All right, great. Good afternoon, everyone. Tyler Van Buren here, Senior Biotech Analyst at TD Cowen. Thank you very much, once again for joining TD Cowen's Fifth Annual Oncology Innovation Summit. For our next session, it's a pleasure to have a fireside chat with Allogene, and it's my privilege to introduce David Chang, President, CEO and co-founder. David, thank you very much for joining me.
Hi, Tyler. Thanks for having Allogene on your innovation summit. Very exciting!
Of course. So, before I get started, for those of you in the audience, if you have questions, feel free to shoot me an email at first.last@cowen.com or tyler.vanburen@cowen.com. So, let's go ahead and get right into it, David. So I wanted to start with cema-cel, and the ALPHA-3 trial and the pivot to, the frontline, right? Which is something we're not used to hearing. But for those who, may not be up to speed on the story, it'd be great if you could start by giving an overview of the bold decision, you guys decided to make in January to transition clinical development of cema-cel, formerly ALLO-501A, from the third line to the frontline.
Yeah. So moving the cema-cel program into the earlier lines, that has been in plan for some time. I mean, always, you know, traditionally, in oncology, a lot of times you start the initial proof of concept in the third or later-line stage and then eventually move up. And, you know, we have been trying to find the right place to place the, you know, the earlier line study. And what happened about 18 months ago, you know, which we really consider as a watershed moment, is, finding out that there is a way to identify patients, who complete the frontline treatment. You know, when you complete the frontline treatment, 90% of the patient will have a good response, and they will get followed. Unfortunately, when you follow these patients, about one-third of them will recur.
The problem was that you cannot predict, you know, who will recur at the end of the frontline treatment. So the watershed moment is, you know, finding out there is a circulating DNA-based MRD test that can predict who those 30% of the patients are. So when we came across that study, we moved very quickly, matching up this diagnostic assay to cema-cel, which has shown, you know, 50% response rate in the third line setting. So, you know, with that, we worked with the KOLs and came up with a design that now is in the process of activating the study. What we had to do between the initial discovery of this, you know, the diagnostic assay, which our partner, Foresight Diagnostics, is...
has developed, is working with the regulatory agencies to, you know, finalize the study design and getting the buy-in for the design as well as endpoint. And when that was all taken care of, you know, earlier this year, we announced that we are moving into the frontline consolidation study. So this is really innovative study design, in many ways, meets a lot of things that everybody has been looking for. You know, one is earlier line with a definitive treatment that can potentially increase the cure rate. This is something that the entire field has been asking for, especially the FDA. And second thing is, with a diagnostic assay, you know, you select the patient and only treat those who needs the treatment. I mean, that's really the beauty of the, you know, MRD assay that we are employing in the study.
And then, you know, interestingly, you know, for some time, you know, we have known that when you treat patients with CAR T, patients with low-volume disease do better, both in terms of safety as well as efficacy. And we are going for the MRD positive. This is the lowest volume disease that one can come up with, and so we predict that, cema-cel will behave much better than what we have seen in the early, you know, later line stage. And, that's really taking us to, you know, placement of the ALPHA-3 study into the community-based cancer centers, where the frontline patients are managed. So in many ways, it is a very innovative study design that meets what the clinicians are looking for in the treatment of large B-cell lymphoma.
We are very excited about making this very important pivot and essentially putting cema-cel in a much more attractive path for success, both from the clinical development-wise, as well as from the commercial aspect as well.
That's great. Thanks for that overview. So you mentioned that you made this decision in concert with, or discussions with KOLs. So maybe you could just start by discussing the investigator feedback that you guys have received so far as a result of the transition from the third line to the frontline for the ALPHA-3 trial.
I mean, I think, you know, probably the most telling comments that we have heard, and this is coming from more than one, you know, investigators, I mean, it's almost, you know, uniform reaction that we get, which is: "This is exactly the kind of study that we have been looking for." And, you know, that sort of takes me back to 2015, 2016 when I was at Kite Pharma, launching what was the, you know, pivotal study for Yescarta, you know, ZUMA-1 study. It's the same level of enthusiasm and investigators wanting to participate in the, in the clinical study....
One very interesting, you know, you know, the facet to, you know, the investigator excitement is, the kind of, you know, excitement is coming not just from the academic-based cancer centers, where, you know, CAR T is being administered, but also from the community-based cancer centers, where they are saying, "You know what? Autologous CAR T, the logistics of it was just too difficult. We were not willing to, do the kind of things that will allow us to treat the patients with the Autologous CAR T in our community-based cancer centers.
