All right, great. Thanks. Hello, everybody, Luca Issi, Senior Biotech Analyst here at RBC Capital Markets, and today is our great privilege to have Allogene for a fireside chat. Representing the company, we have David Chang, President, Co-founder, and Chief Executive Officer. David, thanks so much for joining us. How are you doing today?
Well, thanks for having me here. Unfortunately, I lost my voice a little bit, but I'll do my best to say it properly.
We appreciate that. We appreciate that. Thank you. Thank you, David. Look, we have a long list of questions here, and obviously, you're reporting your earnings on Monday. But maybe before we go into the specifics, can you just talk big picture about what progress has the organization made over the last few months, and most importantly, what's ahead here for Allogene?
Yeah. So, you know, Allogene, we've been advancing allogeneic CAR T therapy. Earlier this year, we made a very important realignment of the pipeline, and this is really focusing on innovation and differentiation as the key. Cema-cel is our lead program. This is a CD19 allogeneic CAR T. Initially, we were following what was done with autologous CD19 CAR T, which was really going after the third line. And this year, with some advances that were made in other areas, we pivoted that program from the third line to the front line as a consolidation strategy. So by doing so, essentially, instead of playing in a with a market opportunity that's in the range of $500 million, we just increased that market opportunity.
You know, together with the CLL, which is a second program that we are advancing, cema-cel into, the market opportunity became $9.5 billion. So, along with that being differentiated, you know, there is essentially no competition in the front-line consolidation, so that sets the program really well for both the speed at which we can execute the study as well as, you know, if we were successful, you know, how we can get into the market and potentially change the practice of how the front-line patients are managed.
Got it. Got it. Super helpful. Maybe can you talk a little bit about the Servier deal that you also announced on-
Yeah
Monday? Obviously fantastic that now you regain rights for ex-U.S., you know, obviously U.K., Europe, and other geographies. However, I thought it was also, they were also responsible to pay for some of the costs, so how should we think about the impact, the burn, if any, at all?
Yeah, I mean, you know, this is a fantastic deal. Essentially, we got rights to Europe as well as U.K., and also we can exercise the rights to the rest of, you know, world, like China and Japan, provided that we can demonstrate our capability to develop the programs there. The main thing about this deal, you know, which has been in making for quite some time, since 2022, when Servier decided to deprioritize their CAR T program. We have been, you know, trying to look for the right opportunity with the right economics, to get the rights, to parts of the territories that, essentially Servier has vacated.
So this is step 1 of the process where we're getting the rights to Europe and UK, and as we advance the program, you know, we will continue to, you know, look for additional territories. And also timing of that, I mean, this is really, you know, you know, fitting to our strategy. When we are in the third line, you know, getting the, you know, the European rights, I mean, that meant very little. But on the other hand, as we moved to the front line and also to CLL, the market opportunity, you know, just in the U.S., was about, you know, $6 billion. By getting the European rights, now the market opportunity went up by more than, you know, 50% to $9.5 billion.
Got it. Got it. Super helpful. Maybe, you already articulated the pivot from the third line setting to first-line settings. Can you just maybe talk about that trial in the first line? How are you thinking about enrollment and time to enroll that trial? Obviously, you're using an approach to enroll patients that are MRD positive post R-CHOP. The trial, I believe, is 240 patients, but only the minority of patients are actually going to be MRD positive post R-CHOP, so you probably need to screen a lot more patients than that. So in that context, how should we think about the timelines here to enroll that trial?
First of all, you know, this is a very innovative trial design. What we are doing, and I think, you know, maybe I should spend a minute or two explaining how the frontline treatments are carried out in the large B-cell lymphoma. R-CHOP or related chemoimmunotherapy is very effective treatment, you know, for large B-cell lymphoma. So however, there are about 40% of the patients who do not benefit from R-CHOP. You know, there's a 10%, relatively minor, you know, but in these patients, what's known as a primary refractory patients who do not respond to R-CHOP and progress right into the second-line treatment. The other 30%, these patients initially have a good response, but as you follow them, their disease will recur.
Before the MRD assay, which I'll talk about, there was no way to identify who are these 30% of the patients, you know, that will—whose disease will recur after R-CHOP. What the MRD assay is allowing us to do is identify those patients and we are targeting those patients to ALPHA-3 study, and patients will randomize to either the standard of care, which is observation, or cema-cel treatment. So as you said, this is 240 patient. We project that the study readout will occur by, you know, towards the end of 2026. So the current timeline is that we expect the study to initiate within next month or two. And then there's two other important milestone.
