Great. Let's get started. Welcome to the Piper Sandler Healthcare Conference. I'd like to introduce our next company. We have Allogene and their CEO, David Chang. Welcome, David.
Thanks for having me here.
You know, you're clearly focused on Allogeneic Cell Therapy. Can you just talk about, I guess, you know, with the lead program on the CD19, just, you know, an overview on your focus there in large B-cell lymphoma, and then we can probably talk about, you know, the autoimmune side of things.
Okay. As some of you may know, Allogeneic Cell Therapy, you know, we view that as the way to really democratize the cell therapy. You're not talking about just simplifying the logistics of cell therapy, but also making the cost of goods manufactured much cheaper, and also being able to take the therapy away from, you know, outside the specialized cell therapy centers to the community-based cancer centers where the patients are managed. Our lead program is CD19-directed CAR-T programs called Cema-cel. We have been studying that product and have published extensively our experience in the relapsed refractory large B-cell lymphoma. Based on that experience, and also taking into consideration the evolving landscape of lymphoma treatment, we took the program into a very unique situation in a so-called large B-cell lymphoma consolidation treatment. You know, taking a step back, large B-cell lymphoma is a curable disease.
Standard R-CHOP-based treatment will provide cure to about two-thirds of the patients. One-third of the patients do have a disease recurrence. At the beginning, there's no way of telling who's going to have a durable response and who's going to have a relapse. What really changed the setting here is advancement in the minimal residual disease detection method. We are partnering with a company called Foresight Diagnostics, which is providing the MRD assay supports. Essentially, our approach is letting the frontline patient complete the six cycles of R-CHOP and then test for the MRD. If you are MRD positive, and there's enough evidence that suggests that MRD positive patients will have a disease recurrence relatively quickly, capture those patients and randomize those patients to either Cema-cel treatment or what we would consider standard care, which is watching, you know, careful watch and observation.
That's the study that we are doing, Alpha3 study. We have been doing the study for the past year, and we expect to have the initial interim analysis released in the first half of next year. In this, it will be a limited number of patients, and we'll be focusing on biomarker analysis of being able to tell whether patients who are all MRD positive, that's the requirement to go on the study, what is the difference in the MRD clearance rate, MRD conversion rate between the two treatment arms. That's the information that we will share first half of 2026.
On the interim, what can we expect? Like, what's—is it the MRD conversion, and are we going to get, you know, numbers around the interim analysis?
Yeah.
What is the read-through on the interim to the final event-free survival primary endpoint for the Alpha3 trial?
Yeah. So what we have said is at the time of interim analysis data release, obviously we'll talk about the safety, but the most important thing is the MRD conversion, and we will show the details of MRD conversion. Now, you know, the question behind your question is, you know, what does the MRD conversion tell you about the eventual clinical endpoint? The primary endpoint that we are using in Alpha3 study is event-free survival, which is an endpoint that has been used for other CAR-T treatment in the second-line settings. We expect that if we see a differential of about 30%, we can more or less get a very good prediction to the eventual EFS endpoint.
Where we're getting this 30%, first of all, with a limited number of patients, you know, 30%, is a reasonable number, but probably a more important thing is when you look at the second-line study of CAR-T, you know, between the CAR-T treatment and what would be considered as a standard care, which is autologous bone marrow transplant, the differential that they saw in the complete remission rate was anywhere between 27%-33%. If you equate MRD conversion going from MRD positivity to MRD negativity to same as CR, I think we're in a very good place because with 27%-33% difference in the CR rate, the eventual outcome of the study was clinically and statistically significant improvement in the event-free survival, progression-free survival, and in the case of Yescarta, even the overall survival benefits. We see this 30%, as a very meaningful difference.
Having said that, in other areas in oncology, people are also leveraging the MRD test. Most recent publication is coming from bladder cancer trials. These are patients with bladder cancer who had total cystectomy. The study that actually got published a few months ago, IMvigor study, they selected patients and randomized patients to checkpoint inhibitor or observation based on if they were MRD positive. The clinical outcome of the study was, you know, statistically significant, and it will probably lead to label updates. Another thing that's important to sort of mention in this case is in that study, the MRD conversion difference between the treatment, checkpoint inhibitor, or the observation, that was only 11%. Still with the 11%, they saw clinically meaningful difference in the disease recurrence rate.