But you are off the shelf, you are essentially providing us with a drug in a vial, and we see this as an opportunity to, you know, to, you know, expand the use of CAR T in the community-based cancer center." So, you know, two levels are very, engaged, and, you know, interesting feedback's coming from the KOL. So we are very excited about the ALPHA-3 study.
Yeah, we've heard the same thing from our top KOLs that we interact with all the time. They all wanna be involved with this study.
Mm-hmm.
I can imagine, especially at some of these major institutions, how many companies approach them with trials, right? So it must be refreshing for them to see a trial like this. But to some extent, a frontline trial like this has not really been feasible, right? I mean, when you think about testing for MRD in the frontline, historically, it just hasn't really been developed, which is why this partnership with Foresight Diagnostics that you mentioned is so critical. So it'd be helpful to hear you just elaborate on that partnership, and the test, and why their test is going to make this strategy both clinically and commercially feasible.
Yeah, so the, you know, the partnership that we have with the Foresight Diagnostics, I mean, that is a very strong partnership. We love their assay, and they love the fact that we are using that assay to address the unmet medical need. You know, so the path that we are taking with the diagnostic assay is a companion diagnostic assay development, is a companion, drug development. So at the end of the ALPHA-3 study, we are hoping that it will allow the approval of using cema-cel in the frontline consolidation setting. And also, Foresight is expecting that their assay will be approved for the patient selection. And in addition, they're also developing the assay as a lab-based, assay to allow the physicians to prognosticate the patients at the end of the, you know, frontline treatment.
So I think there is a convergence of what Foresight wanted to do and what we wanted to do, and we have found this common ground that allow us to work very effectively.
Yeah. Just so people understand, it would be helpful if maybe you could highlight what MRD testing was like before Foresight, and how that will change with the Foresight test.
Yeah, so MRD assay has been embraced very strongly in the hematology in our community. When you look at multiple myeloma, we recently had ODAC hearing on multiple myeloma and using the MRD as potentially an endpoint. You know, that was about 10 years in making, and also in the leukemia setting, MRD as assay has been constantly used. In the non-Hodgkin's lymphoma, in large B-cell lymphoma setting especially, MRD assay has to be a circulating DNA-based assay. And what the Foresight has done is increasing the sensitivity of the assay that allows you to be very specific, as well as very predictive in terms of the outcome. So the outcome here is when patients complete the six cycles of R-CHOP, you know, that's their end of the frontline treatment.
After that, you know, they are basically watching and waiting, you know, having a periodic tumor assessment to see whether their disease is all taken care of or whether their disease comes back. What Foresight has done is looking at patients at the end of six cycles of R-CHOP and seeing how many of them are MRD positive and MRD negative. Interestingly, it sort of breaks down to about two-thirds being MRD negative and one-third being MRD positive. And when you follow those patients, those who are MRD negative, they do not have any progression events in next two to three years, which is the most critical time period. Whereas if you are MRD positive, you will have a progression event with a median, you know, follow-up time in the range, you know, probably less than six months.
So this is very powerful assay that fits very well with cema-cel, which is shown in the third-line setting, you know, more than 50%, you know, CR rate. So that's the beauty, and that's the innovation, and that's why, you know, everyone's so excited about the ALPHA-3 study.
Yeah. And approximately how long does it take to detect MRD positivity after the six cycle of R-CHOP with Foresight versus what has been used in the past?
Yeah, so the way that the data has been generated, patients, after completing the six cycles of R-CHOP, they will have the first follow-up about three to four weeks after, and that's when the samples are taken. The turnaround time that we are working with the Foresight Diagnostics is that the assay, you know, once the sample is taken, it will be less than two weeks before we find the result of whether it's MRD positive or MRD negative.
... Okay. And the older testing methods were many weeks, right? Or potentially months.
Yeah, I mean, you know, every company is improving, you know, their MRD assay, and I expect that by the time, you know, that, our, you know, if the study is successful, when our drug is approved, there will be more than one MRD assay, which is also, you know, how this field is really evolving. So others doing this, yes, right now it takes a little bit longer, but as time goes on, I'm very confident others in the, you know, in the MRD assay space will also make an improvement.
Okay, great. Good for patients, obviously. Would be good for you guys as well, if patients have better understanding of their MRD status. So, what progress have you guys made to initiate Alpha-3, and what do you think an approximate timeline for enrollment, completion might look like?