Middle of 2025, we will make one selection, which is the selection of lymphodepletion, and that's one. And then the following year, in 2026, in the first half, we expect to complete the enrollment as well as carry out first efficacy interim analysis. And then after that, six months after that, we projected we will be carrying out the primary analysis of the EFS, which is the endpoint that we are using.
Got it. Got it. Super helpful. You already touched upon it, but I'd love if you can expand a little bit more on the Foresight assay, maybe why is that so innovative? How does it work? How do you dichotomize MRD positive or MRD negative? And maybe if you can remind us what's the sensitivity and the specificity of that assay, that'd be great.
Yeah. So Foresight is the diagnostic partner that we are working with. They advanced a very innovative, you know, the MRD assay known as PhasED-Seq assay. So the sensitivity of this assay is more than 90%, and also the specificity is, you know, extremely high, which is really what's allowing us to carry out the ALPHA-3 study. If, you know, if patient is identified as MRD positive, their disease will recur, and their disease will recur at very fast pace, with the median time of recurrence between 6-8 months.
So that is really, you know, one thing that's adding to, you know, the power of the ALPHA-3 study, which is the frontline consolidation study, selection and treating only the patients who will need the treatment, which is a departure from how the frontline patients, new drugs are being developed for the frontline LBCL. It's an add-on to R-CHOP, but in this case, we let the patient complete the R-CHOP, carry out the MRD assay. If you're MRD positive, that's when we randomize them to cema-cel versus watch and wait.
Got it. Got it, got it. Very helpful. How should we think about the powering in that trial?
Uh-huh.
I mean, I think you probably have a pretty good idea of how the control arm will behave because there's a lot of literature around that one.
Mm-hmm.
But the active arm, I mean, isn't it? Was this, your therapy was never tested in the first line setting, so how do you go about making powering assumptions for the trial?
So it has not been tested in the front line setting, but on the other hand, we studied, you know, cema-cel in the third line setting pretty extensively to know that, in patient population that has a bulky disease, that would be the case in the third line setting, we can get a CR rate in the range of, you know, about 50% and durable CR in about, you know, 30% of the patients. So the data that we have generated in the third line setting is very similar to what autologous CD19 CAR T has shown in the third line.
Now, you know, the real twist is, in the field, it has been known for some time that patients with a low volume disease, so these are patients that could be identified as having low LDH or some of tumor dimensions that are relatively small, they tend to benefit a lot from the CAR T, both in terms of response as well as the safety. So now, when you think about what we are doing in the frontline consolidation, we are treating minimum residual disease, molecularly, you know, disease itself. So, you know, from that perspective, we're hoping that whatever we see in the third line setting will be, you know, much better in the front line setting. So, you know, back to powering of the study, this is a 240-patient study, relatively small study.
There are certain statistical assumptions that we have made, in terms of when we will carry out the, you know, the interim as well as primary analysis, and this is a very well-powered study.
Got it. Got it. Super helpful. And yeah, certainly looking at the data in the third line setting versus the second line settings for autologous CAR T, hopefully, that bodes well for moving it this even earlier-
Yeah
-in the treatment paradigm, so I think that's quite important. Can you talk-
And then also related to this-
Yep, yep
is, you know, currently, only about 20-25% of the LBCL patients, you know, have, you know, get referred to the, you know, the CAR T centers. The bulk of the patients, you know, you know, 60-75 of the patients, they are treated in the community-based cancer centers. So one other thing that we're doing with the Alpha-3 study is site selection, going, you know, placing the study in the community-based cancer centers, rather than limiting the studies to the, you know, the so-called the cell therapy centers. So we are hoping that they will also, you know, speed up the enrollment and also make the transition very simple, 'cause patients do not have to be referred from the treating centers, you know, to get CAR T therapy. The CAR T therapy will be given in the community-based cancer centers.
We believe that this is really important to continue to grow the utilization of the CAR T more broadly beyond what, you know, we are currently limited to the authorized T cell centers.
Sure, sure. No, that's, that's actually helpful. Can you talk about the interim look in mid-2025? Is your expectation that the CD52, the arm that contains CD52, anti-CD52, is gonna outperform the arm that does not contain anti-CD52? I was always under an impression that that was your assumption, at least when we talk about the third line settings. However, I kind of felt that maybe your language has changed a little bit around it, and maybe you're optimistic or cautiously optimistic that you may not need anti-CD52. Am I overinterpreting all this, or what are your thoughts?
