covering the biotech space, specifically the cell and gene therapy area. Today I'm joined by Dr. David Chang, the CEO of Allogene. Thank you so much for taking the time to join us, David.
Jack, thanks for having me here.
David, Allogene's a really innovative company, you know, developing allogeneic CAR Ts, an area that you have, you know, in-depth expertise, having pioneered the autologous first-generation treatments. Maybe before we jump into specifics about the programs at Allogene, can you talk about the general kind of evolution of CAR T therapy over time?
Yeah, I mean, you know, I think that's a really good way to, you know, set the discussion around, you know, what's going on in the cell therapy. So, I was fortunate to get involved in the original CAR T programs when I was working as a head of R&D at Kite Pharma. And, you know, that's 2014. And at the time, you know, the question was really: Well, cell therapy, is this for real? And whether this is even going to be a marketed product. Now, you know, turn the clock to 2022, you know, the cell therapy product reached a, you know, revenue of $2.7 billion, having treated more than 6,500, you know, patients in 2022.
But, you know, if you really, you know, step back and think about the number 6,500, you know, that's mostly coming from non-Hodgkin lymphoma. And what the data says is that about 30%-40% of the patients who get treated remain disease-free. So, you're talking out of 6,500, if you use 24, about 40%, about 2,500 patients being, you know, cured of the disease from the cell therapy. And with that, there's been a lot of excitement. You're looking at potential, depending on who you talk to, the growth of the cell therapy getting to about $10 billion market within the next five years, and that's just in non-Hodgkin lymphoma and multiple myeloma. Having said that, still, you know, the autologous cell therapy, because of the logistics and also the manufacturing, it cannot reach all the patients.
The current estimate is only about a fraction. Close to about 10% of the patients are able to receive CAR T therapy, and that's where really the value proposition of allogeneic CAR T is coming in.
Yeah, and then maybe just stepping forward on that, allogeneic CAR T is the derivation of a CAR T from a donor-derived product.
Yes.
What do you have to do to make sure that donor-derived product reacts like a self-derived or an autologous product? And maybe you could talk a little bit about the engineering that Allogene has put into their-
Yeah
... their programs.
So, you know, the most important thing is the cells. I mean, the way that allogeneic CAR T works is this is really there's no HLA matching. You're just picking a donor, manufacturing the cells, and giving it to any patients, and obviously, as an off-the-shelf, it's on demand. So, the first thing that we, you know, one has to address is that, you know, you know, this allogeneic, you know, CAR T cells do not cause any safety issues. And that's done through the engineering of the... You know, this is gene editing. I mean, I would say without gene editing, entire allogeneic cell field would not be, you know, really viable. First thing is editing out the T cell receptor locus so that the CAR T cells cannot attack the patient's normal tissue. So that's number one.
Another thing that's really important is the reverse of that story, where the patient's immune cells, seeing the CAR T cells as a foreign body and rejecting it. So this is where trying to protect the allogeneic CAR T cells from getting rejected by the patient's immune system. And for Allogene, we do achieve this by using anti-CD52 antibody. It's a product called ALLO-647 that we use as a part of lymphodepletion. And in order to use ALLO-647 effectively, we have to do a second gene engineering, which is editing our CD52, which makes AlloCAR T cells from immune from the CD52 antibody.
Yeah, that's great context. And then now with that all in mind, how has it worked in the clinic? I believe you have clinical data from this lead CD19-
Yeah
... program in a very similar setting to the autologous treatments. I mean, what are you seeing? I know a big question for the field's been durability. Any context you can provide around the results-
Yeah
... from this donor-derived approach?
