Good afternoon, everyone. Thanks so much for joining us. I'm Salveen Richter, biotechnology analyst at Goldman Sachs, we're really pleased to have the Allogene team here with us. We have David Chang, President, CEO, and Co-founder, as well as Eric Schmidt, CFO. Maybe to start here, Eric, you know, given the news today, maybe you just want to walk through, just provide us some of your thoughts.
Who's he referring to? Salveen, as you know, we at Allogene announced my resignation today from the company, that was with very mixed feelings, as you can imagine. I've been at Allogene for five years, I've had the pleasure of working with David and Ari and Christine and many others to create what I really think is a preeminent cell-therapy company. In doing so, out of joy, I've been traveling back and forth, East Coast, West Coast, and doing so very regularly. Of course, with that travel, there are some stresses, but we persevered and again, created, I think, what is going to be an extremely successful company.
Honestly, the only thing that can take me away from this job, which I've truly loved, and these people, which I truly love, is some issues that I need to deal with at home. You know, family first, as I know you know very well, given our long history together, and there are certain sacrifices we need to make for our family, but you can't take that too far.
Maybe to start here, David, do you want to provide just a high-level overview of where we are here in the field of allogeneic CAR-Ts? You know, we know where autologous stands at this point. With allogeneic.
Mm-hmm.
it's been a question of optimization and kind of getting to that right situation on the initial tissue targets and then moving beyond. Where do you think this field is today?
You know, when I think about this here, I mean, it has been, you know, five years since we set the journey to advance the allogeneic. I think there's a lot more clarity about what's happening in allogeneic CAR-T space. The data really supports allogeneic CAR-T provides the long-term durability, and we highlighted recent updates to our phase I CD19 program at ASCO, and we will plan to do, you know, another update at, you know, EHA and Lugano meeting. When you look at the data, together with the cell expansion data, which we are also highlighting, you allogeneic CAR-T is bringing the efficacy on par with what autologous have shown and also safety profile, if anything, looks slightly favorable than what the autologous, you know, have shown.
Obviously, this is a cross-trial comparison. When you look at that kind of the data, analyzed in the, you know, with the modified intent-to-treat. We gave the autologous CAR-T credit for patients who were not able to receive the treatment because of the dropout while they are waiting for the manufacturing. Even with that, it looks very favorable. That together, coming with the benefit of being- off -the shelf, being ready to treat the patients without any bridging therapy. In our study, the median time to start the treatment is about two to three days, which is really, you know, translate to scheduling the clinic schedules and things like that more than anything else. You know, we do believe that there is a strong value proposition, coming from the allogeneic.
You know, another thing, you know, that we have been talking about for a little bit, but we're getting increasingly excited, is the potential allogeneic CAR-T therapy to move into solid tumors. I'm referring to our ALLO-316 CD70 program that we have shown proof of concept. Not only the clinical proof of concept, the cell expansion data that we are seeing, with ALLO-316, our CD70 program, is really, you know, quite striking. You know, taking a step back with all the noise around the cell therapy that everyone is experiencing in recent days, but when I look at where the allogeneic field is going, I would say that there's a lot more clarity.
For us, it's really executing the lead program, which is in the pivotal stage and getting across the finish line.
Maybe let's start with, your lead program, the CD19-
Mm-hmm.
-program here. That's targeting large B-cell lymphoma, and it's in a pivotal phase II at this point. Can you just describe at this point where you think the commercial opportunity lies? Is it, is it still what you thought in the beginning, that you had to just have a profile that was in line? Do you think that differentiation, you know, on one aspect is required, which you are on the safety side?
Mm-hmm.
You know, if that profile holds, I mean, help us understand where you get positioned. Is it just the patients who, you know, the 10% or so patients who can't wait for therapy, or is it just become a much broader kind of overlay?
Yeah. You know, I think, you know, that's a really, you know, fantastic question. I mean, ultimately, you asked a question, you know, if you asked a question to any clinicians about you have a product that is readily available, and you don't have to go the complex logistics of scheduling the patients for leukapheresis or waiting, for what will amount to be, you know, more or less about a month, before the autologous, you know, cell products are manufactured and then starting the treatment. During that time, you have to deal with uncertainty, and you also have to use some kind of bridging therapy to make sure that the patient's disease, you know, does not get out of control. That versus, you know, you have a product that can be infused. within days after you make the decision to make the treatment.
I think, you know, as a prior practicing oncologist, you know, in the academic setting, you know, when I think about those things, this is also the comments that we constantly, you know, get from the KOLs. I mean, that is really a very differentiated value proposition. I think there is a lot more that we have to do. In addition to where we are, which is a third-line setting, you know, our intent is move the, you know, ALLO-501A into the earlier line as quickly as possible. When you think about the earlier line, the value proposition even goes up higher.