No, I mean, you know, the language really has not changed. I mean, you know, in the third line setting, we used standard FC, this is fludarabine and cyclophosphamide lymphodepletion, and we add our own CD52 antibody, ALLO-647. That's the FCA regimen that we have studied cema-cel in the third line setting. And as I said, third line setting is a bulky disease. We are going into the MRD, so we also have to adjust for some changes. You know, we are dealing with a much smaller disease volume. For that reason, the study will initially randomize patients 1:1:1 to control, this is a watch and wait, and two different lymphodepletion, FC, which is a standard lymphodepletion that gets used, you know, like a CD19 CAR, and FCA, which is what we have been using in the third line setting.
Middle of next year, we'll be looking at the data, primarily focusing on MRD conversion. You know, patients who go on the study is MRD positive. Question is, how many of those patients after cema-cel treatment will become MRD negative? And we will use that basis to, determine which lymphodepletion to go forward. So stay tuned. I mean, it will happen as a two-step process. Obviously, we wanna see a lot more MRD conversion in the cema-cel treated, regardless of the lymphodepletion, compared to the control arm. And the second one is between the FC and FCA, which one, you know, behaves better.
It's a really two-step process. You're not only comparing +52 versus -52, but you're also comparing the active versus the-
Oh, yeah
... watch and waiting, and you'll see, you'll see what that data tells you.
I mean, that's why we believe that when we announce which lymphodepletion that we are moving forward, that in itself has a pretty significant de-risking information related to what's happening with ALPHA-3 study.
Got it. Super helpful. And will you just show us a qualitative type of press release or data disclosure, or are you gonna offer-
Yeah
... some numerical data around that interim, or how-
We will do so, but we have to be very sensitive about keeping the trial integrity intact. Because MRD conversion can potentially be viewed as, you know, positive clinical outcome, and if that happens, we can now affect the rest of the trial. So we do not wanna do that, so we'll have to be somewhat careful about exactly what we communicate. Certainly, we will communicate that, you know, one lymphodepletion has been selected, but beyond that, I don't think we can really talk much about quantitative aspect of what kind of MRD conversion we have seen.
Got it. Got it, super helpful. Maybe the last one on CD19. One of your competitors actually talk about partial HLA matching and the fact that maybe the data set with, you know, patients-
Yeah
... where there was a partial HLA match between the T cells that were infused and obviously the HLA subtype of the patients, maybe the data is a little bit more compelling. We have yet to see the data. Obviously, we'll see the data at ASCO, but conceptually, what do you think about that approach?
Yeah, so I can't speak for, you know, the competitor that is talking about HLA matching. Conceptually, it's a little bit hard to understand. I mean, HLA, there's altogether 12 HLA that needs to be matched in the transplant setting. You know, whether partial HLA matching provides something, obviously, we will have to see the data. However, in our case, we have looked at, you know, HLA matching and outcome in the, in the third line setting, and we did not see any correlation whatsoever. And obviously, in our case, we are developing cema-cel as an allogeneic CAR T independent of HLA matching. So it's a really true allogeneic, you know, one product that can be used in all different patients.
Got it, got it. Super helpful. Let's pivot maybe to CLL. I think the first look is at the end of the year. Can you just maybe talk about the opportunity in CLL more broadly, and maybe why you think that the allo's approach is better than auto? I mean, we have seen, obviously, the approval recently-
Yeah
... and maybe you can speak about what Breyanzi sets and why you think Allo could be better.
I mean, you know, we have said, you know, there is a growing opportunity in the CLL. I can tell you, 10 years ago, CLL experts, many of them are my friends, were simply telling me, "CAR T and CLL right now with the BTK inhibitors and BCL-2 inhibitors, you know, you don't really have, you know, the patients available to conduct clinical study." The same KOLs, you know, now are coming to us saying, "You know, patients are progressing after BTK or BCL-2 inhibitors, and they need a treatment." In many ways, our decision to move cema-cel into the CLL was very much driven by the, the encouragement coming from the KOLs.
We are taking this as a, you know, a, you know, allogeneic, and, obviously, the benchmark has recently been set by Breyanzi, who got the accelerated approval in the CLL setting, having demonstrated a complete remission rate of, you know, high teen, maybe 20%, depending on how you do the data cut. We believe that's a relatively sort of a soft bar compared to what autologous CD19 CAR T has shown in the large B-cell lymphoma. We are doing a phase I study, and we expect to have the readout of the phase I, initial readout, by the year-end. The advantage of allogeneic in this setting is CLL patients, the leukemic burden is high.
So when you leukapheresis the patient's cells to make a CAR T, there are leukemic cells and also you know, the immunosuppressed nature of the leukemic cells that affects the T-cell function. With the healthy donor-derived allogeneic CAR T, we do not have to worry about any of those things.