Yeah, since we announced the pivot earlier this year, you know, much of our focus has been, you know, you know, identifying and activating the clinical, you know, sites, you know, preparing for the activation. So, essentially, you know, we are targeting about 50 clinical sites in the U.S. Our projection is that those 50 sites will be sufficient for the enrollment of, target, patients, 240 patients, for the ALPHA-3 study. So we have identified all the sites, and we are undergoing the work, such as contract negotiation, IRB review. So everything is, very much on track, and the last thing that we are waiting for is the clearance of so-called IDE, which is the, regulatory process that's required before we can use the diagnostic assay. So it- it's very much on track.
We expect, as we have been saying, the study to be initiated mid-2024, and recently we provided more, you know, guidance on the cadence of the study enrollment. We actually now project that the study will complete enrollment by mid-2026. We expect about two years of enrollment for the 240 patients that we are targeting.
Okay, great. I'm going to take the under on that, given the enthusiasm by investors, but I realize, you guys have formal guidance. But I guess based upon conversations with the FDA, what EFS benefit do you believe you guys need to show on the primary endpoint versus control in this trial to succeed?
So as I've talked about, EFS is the primary endpoint that we're using, and in fact, the autologous CAR T trials in the second-line setting also use EFS as a primary endpoint. In terms of, you know, progression that occurs at, if you're MRD positive, as I said, it happens very quick. And with a 240 patient study, is well powered to demonstrate clinically meaningful difference. And in terms of, you know, what is a clinically meaningful difference, I mean, that's, you know, the- in my view, the best way to really understand that is what the clinicians are saying. So, they're saying about, you know, a quarter of the patients that you treat with cema-cel, if they can be cured, meaning if they are pre- you know, their disease do not occur.
I mean, that's something that this field, you know, with all the development that has occurred in the large B-cell lymphoma, has not been able to accomplish over the last 20, 25-year time period. So that's what the clinicians are saying. Obviously, we are hoping for more, but, let's see what the study shows.
Okay, great. Last one on the frontline strategy that you have particular insight into, given your experience. Do you believe that autologous CAR T therapies are gonna follow you into this setting?
Yeah, I think, you know, right now, you know, this is a study design that nobody has thought about before. Obviously, you know, without the benefit of MRD, you can't even conceive, you know, what to do in this space. As we progress, you know, would others possibly consider doing a similar study? Possibly. We'll have to see. In this setting, you know, I think one important thing is speed matters, 'cause MRD positive patients do progress relatively quickly. You know, when you talk about autologous CAR-T, with the need to refer patients to the cell therapy centers, and also from then on, collecting, sending the patient for leukapheresis and then, you know, manufacturing the cells, that simply does not work.
Our current estimate is, you know, to go through that process, you know, will take, you know, about, you know, 10 to 12 weeks, and during that time, about one-third of MRD-positive patients would already have had a disease recurrence. So I think the fact that, you know, cema-cel, as an off-the-shelf, can be readily made available, together with the fact that we are placing the clinical studies in community-based cancer centers where they do not require the referral, I think that will be the key differentiation, and being able to treat patients early, as quickly as possible, I think it's going to be very critical.
Okay, that's clear. Let's move to CLL with the ongoing ALPHA-2 trial. Why decide to pursue CLL with cema-cel, and why do you believe it could be a better option than the approved CAR Ts?
... I mean, number one, you know, there is a growing unmet medical need in patients with CLL when the BTK inhibitors or the BCL-2 inhibitors are no longer working. And we've been hearing from the investigators, who have been pushing, "You know what? The need is growing." You know, it has been about, what, close to 10 years, and patients do eventually progress after BTK or BCL-2 inhibitors. And also what we have seen recently, you know, BMS, with their Breyanzi, took their relatively small study for regulatory approval and was successful in achieving getting the accelerated approval for Breyanzi.
You know, bar that was set, you know, 20% complete remission rate for modified intent to treat analysis, and 14% if you treat the data as an intent to treat. So when you count everybody who's involved in a study, you know, how many patients had a complete remission rate, the percentage is 14%. And we consider that to be a, excuse me, a reasonable bar for us to move into and with cema-cel. And the benefit that cema-cel is bringing here is addressing the, you know, very fundamental issue of autologous CAR T in the CLL. In patients with CLL, you know, they have leukemic burden, and the leukemic cells also affect the functions of the T-cells, from which you have to manufacture autologous CAR T.