You know, that's why, you know, earlier this year, we made it very clear that, you know, part of the goal this year is to finalize the study design for the earlier lines and then, trying to get the study started, you know, as soon as possible, sometime in 2024. We're continuing to work toward that path.
How do you move earlier line in the context of being used, maybe in some cases, refractory to the autologous?
Earlier line, I mean, there are many different ways to think about it. The CAR T, you know, autologous CAR-T, all started in the refractory 2-plus line setting. That means the patients have had to receive at least two prior lines of treatment for their lymphoma. The autologous CAR-T since then has moved to the second-line. The earlier is really somewhere between first and second-line or in that setting. Here, you know, there are various different things that we can entertain. The field is evolving. The concept of MRD-positive disease, this is an area where, you know, drugs like BLINCYTO has a very success in, you know, going after MRD-positive disease. That concept is also beginning to emerge in the B-cell lymphoma, something that we can leverage.
Also the fact that, especially in earlier lines, where there is more urgency to treat the patient, being able to offer the product right away, I think that's also a very differentiated, you know, benefit that we can offer. Stay tuned about, you know, as we finalize the study design and as we talk more about what our intent is to really get to, earlier lines.
You initiated the pivotal trial back in October and began enrollment.
Mm-hmm.
In the fourth quarter. Just help us understand where you stand on enrollment and site activation and trial progression. Are there any headwinds that we should be aware of?
Yeah. I mean, in terms of site activation activity, that is going very well, and it's almost done. I mean, I think the one, the additional layer of site activation that we are looking to forth in the next few months is so far, we have carried out all the clinical studies in the U.S. Part of the plan was as we expand the study and the patient requirement on the pivotal study, we would expand outside the U.S. We are waiting for the ex-U.S. sites to open up. As for the enrollment, we're not going to, you know, provide any, you know, play-by-play updates on how the enrollment is going. We are, you know, currently projecting that the study will complete the enrollment in the first half of 2024.
Got it. Would that be the point at which we see? Well, when would we see data? Would we still see data in 2024, or would it be?
Yeah, I mean, you know, in terms of what people care about, the initial response rate, if that is important, that's the data that could be available within a month or two after study completes the enrollment. Probably the more important and what we consider as a BLA-enabling data, that's where you follow the patients for at least six months, and that will be available towards end of 2024.
Right. The updated presentation at ASCO recently included.
Mm-hmm.
-longer-term follow-up data from the phase I trial, we saw 12 patients who were treated with the phase II regimen with a median follow-up of 23.1 months. What was the reason for presenting data from this specific subset of patients? How do you think about just the overall disclosure there, when you think of complete response levels?
In terms of what we presented is four patients with large B-cell lymphoma who are being treated, who had been treated in the phase I with the same regimen that we're using in the pivotal study. Obviously, we have treated a lot more patients than that, but that 12 patients we felt was most relevant from the technical perspective of predicting what may happen in the pivotal study. We keep highlighting. Obviously, the response rate and complete remission rate is something that we have talked about before, and, you know, that hasn't changed. It's really the attention to the durability, which has been the central question in the allogeneic CAR-T. I mean, there is still large skepticism about whether allogeneic CAR-T can provide the durability of response that matches up to the autologous CAR-T.
We felt compelled that we need to continue to educate the investors, analysts, as well as the field, that allogeneic CAR-T, you know, can provide the durability, and that's exactly what we have done. In addition, you know, what we also included in the ASCO presentation is the immune cell reconstitution. How does the recovery of the neutrophils, how does the recovery of the lymphocytes and other immune cells after allogeneic CAR-T? I would say the data is more or less very similar to what has been reported in the autologous CAR-T. There are many different things, and I think these are important scientific as well as a clinical question. We felt that, you know, providing that kind of data and having it out, for the KOLs and the investors and investigators, you know, was important. The reception to the data was extremely positive.
When you look at the durability here.
Mm-hmm.
in the context of CD19, how do you think about it kind of translating to different tumor types?
Yeah, that's an interesting question. I mean, I don't think that's something to be seen by indication, by indication. I mean, what we have learned over the years is, you know, what happens in ALL is slightly different than what happens in large B-cell lymphoma. Even in lymphoma, what happens in large B-cell lymphoma is slightly different than the follicular lymphoma, which is, you know, same B-cell non-Hodgkin's lymphoma. There are some differences, and I think that difference is really coming from the underlying disease itself, of not, you know, how CAR T cells are behaving differently. Rather than jumping and speculating too much, I think it really has to be, you know, data-driven.