So in the CD19 program, so far we have treated more than 80 patients, which gives us a lot of confidence about the data that we are seeing. And throughout the phase one program, we explored different lymphodepletion, different doses of anti-CD52 antibody, ALLO-647, and also, we tested different cell doses, as well as trying to work around dosing of the cells. Ultimately, we landed at a specific lymphodepletion and giving the cells once. So, you know, the data that we have seen so far is that for the large B-cell lymphoma, so this is essentially the entity called DLBCL in the prior nomenclature. And what we're seeing is the depth of response, initial response, and more importantly, the duration of response, and the best surrogate for duration of response is a 6-month CR rate.
What we have shown is that the six-month CR rate looks very comparable to what has been reported in the pivotal studies of autologous CD19 CAR T, like Kymriah, Yescarta, and the Breyanzi.
Yeah.
And then you even have long durable responses as well, way beyond six months...
Yeah
... as well. Maybe you could talk about that long-term durability data that you've seen?
Yeah, you know-
from the Allogene platform
... in some of the earlier patients that we have treated, I mean, at this point, you're talking about patients, more than, you know, 30 months out of the, you know, ALLO-501, that's the product name-
Yeah
... infusion, and then, they are still in complete remission. So that's really, essentially, you know, looking very similar to what autologous CD19 CAR T has been showing. So overall, you know, I think the median duration of response that we are seeing is, you know, around 3 months, about 30 months, which is really, the kind of hope that we were, you know, you know, target that we are trying to get to.
That's great, cause I mean, being able to deliver this therapy directly to a patient after, shortly after diagnosis, I know there's a lymphodepletion aspect-
Yeah
- but that would really unlock cell therapy for a number of people.
Yeah. I mean, it's really, you know, more than the speed of the treatment.
You know, it's taking away all the complex logistics, and patients don't have to undergo leukapheresis or go, you know, receive the, you know, the bridging chemotherapy before, you know, while they're waiting for the cell therapy. All that, you know, goes away, and the cell product is available in a vial to be infused to patients on demand.
That's-
You know, clinical studies that we have done, the median time from the enrollment to duration is, you know, about 2-3 days. Not only that, just as the promise of allogeneic CAR T, we have been able to treat essentially everybody who gets enrolled into the clinical study.
Yeah. And then on the safety side, just based on the existing data, how are you feeling the safety profile is shaping up as compared to the first generation autologous treatments? I know there have been some questions around CD52, lymphodepletion-
Yeah
... and the risk of infection. I'd love to hear any comments you have.
Yeah, let me just get that out of the way.
Yeah.
I mean, CD52 anybody, because of the prior history, there's a lot of noise around the infection. But when we look at the data in the CD19 program, and now we also have had the chance to look at the data coming from our BCMA program, the rate of infection is not any different than what has been reported with autologous CAR T. So that, you know, really is, at this point, I think we have sufficiently addressed. And the second question is, you know, the safety that is associated with chimeric antigen receptor, you know, therapy, cytokine release syndrome, and the neurotoxicity.
In phase one, it's probably a little bit too early to make any kind of comparison to the autologous, but numerically, the incidence of grade three events that we are seeing in our study is much lower than what has been reported with the autologous CD19 CAR T. So, we will see it, you know, when we complete and report the data from our ongoing phase two study. But, you know, we'll look... You know, we are feeling pretty good about the phase one data that's supporting the ongoing phase two study.
That's great. You have two ongoing phase 2 studies.
Maybe you could outline just the ALPHA2 and the Expand trial.
Yeah.
I'd love to hear any progress that you've made towards enrolling those studies as well.
Yeah. So what we are doing as part of the potentially pivotal study, I mean, in CAR T therapy, phase 2 data could support the registration. So that's why we use somewhat awkward term of potentially pivotal. We are doing two studies, one's called ALPHA2 study. This is a single arm study that's targeting about 100 patients, and this is to demonstrate the efficacy of allogeneic CAR T, ALLO-501A, in large B-cell lymphoma. And we believe that will be the basis for the regulatory approval, using the endpoint of overall response and duration of response as a key secondary endpoint. Another important study that we are doing is really trying to validate the proprietary lymphodepletion regimen that we are using. You know, this is very important.
