Good morning, everyone, and welcome to the JMP Securities Hematology and Oncology Summit. It's my pleasure to introduce Allogene Therapeutics. Presenting for the company is David Chang, President and CEO. Welcome, David. Really appreciate, you know, the time. Before we get started, you know, I never know exactly who's in the audience, and so would love for you to spend maybe 2-5 minutes kind of giving us an overview of the company before we dive into some specific questions.
Well, first of all, thank you very much for having Allogene at your conference today, Reni. And, you know, I think a lot of those in the audience know a little bit about Allogene's history, but, let me just go through at a high level. Allogene is really a company that set out to advance the allogeneic CAR T therapy, you know, which we believe is necessary to advance the growing field of cell therapy to the next stage. As we all know, the CAR T, you know, was first approved in 2017, and now is growing as a, you know, multi-billion-dollar market, across heme malignancies, specifically in non-Hodgkin lymphoma and other B-cell malignancies, as well as, the multiple myeloma.
Also, the CAR T field, which, you know, right now is all, you know, mostly in the autologous. It is expanding into other areas, including, you know, solid tumors, different targets, you know, including, you know, Claudin 18.2, Claudin 6, I'm sorry, GPC-3, and multiple others. T he field is really growing, not just as what it started as, which is in heme malignancy, but also in solid tumor, and lately also outside hematology oncology into autoimmune indications. In this setting, Allogene believes that the field needs another big booster, which is advancing what is autologous, with its bespoke manufacturing process and complex logistics, to essentially taking CAR T therapy as, you know, more, suitable, suitable for pharmacologic, pharmaceutical model, off-the-shelf, on-demand treatment, where we can manufacture the cells.
T his requires a lot of science behind it, you know, from healthy donor as a starting material and making it available to patients as the need rises. So when you look at this slide, it really represents the history of Allogene, as well as how we are stepwise advancing the pipeline. S tarting with the CD19, this is a program that, you know, has a long history and also approved across many different indications in B-cell malignancies. We have ALLO-501A, which currently is in a potential registrational study in the third-line large B-cell lymphoma. We also had another program, ALLO-647, which is being studied in EXPAND as a potential registrational study to support the use of ALLO-647 as a proprietary lymphodepleting agent for the allogeneic CAR T therapy.
T he first two study, ALPHA2 and EXPAND study, really go hand in hand together as we march the program towards potential BLA submission. Another program that we have been talking about is really trying to maximize the commercial opportunity of the allogeneic CAR T. This is ALPHA3 study, which we plan to initiate sometime in 2024, and this is really going into the earlier line, large B-cell lymphoma, in a very differentiated way, maximizing the emerging science as well as growing unmet medical need. We are also working with a CD19 next generation, that improves, you know, some of the product, characteristics of the current 501A, and this is a preclinical stage, program, that we are preparing for the IND enabling work.
We also had programs in BCMA targeting CAR T, ALLO-715 and ALLO-605. This is in multiple myeloma indication, and, you know, after reviewing the phase I data, we are trying to make some improvement in the manufacturing to make the product more competitive. Right now, in the current, you know, the financing environment, we are essentially, you know, holding on this program without incurring any additional operational cost beyond what we are already doing with ALLO-501A. Next to some additional targets that could go into the heme malignancies, a CD70, this is ALLO-316. That is not in the heme malignancy right now. We are studying that in the renal cell cancer, you know, right now, as I will come back to.
A lso, we have a program targeting a FLT3 that can go into the AML indication. Bottom is where we have been putting a lot of focus lately, which is trying to advance the CAR T into the solid tumor space, starting with a CD70. TRAVERSE study is a phase I study that where we are evaluating lymphodepletion as well as ALLO-316 cell dose in patients with post-TKI and post-checkpoint inhibitor setting in the renal cell cancer. We also have recently talked about additional targets where we have programs that are in IND-enabling stage, and that is DLL3, ALLO-213 for small cell lung cancer indication, and claudin 18.2 that can potentially be developed in gastric and other pancreatic cancer.
This really captures what Allogene is doing across both key malignancies as well as in the solid tumor. As a company that is really dedicated in allogeneic, we are working on the first generation allogeneic platform, as well as working on the next generation allogeneic platform, which we believe is essential to fuel the continued innovation in this area.
Got it. Thank you very much for that overview. Let's just jump right into, you know, the ALPHA2 and the EXPAND, you know, kinda ongoing, potentially pivotal studies. Can you talk about each study, you know, individually, and I guess maybe just point out to investors, like, what are the key data points that drive your certainty that both studies will, will ultimately succeed?