You know, in the allogeneic field, so far, we have tested ALLO-501A, that is directed against CD19, and then also ALLO-715, you know, which is directed against BCMA. You know, even in ALLO-715, we see very similar, you know, the durability once the patient gets to the complete response, and especially if they are MRD-negative, if the durability is quite striking. The solid tumor is a wide-open question. We are still in those escalations, so that answer probably is better to be sort of, you know, provided sometime later as we have more data.
Help us understand the trial design for the phase III second-line trial, how that would be conducted.
Yeah. you know, you potentially, you know, back to CD19.
Yeah. CD19, sorry.
You know, the study that we are doing, you know, right now is a third-line study. That study is a single-arm study. We'll be looking at complete remission and duration of response. What you're asking is the next study, the earlier lines. The precedent here is that it will be a randomized study, you know, comparing against a standard of care.
You have a second pivotal trial called EXPAND, that's looking at the combination of 647-
Mm-hmm.
-which is your anti-CD52 to the lymphodepletion-
Yes.
-regimen. Can you just give us some color on what's playing out with the sites and your confidence in enrollment at this point?
Yeah. The second study is really to demonstrate the contribution of CD52 antibody that we are using as a part of lymphodepletion. The study design is randomizing patients to those who just get chemotherapy-based lymphodepletion versus chemotherapy plus ALLO-647, and everybody gets ALLO-501A. There is enough evidence that without anti-CD52 antibody, you will get early rejection of allogeneic CAR-T, which translates to not having much cell expansion or the efficacy. The confidence on that technically is very high. In terms of enrolling the patients, I mean, you know, there are people, you know, who know our data very well. They themselves are asking questions about, "You know what?
I don't feel comfortable, you know, risking half of my patients being randomized to FC." I think it's really, you know, the right question. You know, there are other, more, you know, sort of. I would say, you know, there is a fundamental question that needs to be answered here. I want to, you know, participate in this study. That study, the activation, you know, like the first study, is going well. It got started a little bit later. It's a new study versus previous study. That was a transitioning from phase I to phase II in a seamless manner. The EXPAND study was a totally new study. Activation and it got a little bit delayed. Now the activation as well as patient screening is ongoing.
Great.
From the study perspective, I mean, it's a much smaller study than the ALPHA2, which is the pivotal study. This study, you know, will be enrolling 70 patients. Essentially, we are targeting to enroll 35 patients to each arm of the randomized study.
On the back of this, you know, how would you incorporate it into your other studies outside of CD19?
In other studies.
Like BCMA.
In BCMA, I think, the, you know, so far, you know, we have growing, and this is something that we have seen consistently across different programs. CD52 antibody is very different with the allogeneic platform that we are using, and CD52 antibody is what's differentiating us, being able to show the long-term durability, whereas other allogeneic approach so far has not shown the kind of durability that we have shown. In terms of other studies, I think it's a little bit, you know, up to how we engage the regulatory agencies about for every program do we have to do, you know, the second study? Personally, I don't think so. But, you know, at least for once, we got to show good evidence that anti-CD52 antibody, you know, makes a big difference.
To fast forward, say, everything works out well according to how you're kind of planning.
Mm-hmm.
these, I guess, the cadence of these studies. When do you think you could have this CAR T on the market for CD19-directed tumors?
I think, you know, at this point, with the trial completion and the BLA-enabling data availability, which I've said, you know, which is towards the end of 2024, and when you consider review time and everything, potentially late 2025, you know, maybe 2026 in that time frame. We're not that far away from having the allogeneic CAR-T product in the market.
I'm just going to pivot before we go back to the portfolio, but I think you've talked about large biopharma interest in this field.
Mm-hmm.
Clearly, we've been seeing the success that's happening with autologous. As you're, you know, executing in this front, how are you thinking strategically about where biopharma thinks about allogeneic fitting in the pattern on the forward, and then your interest in having partners on the forward, too?
Well, I think, Salveen, there's no doubt we have too much on our plate right now for a small company. We've focused, needing to focus and executing on our pivotal programs and our CD70 program and hoping to keep the BCMA program moving forward, too. That's where we've been spending our resources. Beyond the programs that you've already highlighted, we've got a lot more in the hopper, especially in solid tumors, where we're really excited by our first CD70 data in renal cell carcinoma. Good proof of concept there and so much more that we could do with other androgen targets. We've talked about DLL3 and Claudin 18.2. Right now, we're capacity constrained, and as a result, we are open for business, and if partners can help us grow this pie and accelerate these programs, you know, we'll be all ears to that.