We view MRD conversion as a very important forecaller of, you know, what eventual clinical endpoint may look like.
You know, that's clearly, you know, significant derisking into the EFS endpoint. Can you talk about how the trial involvement has been going so far? When can we expect, you know, completion of enrollment? And, you know, with the MRD conversion, with the interim analysis next year, you know, will you be guiding for when the trial to complete?
Yeah. You know, so far we have been conducting the study in approximately 50 U.S. centers. That includes, you know, maybe a couple of sites in Canada. All these sites are very active, and, you know, we are screening patients for MRD and, you know, both a number of patients undergoing screening, as well as patients who are being randomized to our study, and that has been going steadily up. In terms of the trial completion, as well as the projected, you know, the timeframe for the clinical endpoint, you know, there will be two different analyses, primary analysis, as well as interim analysis of event-free survival. We'll provide those timelines more in detail when we communicate the interim MRD conversion rate in the first half of next year.
Got it. You know, I guess as it relates to patients that receive R-CHOP and that are MRD positive, what percentage of patients are MRD positive?
About one-third of patients who get treated with R-CHOP, you know, will have a disease recurrence. If you follow that logic, about one-third of them should be MRD positive. We are testing the MRD immediately after the completion of R-CHOP. So, you know, the number won't be exactly one-third. We estimate for the purpose of enrollment projection that about one-fifth of the patients will be MRD positive at the end of our frontline treatment.
Is it typically normal to test for MRD positive right after R-CHOP? Or what's, you know, what's a timeframe where MRD positive, if it's measured, would be measured post-R-CHOP?
Yeah. I mean, the published data that gives the estimate of MRD positivity at the end of the frontline treatment usually tests the MRD testing between, you know, one to three months after completion of the treatment. The way that we screen the patient and enroll the patient after completion of R-CHOP falls within that window.
Got it. Got it. Okay. Assume the trial is positive. You know, what are the challenges for market adoption? Because this is not, you know, a traditional, okay, refractory or second line. This is post-R-CHOP as a consolidation therapy. Your thoughts in terms of challenges to adoption, first is consolidation therapy, and then second, given that physicians would have to test for MRD positivity with the Foresight test?
Yeah. I mean, you know, like anything else, commercial adoption will be very much data-driven. The objective of Alpha3 study is not just improving the EFS. I mean, what we are trying to do is improve the cure rate of the frontline treatment. That is why instead of, you know, calling it, you know, sort of second line, we are calling it the frontline consolidation study. If we can show that, you know, we can reduce the number of disease recurrence in this patient population, I think the adoption will be great because it is considered to be one of the, you know, great medical needs in the large B-cell lymphoma. In this case, obviously, what has to follow is the adoption of the MRD testing. You know, that has been a growing trend in hematology and now also a growing trend in solid tumors as well.
We do believe, and there's ample evidence to suggest that adoption of MRD testing in this kind of setting continues to go up pretty high. I think all we really need to show is, you know, the clinical data showing that this is providing a meaningful improvement in the event-free survival. I mean, that's the primary endpoint. And then that translates to a patient not having any disease recurrence at all, i.e., you know, a patient getting cured after the frontline treatment. You know, with those two elements, I think the adoption will be very, very, very good.
Predominantly, this is going to be used probably in the community setting.
Exactly. Yeah.
In your trial, what percentage of sites are community versus academic?
I'm very glad that you brought up that question. One of the things that's limiting the adoption of the CAR-T is that the CAR-T therapy right now can be only given in the specialized cell therapy centers. Whereas the majority of the large B-cell lymphoma, and frankly, the majority of the B-cell lymphoma patients are managed in the community-based cancer centers. With that understanding, from the beginning, we targeted community-based cancer centers as, you know, for the enrollment into the Alpha3 study. Right now, you know, I would say the breakdown of academic centers versus community-based centers, it's probably, you know, 40-60, or 50-50. It's very close, about half of community-based cancer centers. Frankly, those centers are the centers that's, you know, really, you know, screening patients, and the participation from the community-based cancer centers has been extremely high.
For the community centers, are they keeping patients in their center, or is this done on an outpatient basis?