So far, very few companies have been showing the durability of response with allogeneic CAR T as we have, and we believe, you know, the basis for that is our lymphodepletion regimen, which relies on an anti-CD52 antibody, ALLO-647. The second study, the Expand Study, is really intended to show the contribution of ALLO-647 to the standard fluci. So that's a 1:1 randomized study. One group gets a standard fluci lymphodepletion, and the second group gets fluci plus ALLO-647 as lymphodepletion, and they both get ALLO-501A afterwards. And that study uses a progression-free survival as an endpoint, and we're targeting enrollment of about 70 patients into that study.
Great. Maybe on the ALPHA2 Study, one of the questions I get from a lot of investors is how you're going to enroll this trial-
... with commercially available autologous treatment. To that same end, are you going to get sicker patients because these are the patients that can't get autologous treatments in the same setting? I'd love to hear any thoughts you have around-
Yeah
... enrollment and how you're controlling for a similar population to the autologous approved therapy.
Yes, you know, autologous CAR T therapy are available, but still, when you look at the number of patients who are getting CAR T therapy, there are a lot of patients who are not able to get the autologous CAR-T therapy for various reasons. So in the U.S., where the therapy is more available, I think that's a sort of a small group of patients that we are targeting. But what we are also doing is expanding study to outside the U.S., where the availability of autologous CAR T commercially is much more limited. So that's where, you know, we will get another large portion of the patients being enrolled to the ALPHA2 study.
Great. And that expansion is occurring in the H2 of this year. How do we think about the cadence of that global expansion?
Yeah. Well, that's going on right now.
Yeah.
I mean, so, you know, ALPHA2 study, we initiated study in the Q4 of last year, and much of, you know, the H1 of this year is really getting the regulatory approval and initiating the sites, not only in the U.S., but also especially in Europe and Australia.
... That's great. And how should we think about updates as it relates to enrollment? I think this is like a study that people are watching very closely.
in the allogeneic cell therapy space. It's one of the first pi--
Yeah.
It's the first pivotal CAR T, allogeneic CAR T, to come through the clinical trial development. How should we think about enrollment as we move through? I believe your guidance is for completion of enrollment in the H1 of next year. How should we think about it?
Yeah, so for ALPHA2 study, you know, from the beginning, we have said, you know, we are targeting the completion of enrollment in the H1 of 2024, and we are still maintaining the same projection. As for, you know, the detailed, you know, enrollment and all those things, on a pivotal study, we generally stay away from providing, you know, a play-by-play update on what's going on in potentially pivotal studies. So we'll just have to wait till, you know, sometime in the H1 when we announce that enrollment has been completed.
Great, that makes sense. And then to that end, as it relates to enrolling patients in the study, are you enrolling patients both on the inpatient and outpatient settings for ALPHA2? And how do you think about the mix and what that means for potential commercialization in the longer term?
Yeah, I mean, we are giving the sites option of either treating as an outpatient or inpatient, and in fact, a number of patients has been treated as an outpatient. We like to maintain that, you know, flexibility or actually, you know, flexibility as well as experience of what it's like to treat patients as an outpatient with ALLO-501A. Eventually, that experience will really influence how, if the product is approved, you know, physicians use the product.
Great. Then on the Expand Study, it seems like not only based on Allogene's internal data, but external data to Allogene as well, support this-
... CD52 lymph depletion. I understand the regulators may be, you know, keenly interested in having a direct comparator study, but I guess, how do you think about enrollment of that trial in the context of, of the existing data set? And are there specific geographies or, physicians that are apt to enroll-
Yeah
... in a non-CD52 lymph depletion, allogeneic CAR T at this point?
I mean, you know, scientifically and from the clinical trial perspective, it is an important study, but there is also, especially among the investigators that have been supporting our clinical study, they are reluctant to randomize patients to half the patients not getting ALLO-647. So in the U.S., I think it will be a little bit of a challenge, but then there are sites that value the, you know, testing the important scientific question, and also outside the U.S., we get a lot of support for that study.
