Great. Good afternoon, everyone, and welcome again to TD Cowen's I&I Summit. My name is Tyler Van Buren, Senior Biotechnologist here at TD Cowen. Thank you for joining. Very pleased to be hosting a session with Allogene. From Allogene, it's my pleasure to introduce David Chang, Co-founder, President, and CEO of Allogene. David, thank you very much for joining me.
Tyler, thanks for the nice introduction, and great to be on this panel.
Great. So before we get started, if you—for those of you in the audience, if you have questions, you can submit them via the web portal, and we'll do our best to get some of those questions asked in our fairly brief 20+ minute fireside chat. With that, maybe we'll go ahead and get into it. Since I&I is the focus of the summit, we'll start with your efforts in autoimmune with ALLO-329. You know, and there's obviously a lot of CAR T approaches and clinical trials for autoimmune. Maybe it'd be great if you could start by discussing 329 in a bit more detail and mechanistically what's differentiated versus some of the other approaches.
Sure. You know, happy to—before going into that, I think what we are seeing in the autoimmune space is really remarkable about how this concept of cell depletion has become, you know, such a hot topic, you know, where different modalities are going into. Certainly, this is an area that, you know, we know a lot about, having worked in the CAR T space for some time. We have what we believe is a highly differentiated product. This is ALLO-329 that we are currently enrolling patients into the phase I study. How is ALLO-329 different? Let's start with the most important question, you know, topic. This is an allogeneic. It's an off-the-shelf product that can be made available right away when there is a patient who is qualifying for the clinical study at this point, but eventually when there is a patient need.
It doesn't require any kind of ancillary, you know, management issues such as leukophoresis or timing of the, you know, product manufacturing to the delivery of medication treatment. I think that is very important. Certainly, in terms of product manufacturing, we do have the manufacturing capacity as well as bringing down the cost of goods manufacturing to the biologic level, which is a very important thing. Now, you know, from the mechanism perspective, ALLO-329 is, from the very beginning, designed as a dual CD19/ CD70 CAR. Why? Because we want to bypass the lymphodepletion requirement. In fact, in the ongoing study, we are testing reduced lymphodepletion or no lymphodepletion in a parallel cohort.
You know, I think when we can sort of reduce or eliminate the lymphodepletion requirement, we believe it can make ALLO-329 administration safer, and safer to the point that it can be used in a broader, you know, autoimmune indications. Very important. The second thing is the fact that, you know, CD70 is one of the targets that we are going after. This is a very important target because CD70 is expressed in a lot of activated lymphocytes. You know, B cells overexpress CD70 or upregulate CD70 when they get activated. That is T cells as well as antigen-presenting cells, including the dendritic cells. All these cells are really what is contributing to the breakdown of the tolerance and the development of autoimmunity.
Mechanistically, the fact that we can go after not just the B cells, but other cells that contribute to the pathogenesis of autoimmunity, I think that is a very important differentiation. How, you know, will that, you know, what difference does it, you know, make? I mean, you know, why is it important? We believe that when we can go after not just the B cells, but other cells that are important for the pathogenesis, that could potentially lead to much durable responses, as well as our ability to go after, you know, much broader autoimmune indications, not just the ones that we know that B cells play an important role, but there are also a lot of autoimmune disorders that are more T cell- heavy. I think we can go after, you know, those indications as well.
Right now, you know, we are all focused on generating the initial proof of concept that, you know, we can accelerate as well as expand our sort of, you know, the studies that we are doing.
That's great. Thanks very much for that introduction, David. Maybe with the phase I RESOLUTION trial, we could get into some of the details with that. Are you enrolling autoimmune conditions that are T cell mediated? Also, maybe you could talk about the different arms and lymphodepletion and how patients are being enrolled into those arms.
Yeah. Right now, we're doing a phase I study. I mean, ALLO-329 has never been studied in human. I mean, you know, CD19 CAR has been. CD70, we have studied in patients with renal cells, but, you know, as a dual CAR, it has never been tested. We're doing a phase I dose escalation study. The objective is really to establish the safety, but also, you know, try to get early signs of efficacy. The initial target patient population that we included in the phase I study are the patients with the rheumatologic disorders. We're talking about lupus. There's a lot of proof of concept already coming from CD19 B cell depletion and how well it works in lupus, as well as people with more severe conditions of lupus, such as lupus nephritis. Lupus, as well as lupus nephritis.