You mean, whether they are hospitalized?
Whether they're hospitalized, yeah.
We give that option to the investigators. I mean, you know, for different reasons, if they want to, you know, admit the patient for a day or two, we do not stop them, but we do not require patients to be hospitalized for infusion or the follow-up.
You have had patients, I assume, that have been dosed in the outpatient setting.
Yeah, without going too much into details, I can say that the majority of the patients are, you know, not admitted at all for this treatment.
Okay. I guess we'll look forward to the interim analysis next year on that.
Yeah.
I did also want to pivot to ALLO-329, the autoimmune program. I think some data expected there as well.
First half of next year.
First half. What can we, you know, what do we look forward to in terms of biomarker and response data? What types of indications are you enrolling in the autoimmune clinic?
Yeah. Our program, ALLO-329, we believe it's highly differentiated. It doesn't use lentivirus to make the CAR-T cells. It uses site-specific integration. It takes away the T-cell leukemia lymphoma concerns that the autologous CAR-T therapy has in the heme malignancy setting. Number two, we designed this with autoimmunity in mind and included not just CD19, but also CD70. It is a dual CAR that has a potential to deplete not just autoreactive B-cells, but also activated pathogenic T-cells that contribute to autoimmunity. That's the whole premise of this program that's designed for the autoimmunity in mind. We are currently conducting a basket study and enrolling patients with lupus or inflammatory myositis or scleroderma. We are doing a dose escalation phase I study using a two-parallel cohort. One cohort being lymphodepleted with a very simple one-day infusion of cyclophosphamide.
This is very simplified, reduced lymphodepletion. The second cohort, we are taking a little more bullish approach of not using any lymphodepletion at all. Those two parallel cohorts are currently enrolling. We are projecting that in the first half, we will be able to provide a handful of patient data, either the ones who are lymphodepleted with cyclophosphamide alone or the ones who got no lymphodepletion at all. The kind of data that one should be looking at in this setting is, you know, falls into number one, do CAR-T cells expand and do they deplete B-cells or CD-positive T-cells? That will be question number one. Number two question is a lot of autoimmune disorder patients with autoimmune disorders, they have disease-specific biomarkers such as autoantibodies, where you expect the titer of autoantibodies to go down.
In some cases, for example, patients with myositis, another biomarker that is frequently elevated is a muscle enzyme, CPK. With the successful treatment, we expect those disease-related biomarkers to go down. I think those two will be the crux of the initial data presentation. Obviously, some patients were treated early, you know, we can measure, you know, symptom measurements like DORIS response in lupus or, you know, similar disease assessment in scleroderma and others. That is more or less the expectation that we are setting for the first half of 2026.
How much follow-up will we have?
It will be limited. I mean, you know, we just started, you know, the phase I study. So some patients may have had, you know, a few months of follow-up, but relatively short period of time.
Got it. And then you're disclosing both cohorts or it's going to be one of the two, whether?
The current intent is both, you know, all the patients who we have treated at the time of presentation.
Will you be able to make a decision on data on which cohort to move forward with? Or do you expect that you would need more patient exposure before you make a decision on whether you require lymphodepletion?
Yeah. I think what you're asking is, based on the data, you know, can you decide on the dose and the lymphodepletion regimen that you will continue to advance the program? First of all, you know, what we intend to do is show that this program, this product is active. I think that is what the investors should be looking for. And then afterwards, I mean, this is really the development question, you know, what are the, you know, fast-to-market strategy and what are the indications that you can fully differentiate, you know, from other products because their target product profiles simply do not match what we have for ALLO-329. For example, because CD70, we have potential to go after activated T-cells. Are there autoimmune disorders that are more T-cell driven? Without a question.
Those are the kind of indications that we can really differentiate our product from, you know, the CAR-Ts or T-cell engagers or even in vivo CAR-T products that are simply targeting the T-cell components. Those are kind of in the development stage. I mean, we have already plans laid out, but, you know, in terms of determining cell dose and the lymphodepletion regimens, you know, it may take a little more patience to treat. I mean, I think those are important decisions we do not want to make based on a very limited number of patients.
You mentioned the CD70 and the potential there. What types of indications would you target, you know, that have CD70 biology?