Got it. Got it. Super helpful. Maybe pivoting to autoimmune, over the last few minutes here, maybe a big picture question. I mean, in that foundational paper that the German authors published in the New England Journal of Medicine, I think there were, like, 15 patients with lupus-
Yes.
-that were, like, functionally cured. However, the other day, we did the math, and there was actually 22 companies now that are, in some sort, form, or shape, pivoting to, you know, CAR T for I&I . Is this becoming too crowded too fast? Is this, like, a structural problem that we have in biotech? Whenever you have, like, a breakthrough, you have, like, too many companies too fast going after it.
Yeah.
Any thoughts there?
You know, one may say that, you know, given how fast a lot of companies pivoted what they were doing in oncology into the autoimmune. But let's think about what the German, you know, investigators have shown. What they have shown with the CD19 autologous CAR is that you can reset the immune system, you know, which really takes away, you know, it takes, you know, how you treat the patients with autoimmune disorders with a chronic treatment to a one-time treatment that can reset the immune system and keep the disease at bay for a number of years. That's why the excitement is, and that's why everybody's interested in moving their programs into the autoimmune. Certainly, it's getting crowded, and this is another case where, you know, we thought about pivoting our ALLO-501A program, our CD19 CAR T, into the autoimmune.
At the end, we decided not to do that. We went back to the drawing board and designed CAR that really would fit the need of autoimmune disorders and came up with CD19, CD70 duo CAR, or ALLO-329. So the reason that we are adding CD70 into the equation is that CD70 allows the ALLO-329 to deplete not just the B cells, but activated T cells, which plays a role in autoimmune disorders. And also, having a CD70 CAR, as we have seen in another program, in ALLO-316, that's a renal cell cancer study that we've been doing. We know that when you have the CD70, we can let the cells expand to a much greater, you know, degree than not having a CD70.
So what's really needed in autoimmune disorders, it's the depth of the B-cell depletion, and we believe ALLO-329 can achieve exactly that, and also, you know, without the need of lymphodepletion. So objective of ALLO-329 is, you know, attack the fundamental, you know, cell disorders in autoimmune, both B cells and T cells, and also do that without the need of lymphodepletion. Once we can do that, I think that will really open up the use of CAR T in autoimmune disorders. Think about simply just giving cells without lymphodepletion. I think that is a very attractive proposition to anybody who's treating autoimmune disorders.
Sure. That's certainly great to see, you can use T cells-
Yeah
... as a PK marker and B cells as a PD marker, so that's a unique opportunity in that setting. You already touched upon this. Maybe you don't need, you know, the same aggressive lymphodepletion that we need in cancer, like, and there's optionality to dial back that lymphodepletion.
Mm-hmm.
Walk us through how you're thinking about that part. Are you gonna start with standard cyclophosphamide and fludarabine, and then you're gonna start, you know, lowering one versus the other? Which one do you pick first?
I-
Like, walk us through the mechanics that we're thinking here.
That's a fantastic question, and I would say that everything is on the table. You know, one option is, you know, start treating patients without lymphodepletion and then add cyclophosphamide and add cyclophosphamide and fludarabine. That's one option. The other option is start with the lymphodepletion and then start tapering off. We are considering both options, but, you know, we are still about 6-7 months before the IND, and we will finalize. Actually, you know, there's a lot of work that's already being done. We will start clarifying exactly how we design the phase I study as we get near the, you know, clinical study start. I think it's a little too early to talk about details of the study.
Okay, that's helpful. Last question in the last few seconds, maybe on CD70, I believe you mentioned that the publication is going peer-reviewed, peer reviewing as we speak. Can you just maybe talk big picture at what you found there? Like, it sounds like you have found a way to potentially address-
Yeah
some of the toxicity that you've seen.
So publication that you're talking about is, you know, how to address the hyperinflammatory response that we have seen with the CD70 CAR T program in renal cell cancer. We found that there is commercially available drug that is highly effective in controlling this phenomena, and, you know, the publication that's undergoing in a peer review is describing patients who developed this hyperinflammatory syndrome and how that was managed with this particular drug, and what the patient's response was. So I think, you know, that will be very interesting paper, and also, towards the year-end, we will update the renal cell cancer dataset, essentially doubling evaluable patients from the previous, you know, communication at AACR last year.
Super helpful. I have 300 more questions, but no more time. So thank you, David, for the time. Thanks, everyone, for joining us, and best of luck for the rest of your conference.
All right. Thank you for having me here.
Thank you, David.
Thank you very much.
Thank you. Best of luck for your voice, too.
It will come back.