I guess as it relates to the design, kind of touching on the same vein here, it seems like 647 is needed for a durable response or in the majority of patients, you're going to need to have that CD52 lymph depletion.
Yeah.
Um, and-
I would say, you know, our team really scrutinize the data.
Yeah.
No matter how we look at the data, if we don't use ALLO-647, you do not get the lymph depletion that you need, or you do, and also you do not get the cell expansion that would be, you know, needed to get the response and the durability of the response.
Yeah. I guess to that end, do you think you need 70 patients, or is there an opportunity to have a smaller study? I know the endpoint here is PFS. How did that dynamic play a role in the selection of PFS as well?
Yeah.
As well.
So, you know, we do have an independent data monitoring. They will be looking exactly for that reason, you know, the patients in the enrolling in the Expand Study. And obviously, you know, when you have an independent data monitoring, they have certain discretion, you know, to either continue the study or stop the study.
Yeah. Great. Now that we've talked about the pivotal program-
... and some of the existing data, I believe you're also thinking about moving up the treatment paradigm-
Yeah
... in the near to medium term. Maybe you could talk a little about your plans as we think about moving up into the second line and hopefully maybe to the first someday with the-
Yeah. So, you know, right now, you know, a lot of, you know, CAR T therapies or products are being tested in the refractory setting. But we do believe the, you know, the value that we can get, the best value that we can get, especially when there is a potential to, cure the patients, so they don't have to go through the subsequent lines of therapy, is moving into the earlier lines. And the data coming from the autologous is that as the therapy moves to the earlier line, they have consistently shown, you know, pretty, you know, you know, significant benefit. And, and so what we are doing from the Allogene with the, you know, ALLO-501A, is trying to move to the earlier line.
So what we have said is that we plan to have a regulatory discussion to get a feedback on our trial study design and communicate the outcome towards the end of the year. We plan to enroll, initiate the study in the H1 of 2025.
Could you-
2025, sorry.
Could you remind me, is that a first line or a second line indication? What are you thinking-
We haven't said, you know-
Okay.
We have simply said earlier line.
Yeah, cause you would think that the demand would be greatest in the first line, and that could be the best opportunity for allogeneic to offset the autologous, you know, manufacturing issues and such.
Yeah. I mean, you know, I think in general-
Sure
... the earlier line, you know, the earlier you go, the better it is. But we are also aware that, for the large B-cell lymphoma, some patients can be cured with a standard chemotherapy. So you're talking about, you know, any, you know, the newly diagnosed large B-cell lymphoma, they would undergo, you know, R-CHOP regimen.
Yeah.
Outcome of that is about, you know, between 50%-68% of the patient will be cured and will not require any subsequent, you know, therapy. But then there are the other, you know, 40%-50% of patients, you know, who could benefit from getting CAR T early on. Trying to identify that patient population, I think, is one of the, you know, sort of new innovations that's ongoing in the field.
Do you think there's ever a point where we get to an era running cell therapy versus cell therapy clinical studies, if we, if these treatments move up early enough in, in the lines of therapy or in autologous versus allogeneic?
We get asked that question, and personally, I don't really see that kind of study being required for the regulatory approval. I mean, you know, once the product is in the market, I mean, you know, there are cooperative groups and others that may explore something like that, but I don't really see that in the foreseeable future.
Got it. Great. Maybe we can shift gears and talk about CD70, I know-
Sure
... a program that you're very interested in. Maybe just set the stage. Can you talk about ALLO-316 and just generally the data you presented in renal cell carcinoma there?
