all these companies moving into that.
But as you know, in a management of our company, you know, we view that, you know, in this kind of crowded setting, you know, differentiation is key. And also, autoimmune indication, you know, this is an indication that, you know, you don't just capture in a single study.
This is something that you have to think about, and you have to sort of plan out, you know, long-term perspective of how to go after one indication and continue to expand the use across different, you know, disease indications within the autoimmune. So that's what led us to really think about is, what is the target product profile that we should be aiming after? And, you know, and then how do we rationalize?
The most important thing was, you know, do we have a way—do we see a path to reduce the lymphodepletion? I think that was one, and that's what really the ALLO-329 is offering. Then also at the same time, the entire approach allows to go after both pathogenic B cells as well as T cells. So I think this is a very differentiated approach, and we plan to take it very, you know, carefully, in a thoughtful way into the autoimmune indications. The question about the indication is something that we're discussing, so, Zach?
Yeah, so I mean, obviously, we are looking to the field to develop, and most of the data that's been shared so far has been in lupus and lupus nephritis, but there are tantalizing signals coming from other indications, such as myasthenia gravis and others.
So, as David pointed out, we have the added benefit of being able to address pathogenic T cells that express CD70, which has been implicated in autoimmune disorders. So that does broaden the horizon for us to actually consider additional indications outside of lupus. So, you know, that work will be done in the coming months, and we'll be able to share more as we get closer to the IND.
Great. In the last 10 seconds I have, the update coming up in, for TRAVERSE, there are two updates. What is the difference? And are we getting data from TRAVERSE mid-year, at the mid-year milestone?
Yeah, so the first milestone will be a deep dive in this hyperinflammatory signal that we're seeing, as well as some mitigation strategies that we've alluded to the algorithm, and then we'll be able to share additional, more broader update in terms of safety and efficacy, incorporating patients treated under this new algorithm later in the year.
Okay. Great. Thank you so much for your time today. Thanks for joining us.