Yeah, you know, great question. As I've talked about, you know, there are two potentially pivotal study that we are involved in. You know, first one is ALPHA2 study. This is a study in ALLO-501A in a relapsed/refractory large B-cell lymphoma, essentially third-line setting. Study design is a single-arm study targeting approximately 100 patients. Patients who are enrolled, it has to be, you know, CAR T naive, and they will undergo lymphodepletion as outlined there, Flu/Cy that has been augmented with our proprietary lymphodepleting agent, ALLO-647. After lymphodepletion, they receive a single dose of ALLO-501A. Primary endpoint of the study is objective response rate, and the key secondary endpoint is looking at the duration of response, which is the standard by which FDA measures the efficacy in a single-arm study in hematologic malignancy setting.
ALPHA2 study design is really based on the, you know, number of patients that we have treated in the phase I setting. In the phase I setting, we compared ALLO-501A in testing many different doses, you know, ranging from 40 to 360, as well as testing different lymphodepletion. The conclusion from the phase I study is that ALLO-501A, with the lymphodepleting agents that is listed on this slide, provides a deep complete responses that are also durable. You know, another important metrics in this setting is so-called six-month CR rate. You know, essentially, how many patients who are treated maintained in complete remission at six months?
We have reported this at this year's ASCO, as well as European meetings, including the Lugano meeting. The data supports that the existing efficacy data from the phase 1 study is on par with what has been reported with autologous CAR T therapy. Plus, our therapy, you know, our product as a allogeneic cell product, we have the benefit of minimizing the complex logistics related to autologous CAR T therapy, as well as being able to treat almost everybody who is enrolled into the study, versus autologous, where many patients can miss the treatment due to manufacturing delay, during which patient can experience complications from their progressive disease. The second study is the EXPAND study. This really relates to ALLO-647, our proprietary lymphodepleting agents.
We are trying to demonstrate the contribution of ALLO-647 by doing a randomized study. The randomization is really on the lymphodepletion. One arm receives the standard chemotherapy-based fludarabine-cyclophosphamide lymphodepletion, and the active arm receives essentially the same lymphodepletion that we are using in the ALPHA2 study. Everybody in this study, after the lymphodepletion, receives the ALLO-501A treatment. Primary endpoint is progression-free survival, which is the appropriate endpoint when you're doing a randomized study. T he, you know, the evidence for the EXPAND study and the fact that, you know, ALLO-647 anti-CD52 is needed for lymphodepletion comes from various preclinical, as well as data that's coming from the prior assessment of the ALLO-501A.
This is a UCART19 study that Servier and Cellectis has conducted in the ALL, where they have shown that in the absence of ALLO-647, you get no cell expansion, nor the response. Also, we have seen in, from our competitors in this field, where they rely simply on chemotherapy based lymphodepletion. Even with the high lympho chemotherapy doses, they have not been able to convincingly demonstrate the durability of the response, which we are, you know, all waiting for. So I think that's really the, you know, the, the data that we have on hand, both from the phase 1 experience, as well as the data coming from the UCART19, as well as our understanding of different approaches that other company has used to allow the allogeneic cell therapy to work.
I mean, that's really indicating that anti-CD52 antibody use is really required to allow the expansion and persistence that's necessary to achieve the efficacy, specifically the durability of the response.
Can you talk a little bit about, you know, why maybe both studies are required from a regulatory perspective? P robably important for investors, what that cadence of, you know, completion of enrollment and data we should expect for both studies?
Yeah. I think, you know, from the ALPHA2 study, as a single-arm study, that's historically how the approval has been done in the CAR T, so I don't think I need to go too much into that.
Mm-hmm.
The second study is where we get asked some questions about why is this study necessary. You know, frankly, you know, sometimes we do ask that question when I think about the available evidence and how the different lymphodepleting regimen is being used, you know, you know, in the allogeneic setting, by different companies. We do have, you know, that question, but on the other hand, the CD52 antibody, ALLO-647, is our proprietary antibody. We had a very specific reasons to develop our own anti-CD52 antibody, and since it is an approved product, FDA requires some evidence that demonstrates the contribution of the 647.
I t's really the question of does, you know, anti-CD52 antibody ALLO-647, you know, improves the lymphodepletion that's required for the allogeneic CAR T? I mean, that is the essence of the question. On the other hand, at the end of these two studies, pending the data, we expect to get the FDA approval of not only for the ALLO-501A, but also for ALLO-647 to be used across different programs that uses similar technology in our pipeline.