Yeah. So ALLO-316 is our allogeneic CAR T program, you know, after CD70 as the target. So that program from the beginning, you know, we were sort of using that as, you know, initial foray into the solid tumor. You know, from the company perspective, our initial pipeline was going into heme malignancy, but we were really trying to expand market by showing proof of concept in the solid tumor. So CD70 was really pushed into that situation because of the target itself and how it's expressed, and also the fact that a lot of, you know, renal cancer, especially clear cell variants, have a high expression of CD70. So we are currently in phase 1, exploring the different doses of ALLO-316, and as well as testing different lymphodepletion regimens. We have already seen responses.
So from that perspective, you know, being able to demonstrate a proof of concept in solid tumor with allogeneic CAR T, and also being able to show very robust cell expansion, regardless of whether you, you know, have to use FCA regimen or FC. This is really making CD70 316 program, you know, very exciting. So, you know, you know, we are continuing to optimize the cell dose as well as the lymphodepletion. And once that's done, the next plan is, you know, doing the dose expansion. Obviously, in the renal cell cancer, where we already have proof of concept, either as a monotherapy or as in combination with a checkpoint inhibitor. Other solid tumors that express CD70, since now we have a diagnostic test that can select a patient based on CD70 expression.
Also, CD70 has a utility for, you know, CD70 expressing, CD70 expressing hematologic malignancies, like T-cell leukemia lymphoma, as well as large B-cell lymphoma.
As you look to advance this program-
... through dose escalation or, I guess, dose finding regimens, and then expansion, how do you think about the process that you brought into the clinic here? I know with the CD19 product, you decided on an Alloy manufacturing process.
How... Are you, you know, do you develop the cell therapy manufacturing process before you bring a 316 forward, or are you also optimizing that as you do this dose escalation as well?
Yeah, it's a, it's a continuous process.
Yeah.
I mean, you know, you know, this is the big debate in the cell therapy space. If you want to perfect the manufacturing and, you know, you know, line up all the ducks before you take into the clinics-
Yeah
... one, that's going to take a long time. And you don't necessarily know what you're doing until the product goes into human testing. So this is an iterative process. In fact, that we would do it for any products where we continuously try to improve how we manufacture the cells.
But do you expect it to be translatable from program to program? And for example, a heme-
Oh, there's a lot of learning.
... to a solid?
I mean, one of the things-
Or-
... that we're benefiting a lot is that having treated, close to about 200 patients with allogeneic CAR T, the learnings from one program, all the translational data that we have, you know, mining that data and using that as a basis to, sort of design or modify the manufacturing, you know, you know, that has come to be a very useful process.
Great. And on CD70, maybe first, when should we expect an update as it relates to data there?
Yeah. So it will be more towards as we complete the dose escalation.
Okay.
You know, we are also looking to present the data in the academic, you know, presentation. So, in terms of... You know, we're expecting some time, you know, towards end of the year, early next year. And, you know, the plan is really, you know, shooting to expand the cohort in the H1 of 2024.
Great. And then on CD19, you've been very, forthcoming with the durability data in the last couple-
... major medical meetings as, I think, a way to drive enthusiasm for the program and show the differentiation as compared to other allogeneic-
Yes. Uh-huh
... programs. Should we expect that to continue moving forward as we look towards medical meetings-
You mean continued update on the durability?
Continued update. Yeah.
Yeah, I mean, at some point, we're going to have to make a decision, how long do we continue? Because, it's an endless updates.
Yeah.
The fact is, when you look at all the patients who are treated with the CD19, once you get to the six-month time point, at after that, very few patients progress. In the autologous CD19, the estimate is maybe around 10%, and that's more or less what we are seeing with the data that we have. We will go, you know, in terms of whether the, you know, any kind of incremental data adds to the, what we have already presented, but we will continue to do so-
Got it
... from time to time.
And then one program we haven't touched on, there are a number of different scientific-
... programs going on at Allogene, but maybe we could touch on the BCMA program.
Yeah.