The two other indications that are included in this basket study are inflammatory myositis and scleroderma. Already, there is some proof of concept that depleting B cells can change the disease course and sometimes even reverse the damages that were already done by the disease. You know, those are the patient population that we are studying. It is a phase I. We're doing dose escalation. As I've said previously, we have two parallel cohorts, one with the low lymphodepletion. Here, you know, for the chimeric antigen receptor therapy, the standard lymphodepletion is two chemotherapy regimens, cyclophosphamide and fludarabine. We lower the dose of cyclophosphamide, and also at the same time, we took out fludarabine. It is a much simpler lymphodepletion, which we believe will be much better- tolerated.
The parallel cohort is, and this is, you know, really being aggressive, you know, trying to get the proof of concept, is without any lymphodepletion. The study, you know, it's a phase I, so we have to treat the first patient and then do the parallel cohort. The first patient will be treated with lymphodepletion, Cy only, and then thereafter, both cohorts will be open and enrolling, you know, one with Cy only and the other one without any lymphodepletion.
Okay. Great. I guess getting into the Dagger technology a little bit, what gives you confidence that you'll be able to reduce and potentially even remove lymphodepletion with that technology?
Yeah, you know, like anything else, you know, the initial idea gets generated from, you know, pre-clinical as well as the models that we have used. I mean, when you, you know, do the literature about what CD70 does, in terms of where we, why we are targeting, it becomes, you know, CD70 becomes very clear. There is ample literature that suggests CD70 is upregulated in activated cells and activated lymphocytes. You know, that plays, you know, a very important role in the pathogenesis of, you know, autoimmune disorders. Another thing that, you know, gives us even, you know, more confidence is that CD70 as a single CAR, we have a lot of clinical experience. This is coming from ALLO-316 that we are studying in solid tumor, specifically in renal cell carcinoma. We have treated over 50 patients.
We have a pretty, you know, remarkable efficacy data coming from the phase I study, about one-third of patients responding, and also responding patients having very prolonged durability of response. Now, you know, getting close to one year, and several patients have already surpassed the 1-year mark. One-time treatment, getting that kind of response is quite remarkable. The translational data coming from the 316 study is where we get a lot of confidence. The cell expansion, which is frequently associated with how well the chimeric antigen receptor works in treating cancer. We have, you know, cell expansion as well as, you know, the so-called area under the curve, how much cell expands and how long it expands during the first 28 days.
When we look at that and the fact that we are achieving that kind of cell expansion with standard lymphodepletion for allogeneic, I mean, I think that is pretty remarkable. This is where we get the confidence that we have room to reduce the lymphodepletion. Important also to recognize is that in autoimmune disorders, conceptually, this is a lot different than solid tumors or, you know, malignancies. The target antigens are limited. The intent of treating B cell depletion or any kind of cell depletion in autoimmune disorder is not to deplete those cells permanently. It is really deplete enough to initiate the process of resetting the immune system, where the naive cells that are free of pathogenic B cells or T cells start repopulating. It is really a hit-and-run type of concept. We can just go in, deplete sufficiently.
We know that the chimeric antigen receptor does that very effectively. And then, you know, let the body recover. That's the really, you know, where the key to success in autoimmune disorder, you know, especially with the cell depletion approach lies.
Right. Just a quick question on logistics. Do you, and to be clear, you have sites already activated so far. Are they more academic or community? You'll start enrolling patients going into the end of the year. How do you expect this to progress over the next several months? Is there one of the few indications that you think you'll enroll more patients in? Any thoughts you have on enrollment would be helpful.
Yeah. This is, you know, first of all, the question about academic versus community. I mean, that's an important topic when it comes to our registration study in the lymphoma. In the autoimmune, this is a phase I study. We are a little bit more, you know, focused, you know, with opening the sites in the academic centers. So far, the, you know, the investigator excitement around, you know, unique MOA, as well as off-the-shelf, I mean, that has served us pretty well in terms of getting the sites interested. We have a handful of sites already active and enrolling patients. You know, stay tuned. Enrollment always has been a big question mark in any autoimmune studies because of the past, you know, experience in other companies.
My sense is that, especially sort of tracking what has been presented at the recent ACR meeting, enrollment has gotten a little bit easier. We believe that when we have a product that does not require all the preparatory work other than just identifying the patient, I think, you know, I am feeling very optimistic with the enrollment. Having said that, this is a dose escalation study. In terms of the slots that are open, we will be limited by the three plus three design of the phase I.
Understood. Initial proof of concept data are on track for the first half of next year. What should investors be expecting from that initial data readout?