In regards to the cadence of maybe enrollment or data or when we might start to expect this, can you give us some-
Yeah
... ideas?
So far, you know, ALPHA2, you know, we are continuing to monitor enrollment. I mean, you know, recently, meaning over the last, you know, 3-4 months, we have had a lot of site activation outside the U.S. You know, that is an important factor. From the beginning, you know, we knew because there are 3 approved autologous CAR T products for the same patient population in the United States, the enrollment in the United States will experience some challenge. And we are seeing that in our study. And for exactly that reason, our clinical operations team has focused on activating the study outside the U.S., Europe, Canada, Australia, and also in the U.K. So most of, you know, regulatory approval to conduct the study outside the U.S. has been achieved.
Site activation, we have activated a number of sites, and we are monitoring the enrollment from those sites very carefully. So, it is, you know, still, you know, a little bit early, but at this point, you know, for this 100-patient study, we project that the enrollment cadence, which we previously have guided as completion of the study at the, you know, in the first half of 2025, that is still feasible. So, we are maintaining that, but we are carefully monitoring the enrollment coming from outside the U.S.
Right.
The EXPAND study is really, you know, we are, you know, focusing on when the data will be available, not as much as the enrollment. Because, the ALPHA2 study requires not only for you to treat the target patients, but also follow the patients for additional six month to provide the durability data, durability of response data. Whereas the EXPAND study, it's a PFS endpoint, it's really event-driven. Based on, the available evidence, you know, we expect the PFS event in the control arm to occur relatively quickly. So, you know, that's how, you know, our, sort of, you know, timeline assessment is being, planned. And, you know, we are really targeting, getting the EXPAND study data be available, at the time the ALPHA2 data readout that supports the BLA, becomes available.
Got it. And I just wanna correct something, because maybe I jotted it down wrong, but I had targeted enrollment completing in the first half of 2024. I thought you mentioned 2025. Did I hear you?
2024. I'm sorry, did I say 2025? Thank you for pointing that out.
Yeah, no problem. Unless I misheard, but yeah, I just wanted to be sure. You have a poster that's being presented at ASH, and, you know, it, to me, when I kind of look at it, it's a lot of the data that we've seen, you know, in the past, but maybe bringing it all together. I guess, you know, do I have that wrong? Or maybe a better way to ask the question is, what do you- what are the key points that you feel investors should take away from this presentation at ASH? And just as importantly, what do you think are the key points that you'd like the clinicians who are viewing the presentation to take away from this, from this?
Yeah. A n important presentation that we will be making at, in the upcoming ASH is really showing the safety profile of ALLO-501A. In part because, you know, the phase 1 study tested many different lymphodepletion regimen as well as cell dose. There is still some, you know, you know, lack of a clear understanding of the safety profile, related to the lymphodepletion and ALLO-501A. W hat we have done is essentially compiling all the patient data, you know, from the phase 1 study who have received ALLO-501A or ALLO-501, so these are two different versions of product that we have tested in the clinics, and reviewing the safety, specifically related to safety that could be attributed to the use of anti-CD52 antibody, ALLO-647.
You know, because of the history of anti-CD52 antibody use in the CLL setting, despite the fact that we are using significantly less anti-CD52 antibody for our lymphodepletion, and also the lymphodepletion is also done only one time versus CLL treatment continues for you know, lengthy time when the CLL treatment with CD52. This would be compared continues for many in many months. Despite that difference, there is a general misconception that anti-CD52 antibody contributes to infection or safety concerns. O ur data will clearly show that isn't the case.
When we reviewed the infection rate specifically for this presentation, you know, as well as other adverse events associated with the CAR-T, such as cytokine release syndrome, neurotoxicity, and specifically related allogeneic CAR-T, graft-versus-host disease, it shows that all these safety profile trends very favorably. I think this is really, you know, once again, you know, to provide the data supporting what we have been communicating, which is the ALLO-647 use in allogeneic CAR-T setting is safe, and also it provides a differentiated approach to ensure not only the response, but the durability of response, which is really required to maximize the benefit of the CAR-T treatment.
Got it. B efore we get to the kind of upcoming milestones, we're kind of near the end of our time. You know, and I've told you before, I can talk to you all day. I really enjoy our conversations. Let me pose a couple of quick questions that we get from investors kind of all the time. L ast week... Well, not all the time. T his one question just happened recently. Last week, the cell therapy space got some negative news in our view, you know, especially regarding the potential T-cell malignancies, right? The FDA's investigation of it.