I know you would kind of put this on the back burner, and you're looking to optimize the manufacturing process for BCMA? Where do things stand with BCMA, and how should we think about the cadence as-
Yeah
We move forward in the next few years?
I mean, for BCMA, we have two different programs, ALLO-715, where we have a lot of patient data, and the data that we have is that efficacy stands at about where Abecma is like.
There's a CAR T, you know, difference, you know, which is something that we are thinking through. We also have the next generation, ALLO-605, and both programs, we are trying to review the manufacturing, you know, with all the learnings coming from other programs. And at this point, you know, that's, you know, one area that we are focusing on. And another thing that we are a little bit sensitive about is, you know, cash runway and really trying to be realistic, you know, with a company of this size, how many different programs that we can take on. So right now, we are more interested in looking for the right partner before we bring that, the BCMA program back to the clinic.
Great. And then as it relates to the early clinical or early preclinical research, I guess, late-stage preclinical, but preclinical research, I believe you have Dagger technology that you're developing as a-
That's probably one of the most-
Way to, yeah.
... exciting, you know, the next-generation allogeneic platform. I mean, so Dagger technology is an offshoot of our CD70 CAR T program. The biology of CD70 is allowing us to perfect the Dagger technology, and that's really intent to prolong the persistence as well as expansion of the allogeneic CAR T. And in preclinical models, it works fantastic, and we also have the actual preclinical concept and a proof of concept coming from CD70. You know, one thing, if I even mentioned, you know, the most exciting thing about our 316 program, besides the clinical responses that we have seen, is the magnitude of cell expansion and the persistence that we are seeing.
And then we are trying to take that into a Dagger technology, which now can combine with any other CAR T programs, allogeneic CAR T programs, to make sure that the CAR T cells engraft, expand, and persist, you know, for a long period of time. And you know, that's the primary purpose, and also we are seeing with the Dagger technology, there is an opportunity to make the lymphodepletion even lower than what we are already using.
Yeah. When, when you say lower the lymphodepletion, is there a specific component that you would be looking to eliminate? Would it be the, the CD52 or the Cy/Flu or both, potentially in the long term? That'd be pretty incredible if you could combine and-
I mean, it will have to be a, you know, done in a step-by-step-
Yeah
... you know, fashion, but, you know, ideal situation is simply using ALLO-647 only.
Yeah.
Or just using that together with Cytoxan or cyclophosphamide. So, you know, those are the future that that, you know, we are sort of trying to explore. So, you know, preclinical program, I mean, it really comes to, you know, the technologies that will be considered as a next-generation allogeneic technology. And then there is a cell enhancement technology, such like Turbo CAR technologies-
Yeah
... that we are testing. And then, then also, pipeline, you know, the pipeline from perspective, with the, the data that we have seen, we're very interested in in moving additional programs into the solid tumor, and that includes a program that we have targeting DLL3 and Claudin 18.2. And I would say those two targets got a lot of, recent attentions, from positive data coming from many different companies.
Yeah, definitely a lot of positive data-
... in both of those spaces at recent medical meetings. I know we only have about a minute left here. Maybe a lot of great science going on at Allogene. Maybe you could touch on a little bit about the cash runway and how that dynamic plays a role as you prioritize your capital resources.
Yeah. I mean, you know, we've been thinking about cash runway, you know, from, you know, prioritization as well as trying to do it, things as efficiently as possible. As of last quarter, our cash position is at about $550 million, $545 million to be exact, which gives us a runway into the H2 of 2025, and that's way beyond the data readout from our pivotal study. So I would say that, you know, biotech space, I think everybody in this room, you know, knows that financing has been somewhat challenging over the last year or two, but, you know, our cash position is one of our strengths.
Great. Well, a lot of good things to look forward to as it relates to Allogene, as you enroll these pivotal studies and hopefully read out data in the next, you know, 12-18 months as well. So thank you so much for joining me, David. I really appreciate it.
Well, thank you very much for having me here, and thanks for, you know, your support.