Yeah, this is one question that we get asked a lot, you know, how many patients and all that. We have always said, you know, it'll be a handful of patients, you know, given that this is a phase I dose escalation. It will include both patients who are treated with, you know, Cy onl y lymphodepletion or no lymphodepletion. Okay. So that's that, you know, without being specifying, you know, how many patients. Now, you know, what are the signs that will tell us, you know, the confidence? And this is a combination of biomarkers related to what, how the CAR T cells behaving, you know, you know, CAR T cell, you know, kinetics, as well as B cell depletion. And then there is another category of disease-related biomarkers. So these are autoantibodies or, in case of autoimmune disorders, CPK.
That's a muscle enzyme, you know, that gets elevated when somebody has myositis. I mean, people have studies have shown that when myositis is successfully treated, you know, CPKs come down. This is really a pretty good surrogate of what's happening with the myositis process. I think those are the nature of the biomarker. Lastly, given the enrollment and where the study stands, we will have few patients, you know, not that many, that we would have had sufficient follow-up to see whether there's clinical signs of improvement. There are standard measures to assess the disease severity as well as disease status. Also, another important thing is frequently a lot of these patients are already starting with, you know, some kind of anti-inflammatory medications, whether those medications can be reduced or eliminated.
I think those are the kind of clinical endpoints that we'll be looking at.
Great. As we think about assessing the Dagger technology and the ability to remove or reduce lymphodepletion, will you essentially be looking at cell counts and cell expansion and comparing that to, like, the other CAR T data that you have? I mean, I guess obviously you do not necessarily expect it to look the exact same, but I guess you are hoping that it is sufficient, the amount of cells and expansion that you are getting, right?
Yeah. You know, one thing is, you know, cross-trial comparison at the CAR T kinetics is a little bit different because everybody uses their own proprietary assay. It's not a standardized test that you can say one result can, you know, equate to the other one. Timing is also different. At the end, it's a combination of, you know, the trend in, you know, the cell kinetics. I think that is more important. Another thing, you know, that is equally important is, you know, we know what CD19 CAR does. CD19 CAR depletes the B cells. So, you know, the extent of B cell depletion is another thing that will give a very good indication of what's happening with the, you know, the ALLO-329- treated patients.
Got it. Okay. Do you plan to make a decision on whether or not Cy is necessary from these initial data in the first half, or what level of difference or lack of difference would you need to see in terms of efficacy and translational data to prioritize the no lymphodepletion regimen?
That is a great question. I think, you know, to fully answer that, I mean, you need a little bit of follow-up because ultimately, you know, what should determine how you dose the drug is, you know, the clinical outcome. But we have enough from other information to triangulate. And this is really the core of the drug development. There are certain indications that, you know, from, you know, my conversation and our team's conversation with the investigator, you know, Cy only would be well, you know, received. I mean, you know, these are the indications where, you know, the standard of care is less well- established or the disease is very hard to manage. You know, myositis or scleroderma sort of, you know, fits in that category. You know, indications like lupus, there are a lot of other treatments.
You know, there will be more like, you know, trying to get the treatment to work, you know, without, you know, much lymphodepletion just to really improve the safety profile and make the target product profile competitive, both from the clinical trial enrollment as well as when the study is successful in the commercial marketplace.
Great. All right. I realize this is an I&I summit, but as we're approaching time here, need to try to get to the lead program with ALPHA3. Maybe you could just talk briefly about how enrollment is going and how the reception from investigators has evolved for the study since announcing it back from the start in 2024.
Yeah. In enrollment, status is one of the, you know, the most frequent questions that we have to fill. We're going to maintain the position in terms of, you know, day-to-day, you know, we're not going to go into the details other than reiterating, as we have done in our earnings call last week, that the communication of interim criteria analysis is very much on track for the first half of next year. You know, we'll start narrowing down as we get, you know, closer to the, you know, what we expect the data communication to occur. In terms of the investigator excitement, I mean, this is one of the studies that I, you know, consistently hear. We love the study design. This is exactly the study that's needed. This is not just coming from the U.S. investigators.
I mean, we have said in our earnings call, we are taking studies to, you know, Pacific Asia region, specifically South Korea and also to Australia. They love the study design. They are just saying, you know, let's just activate the study as quickly as we can so they can, you know, start participating in the study. Excitement is high. Certainly, the enrollment as well as patient screening has been at the highest level.
Yeah. I mean, it seems so obvious in the front line if a patient finishes 6 cycles of R-CHOP. And for those 30% of patients, you know, now you guys are developing a test that is going to allow the doctor to say, you've got, you still have cancer cells floating around in your body. Do you want to wait to see that come back with a vengeance and for a second-line treatment, or do you want to try to get rid of it now? I've got to imagine most people who are healthy and fit would opt in for that. There is a lot of excitement coming from that, the fact that these investigators are being made aware of the fact that there's now a technology available where they can tell the patient that relatively quickly after R-CHOP.