Yeah. So CD70 is, you know, in a simplistic way, it can be looked at as a marker for activated T-cells. If you look at a lot of, you know, patients with autoimmune disorders, I mean, this is, you know, it does not matter whether you're looking at lupus, myositis, scleroderma. All those patients, they have very high levels of CD70 positive T-cell compared to, you know, healthy counterparts. There is already indication that CD70 may play a role in these different autoimmune disorders. From that perspective, you know, what we are really focusing is, okay, if you deplete the B-cells and also if you can deplete these T-cells that contribute to the autoimmune disorders, you know, what can we achieve?
You know, one is possibly prolonging the remission because not only the B-cells have to be, you know, sort of returning, but also the bad T-cells have to return at the same time. That can potentially translate to much longer remission for patients who are successfully treated with ALLO-329. The second question is being able to go after the autoimmune disorders that are very T-cell driven. Inflammatory bowel disorders, type 1 diabetes, multiple sclerosis to some extent, rheumatoid arthritis, although, you know, the latter two categories, there are many other pooled treatments. The development opportunities may be somewhat limited.
For some of those indications, you would potentially enroll next year at some point? Would that be the plan?
Stay tuned. You know, I don't want to, you know, you know, sort of be too much ahead of the game. I mean, our initial intent is let's show the proof of concept that ALLO-329 is active. Once we have that information, I think our team has sufficient development expertise and also the investigators that we have engaged in our study, a lot of them signing on simply the, you know, with the possibility that this, you know, has the opportunity to address the T-cell component of the autoimmune disorders. I mean, frankly, they say this is the most ideal product characteristic to take it into the autoimmune disorders. From there, I think we can move pretty quickly into either taking a totally differentiated approach or trying to pick a, you know, fast-to-market strategy or, you know, doing both depending on our overall bandwidth.
You know, we've had a couple of minutes left. I wanted to ask you a question. You know, you're clearly a lot of the platforms focus on allogeneic. There's been a recent trend in the last several months from big pharma, you know, going after in vivo CAR-T therapies. How do you think allogeneic compares to these in vivo approaches? Given we haven't seen any clinical data from these in vivo approaches, but, you know, talk about, I guess, you know, if you could compare and contrast the technology because it feels like in vivo CAR-T is like the flavor of the day right now with big pharma.
Yeah. I think in vivo CAR-T has some promise. I think, you know, when you think about all the things that need to be done, it still needs many years of refinement, not just on the, you know, how you treat the patient, but also how you manufacture. I mean, that's going to take some time. Whereas we've been working with the allogeneic CAR-T approach for a number of years. From the manufacturing perspective, everything's been taken care of. We have a lot of clinical data. Frequently, I think, you know, in terms of allogeneic CAR-T, the time is now. In vivo CAR-T, we still have to see a few other things.
Certainly, I mean, you know, you know, I can see some excitement about in vivo CAR-T, whether it's an LNP delivery that people are focusing on with the autoimmune disorders or the viral approach where people are focusing in the oncology indications. You know, with the allogeneic CAR-T, I think we can do both with a single product. Also, we can do very complex gene engineering, you know, with allogeneic CAR-T as we have done with ALLO-329, putting both CD19 and CD70 into a single cell, whereas such has not been demonstrated with in vivo CAR-Ts yet.
Do you think there would be a cost advantage with one approach versus another?
I mean, right now, I think that's the biggest unknown. How much does it cost to manufacture in vivo CAR-T? Because knowing a little bit about the cost of manufacturing, these are not simple products to manufacture. I think there needs to be some very substantial improvement in how, you know, in vivo CAR-T has been, you know, needs to be manufactured. For allogeneic, you know, we feel very confident about what we can do. I mean, frankly, we have said from a single manufacturing facility, we can produce, you know, more materials than, you know, 60,000 patient dosing, you know, from a single manufacturing facility. The cost of goods, that's probably, you know, a fraction of what those CAR-T. You know, we have said the cost of goods manufactured for allogeneic CAR-T is reaching the biologic cost of goods manufactured.
Great. I think we're about out of time. I really appreciate you coming, David, sharing your insights. Good luck with all of the updates in 2026.
Yeah, thank you very much. Thank you for the outstanding questions.