I think depending on the pharmaceutical company you talk to, some are in cell therapy, some are not yet in cell therapy. I believe the pool that's in cell therapy is growing and probably growing because of the success of products that you just mentioned. It's very, very clear, based on the autologous products, that these are probably the most potent anticancer agents we've ever seen and that they're moving forward into earlier lines of development, and they're being very successful there. Of course, commercially, we now have quite a bit of success with the first blockbuster cell therapies as well. I do think there's increased interest in the space. Obviously, as David referenced earlier, we still have a lot of wood to chop in allogeneic cell therapy to move the field forward. You know, you build it, and they will come.
That's the mantra in pharma, and I can't imagine it'll be anything different with cell therapy.
Let's jump to the CD70 program.
Mm-hmm.
We saw some initial proof of concept that looked pretty exciting. Just walk us through where you're going from here with the program, and how we should think about the next update?
Yeah.
that I believe is by year end.
I mean, in that program, you know, we generate initial proof of concept very early on. You know, even when, you know, essentially, you know, responses with the starting, you know, cell dose level, which was only, you know, 40 million cells. Like any other, you know, clinical experience, I mean, our intent is complete the planned dose-escalation. We want to know full range of efficacy as well as safety profile. Also, one thing that we are doing in that study, and this, you know, come back to it has really has to do with the unique biology of our CD70 targeting in a CAR is, and there is an opportunity to sort of start paring down the lymphodepletion. Study started using chemotherapy plus anti-CD52 antibody and also anti-CD52 antibody at very low dose.
With some initial results, we opened another arm that took out the anti-CD52 antibody altogether. We're using two lymphodepletion, and that's part of the initial, you know, the phase I, where we want to sort of fix the lymphodepletion as well as cell dose that we want to, you know, move forward with. That's the goal. Our current plan is, you know, enrollment on that study is really brisk, and we will update the hopefully completion of the dose-escalation phase towards the end of this year and then provide, you know, more clarity on which direction that we want to take the program.
I think you were screening patients for CD70 positivity.
Mm-hmm.
Just help us understand how that's helping you in the context of figuring out which patients may be better responders here.
Yeah. Renal cell carcinoma, if you look at the available data, much of which is based on the RNA expression level, CD70 could be positive in 70, you know, 90% to 100% of the patients. As you start actually looking at the protein level, the number goes down. What we have learned during the initial phase of the study, where we enrolled the patients without checking their CD70 level, but as we had chance to go back and look at their CD70 level, what we found was that patients, there are patients who are CD70 negative, and those patients, you know, there is really no evidence, strong evidence of clinical activity. What we have done is introducing in vitro diagnostic screening assay that will allow us to test the patient's tumor before the treatment, and if they are CD70 negative, they will be excluded from the study.
Is the screen and the ability to identify them pretty consistent at this point? Were there any hurdles in kind of, implementing this in a commercial situation?
Well, for the CD, you know, in the renal cell, I mean, you know, for those who may not know this, In vitro diagnostic assay has to be indication-specific in terms of validation. you know, that has been analytically validated, you know, with the samples and in terms of screening ability. it is investigational screening assay, but the intent is that as we advance the CD70 in renal cell, the diagnostic assay will be also advanced so that we can use that to select the patients if the product goes to the market.
Is there a minimal level of expression that's required here?
That is, you know, at this point, we know that if the CD70 expression is negative, it doesn't seem to work, and scientifically and biologically, that makes a lot of sense. What is the minimum level that you require? That is something that we will, you know, establish as we get more patient experience.
We will get an understanding of this through the upcoming data set?
We will have much better understanding as we treat more patients.
Perfect. Mm-hmm. At the R&D day, you introduced us to this Dagger technology.
Mm-hmm.
Can you discuss what it is and how you're incorporating it within your pipeline and in combination with...
Mm-hmm.
ALLO-647?
Yeah. I'm glad that you brought up the Dagger technology. It's a fascinating concept. CD70 CAR, it recognizes CD70 as a target, and CD70, you know, is expressed in renal cell cancer. It is also expressed in certain, you know, lymphocytes, and especially B cells or T cells that are activated, they upregulate CD70. What that sort of translates is, in the allogeneic CAR-T, one of the hurdles that we had to overcome so far is making sure the allogeneic CAR-T is not rejected by the patient's immune system. With a CD70 CAR, in an early indication that we have, I mean, we have enough laboratory experience. I'm talking about the clinical experience, such as seeing the CAR, you know, CAR T expansion.