Yeah. I mean, I could not have said it any better than what you have just said. I'm going to sort of try to record that and use what you have just said. I mean, exactly. I mean, it is known that, you know, yeah, at the end of the front-line treatment, responses are good, but you need to be followed. There is an uncertain period, you know, especially first year and first, you know, essentially about first, you know, 2.5 years where you are at a risk of having a disease recurrence. The intent of our registration study, ALPHA3 trial, is to identify those patients. And this data is pretty good that MRD positivity is not a good thing at the end of the treatment.
Those are the patients that we are enrolling into the ALPHA3 trial and trying to convert to MRD negativity with a single infusion of cema-cel. The initial criteria analysis is, you know, based on about 12 patients per arm, you know, so one arm is the cema-cel treatment, the other arm is observation, which is standard care. We are trying to see the differential in the MRD conversion rate between those two arms. You know, MRD conversion rate, is that important? Definitely. I mean, all the data indicates that if you are MRD- negative, your risk of disease recurrence, you know, goes down significantly.
Great. On the recent earnings call, you mentioned the IMvigor011 data from ESMO. Can you explain some of the parallels there between that and ALPHA3 in the study and what it says about the oncology field's receptivity to using MRD in the setting and treatment for treatment determination?
I mean, Zach Roberts is our Chief Medical Officer. He loves that study. And, you know, he had to, you know, sort of explain to the rest of, you know, my team about why he likes the study so much. I mean, we sort of laugh about it whenever the study name comes up. The fact is that conceptually, it's an almost identical study to what we are doing with ALPHA3 trial. You know, patients get identified by, you know, risk stratification, you know, high risk of recurrence. And then you follow, you know, with the observation versus, you know, in the case of bladder cancer with a checkpoint inhibitor. And what the study has shown is, you know, these high-risk patients, you know, is where you see the most benefit of intervening with the checkpoint inhibitors. And that's the same concept that we are applying in the ALPHA3 trial.
Another thing that he always talks about is what they have presented in that study, which they have looked at the MRD conversion rate. The delta that they saw between the treatment arm and the observation arm was, I would say, pretty modest, about, you know, 10%, about 11%, you know, but still that translated into pretty significant clinical benefit.
Great.
I mean, another sort of point, you know, just the actual data point, you know, supports it. MRD conversion, you know, is, you know, appears to be a very important indicator of what the clinical outcome may look like.
Yeah. We are over time, but I have to ask about expectations for the first half update since you mentioned MRD conversion. What MRD conversion do you think would support continued pivotal development and really get you guys excited? What would you expect to see with the control arm?
Yeah. I mean, you know, we have said, you know, 30%, you know, that's triangulating, you know, many different, you know, information, you know, what we have seen in the second-line study of autologous CAR T in large B cell lymphoma, what we have seen with additional polatuzumab in the front-line R-CHOP regimen. All those information, you know, we triangulated together with what the investigator has been advising us. You know, that's where about, you know, about 30%, you know, comes from. On the other hand, something like Invigor data is suggesting, you know, even 11% is good enough. From the small, you know, sample size, I think 30% is the right kind of bar to set. Certainly we'll be using that to accelerate the study.
I mean, as we have said in the earnings call, we are increasing the number of sites, both in the U.S. as well as going out into the ex-U.S. territories to accelerate enrollment.
Yep. The control arm, obviously, observation, I would think MRD conversion would be next to zero, right? I mean, spontaneous conversions are probably pretty rare.
Yeah, in the perfect world. That is absolutely a correct statement. You know, we're dealing with the patients, we're dealing with the clinical study, we got to have some buffer. Also, the data, both coming from, you know, full-site diagnostic, and they're really the pioneers in this area, but also, you know, collaborating data coming from Adaptive would suggest that, you know, among people who are MRD- positive, there are certain patients, a low percentage, you know, high teens or 10%-20% do not have a disease progression. You know, we got to have a little bit of buffer. That's why we're not talking about absolute conversion rate, but we're talking about the differential between the control arm and the treatment arm.
Got it. Okay. That's great. We are way over time, so we'll go ahead and wrap things up. David, thank you very much for spending time with us to run over, go over these two programs. Thanks to the audience for attending our summit. Have a good evening.
Tyler, as always, thank you for the outstanding questions and opportunity for me to be in your panel.
Take care.