Kind of wanted to get your thoughts on that, how it might impact your decision-making process in both oncology, and while you don't explicitly say it, you know, clearly autoimmune, I think, is something that all cell therapy companies must be looking at, including yourselves. I'd love to just get your thoughts.
Yeah. I think you are referring to FDA announcing that they will be investigating the occurrence of T-cell lymphoma in patients who are treated with CAR-T. T here is a long history about the cell therapy, specifically, cells that are manufactured using retroviruses, either lentiviruses or gamma retro, potentially causing insertional mutagenesis that can lead to the malignancy. T he hypothesis when you look across vast majority of the data that doesn't appear to be the case, given the number of patients who have been treated with lentivirus-engineered CAR-T across oncology, but also in other indications where gene therapy approach involves the use of the lentiviruses.
S omewhat , curious about exactly what is the existing evidence that triggered this investigation., b ut, we are here to advance, effective and safe, medicine, so we welcome the investigation. I think at the investigation, we will know better about what the FDA's concern is and, how to sort of, how we think about not only the manufacturing, but the engineering of the CAR T. H ere, you know, one thing that allogeneic CAR T approach, provides is many different ways to introduce the transgenes besides, retrovirus-mediated. So there are many different ways that field can be adapting to, pending the outcome of the investigation.
I also wanna emphasize that since the approval of the CAR T , my projection is, more than 20,000 patients have received the CAR T. G iven essentially about, 19 cases, which is what I have read from the Endpoints report, and it is also not clear whether these are really related to CAR T treatment or related to underlying disease, as well as a prior chemotherapy treatment. I think it's really a little bit too, you know, early to, you know, speculate too much.
One thing that I'm pretty convinced is that, you know, given the small number that FDA has cited or the Endpoints note has cited, this is a very infrequent event, and I don't think it will change the benefit-risk profile. I think it will, you know, have to highlight risk if it is real, but I don't think it will change the benefit-risk profile of the CAR T used in heme malignancy setting.
What about in the autoimmune setting? How would you think about it there?
Yeah, it's a little bit different. I mean, you know, first of all, you know, you know, whether it will be seen in autoimmune or not, I mean, that's a different story altogether. So, let's not go too far into how this may affect development of autologous CAR T, where there has been a lot of activities, in the autoimmune. Having said that, you know, autoimmune and rheumatologists, the treating physicians, you know, they are very, safety-sensitive. So I think it's something that we just have to watch out for, as, you know, more data, you know, emerges, in use of the CAR T in autoimmune indications.
Having said that, some of the earlier report, I think everybody in the audience, you know, would agree, is really tantalizing because it really shifts the mindset of how we treat autoimmune diseases with the current approach, which is disease-modifying, to a potentially disease-resetting approach with, you know, a, a CD19 CAR-T therapy. So, you know, I'm very excited, and we are watching the space very carefully.
I think in the last, in our last call or after the quarterly earnings, you had mentioned there was a small little mention of autoimmune efforts as well at Allogene. And so I'm looking forward to seeing that as well in the future. Just in the last kind of couple of minutes we have, you know, these are the milestones we have for you guys. Would love to just kind of get your thoughts, maybe any corrections if you see that there are, or maybe even rank order them and what you think would be the most important shareholder-driving milestones.
Well, I think, you know, obviously, you know, the order that you have put this milestone, you know, the first one is the second line in the LBCL. This is really the earlier line, LBCL, to maximize the commercial opportunity, as well as growing unmet need in this space with allogeneic CAR T. W e you know, have guided that you know, we will essentially you know, finalize the study design, you know, which we will communicate you know, sometime early next year about how we're gonna proceed the study.
Yes, so this is an important milestone, and I think it really, you know, takes the 501 development into, you know, from the, you know, limited, relapsed recurrent, large B-cell lymphoma setting to the earlier line, you know, which is, you know, both clinically as a commercially, you know, provides a lot of, opportunities. And, the second and third one, you know, very much, yes. I think you essentially, you know, captured the key, milestones as we have communicated throughout the year. And obviously, as I've said, you know, we are closely monitoring the enrollment status of ALPHA2, as well as, you know, our effort to coordinate the data readout from the ALPHA2 and EXPAND at about the same time.
Excellent. I know that, you know, there, there's obviously a lot of things going on at Allogene. You know, we're of course, with the conference and ASH coming up, very much focused on the heme, you know, heme side. But I hope at some point in the future, we get to talk a little bit more about the other programs that you have, you know, in development. But David, thank you very much for your time. Really appreciate it.
Randy, thank you very much for having me at your conference, and good luck with your rest of your conference.
Thank you.