What appears to be happening is our, you know, ALLO-316 CD70 CAR is able to go after activated T cells. These are activated alloreactive T cells that are trying to destroy the allogeneic CAR-T cells, they are eliminating those cells while leaving non-activated T cells alone. I think that is what's really contributing to this very unique cell expansion profile that we're seeing with the ALLO-316. You know, nobody has shown anything like this. This is really, you know, differentiating from how one thinks about how to protect the allogeneic CAR-T cells from the immune rejection. The concept has now advanced internally, where we are putting CD70 CAR together with another CAR, thereby protecting the entire, you know, CAR T cells. That's what we call as a Dagger.
We have shown preclinically that it works with CD19 as well as other, you know, target-directed, you know, CARs. It, it really is becoming a platform technoloy and, you know, preclinical group, the research is really preparing to generate all the next generation construct that is based on the Dagger technology. Why is this interesting is that, 1, you will be able to control the allo rejection much better, and also there is a, you know, opportunity to pare down the lymphodepletion, which can open up the use of the CAR T more broadly, especially as you think about early lines in the community setting or potentially even outside oncology.
Right. Just pivoting to multiple myeloma.
Mm-hmm.
Just remind us here on where the strategy lies now, as you think about further optimizing, what are these levers you're playing with, and when will we have an understanding of where that's ending up?
Yeah. So we, you know, the multiple myeloma, we have ALLO-715 that has shown a proof of concept. About, you know, a little less than a year ago, we decided to pause the program to review the manufacturing process for potential improvement. Essentially, you know, looking for, you know, manufacturing process and looking for improvement, that is done. Now, the discussion that we are having is multiple myeloma, especially BCMA targeting therapy, is getting very crowded. Is that the right resource that we should be, sort of, putting into the BCMA program? Or should we, you know, simply think about this as a potential, you know, partnering opportunity? So, you know, that's what's going on in program and, you know, could go into the clinic, you know, sooner than what we had initially planned.
I think there's a bigger discussion that we have to have before making, finalizing what to do with that.
Got it. Is the manufacturing optimization or changes alone enough to get you to the profile you want to get to? Or are you thinking about TurboCAR or any kind of other aspects?
You know, here, the profile that in the multiple myeloma, especially in BCMA, is, well, there are two approved products, CARVYKTI, which is pretty remarkable in a CAR T program with efficacy that is really, you know, nobody else has been able to produce that kind of efficacy and then Abecma. In our phase I study of 715, what we have shown is that our profile is more close to Abecma rather than, you know, CARVYKTI. With the manufacturing process, can we push it out to CARVYKTI? Preclinically, it looks good, but ultimately, that's a clinical question. I think, you know, before just jumping into and, you know, running the study, we want to be very thoughtful about how to make that determination.
You know, I think there is a, you know, pretty reasonable, you know, sort of thought process behind about, well, maybe this is better to think about finding a partner.
Maybe just to pull on that thread. Between capital allocation and partnerships, how are you allocating across everything? Your three programs, your technologies at this point.
Right now, the pivotal study is number one priority, and if anything, you know, there's a growing need as we think about the earlier lines. Number two is solid tumor. Solid tumor at this point, you know, CD70 program, we can continue to do so, but as we talked about, there is a, you know, need to expand that into different directions based on the preclinical data, based on the clinical data that we have generated. Then there is a very attractive targets where the CAR construct is ready to go, move forward, DLL3 and Claudin 18.2, that Eric has mentioned. Again, you know, we're not able to fully, you know, resource that.
Right now, main focus is let's just make sure that CD19 program is fully resourced, and let's keep the CD70 going until, you know, we either raise money or we enter into the partnership that will allow us to really spend more effort on the other solid tumor programs.
Any questions from the audience?
Hey, thanks. As you think about moving CD19 into earlier lines, what type of profile do you think would be competitive in that setting, and what's the bar?
In the earlier lines, I mean, I think, you know, safety, you know, does matter a little bit more than in the late stage. I mean, so far, the safety profile that we see in the third-line setting is, looks very favorable. I think there's a lot of plus side. In terms the efficacy, I mean, obviously, you know, the efficacy, the better it is, you know, much easier, but you're talking essentially in a randomized study, you know, being able to come better than, you know, the standards of care.
Well, with that, thank you so much. Eric, you're going to be very missed in the context of Allogene, and we look forward to continuing to work with you.
Thank you, Salveen.
Thank you.
It's been a pleasure.
Really, Eric will be missed, but he's not going anywhere. Thank you very much for hosting us.
Thank you, David.
Thank you.