By manufacturing the allogeneic CAR T-cells from the healthy donor, we avoid the problem of dysfunctional T-cells, and we avoid problem of having leukemic cells being part of the manufacturing process.
Okay, that's helpful. So by year-end, we're gonna see an update from cema-cel and CLL. What... I guess safety is pretty straightforward, but what do you need to see on the efficacy front in order to make a phase II go/no-go decision?
I mean, certainly, you know, the bar has been set by, you know, Breyanzi. So, you know, we are sort of looking to either meet or surpass the bar that was set, by the Breyanzi. So, you know, we are doing the phase I study that's targeting about 12 patients. You know, the study is enrolling, and we are projecting, with, you know, based on our calculation, that by year-end, we will be able to, you know, to present the initial efficacy analysis on those 12 patients. So initially, we won't have much durability of the response data, 'cause that requires the follow-up, but we are hoping to have enough, you know, the response rate, to, you know, make a determination on whether we should start preparing for the potential pivotal of phase II study.
Okay. Maybe to wrap up the cema-cel conversation, it'd be helpful to get your latest thoughts on the opportunity and the front line, since people have been so used to thinking about third line plus setting for a while here, and also maybe CLL, if you have any comments there as well.
Yes. So, by our estimate, in the U.S., with a frontline approach, the market opportunity could be somewhere in the $3 billion. I mean, there are some assumptions that we are making, but I think that's a pretty reasonable estimate. But also, interestingly, recently, we announced that we have extended our commercial territory to include Europe, as well as the U.K. And simply adding the, you know, Europe, it just increased a commercial opportunity for a frontline to about, you know, $5 billion. You know, CLL also carries a pretty significant unmet need, and in the U.S., we estimated about $3 billion, and if you include, you know, Europe and U.K., that number goes up to $4.5 billion.
Previously, I mean, we were, you know, projecting the market opportunity around $6 billion for frontline and CLL. Now, with the extended territorial rights that we have, you know, that number is somewhere around $9.5 billion.
Okay, that's great. You'll have to forgive me, I'm gonna skip over RCC. We'll get to it in three one six.
Well, at some point, we gotta talk about solid tumors. I mean, the ALLO-316 program is also getting very exciting. But, yeah, I know that time is sort of running out, so.
Yeah. Well, we'll, I'll see if I can lob one question in there before we wrap. But autoimmune, given the interest, gold rush going on in the space, which you guys experienced at Kite, right, back in the day?
Mm-hmm.
and you guys have ALLO-329. So it'd be helpful for you to just describe-
Yeah
... why you believe you guys could have a superior candidate and approach.
I mean, first of all, there are a lot of companies moving into the autoimmune space, but, you know, let's be very clear. You know, there is a, you know, you know, you know, scientific reason and clinical reasons why, you know, people are so much interested in, you know, using the you know, the CAR T cell therapy approach to reset the immune system. I think there's enough evidence, you know, that have been published that it is feasible, and that really fundamentally changes how you treat the patients with autoimmune disorders. It's a very exciting time. We have given a lot of thoughts about, you know, how to best leverage this newly created, you know, opportunity in the autoimmune. And, you know, there are a few dimensions that we thought through this.
You know, one is scale and logistics that only allogeneic CAR T can bring, and also, as we think about the biology of, you know, what happens in the autoimmune disorders, patients who are treated with autologous CAR T, you know, it is very clear you are essentially, you know, trying to reset the immune system by depleting pathogenic B-cells. And you don't need a persistence, you just need a deep depletion of, you know, B-cells, you know, for a short period of time, and that also fits our allogeneic approach very nicely in this space. Now, you know, what we have done on top of that is two other things. One, we are taking a dual CD19, CD70 approach. For the reasons, you know, autoimmune disorders is never a B-cell disorder or T-cell disorder.
It's a combined disorders of both B-cells and T cells. And by having CD70 on top of CD19, our program, ALLO-329, can address both the B-cell as well as the activated T cells, which contributes to an autoimmune disorder. Very important issue. And then lastly, CD70 is, you know, the, you know, brings the Dagger technology into our ALLO-329. What the Dagger technology does is allow the allogeneic CAR T cells to expand, so much better, than, not having a Dagger technology. So essentially, what we are trying to do with ALLO-329 is, you know, aim to eliminate, lymphodepletion, which we consider to be,
This is something that all the key opinion leaders agree, you know. Lymphodepletion: none. Nobody likes it, rheumatologists or neurologists who are thinking about using CAR T to treat, you know, patients with the refractory disorders.
Okay. That's very helpful. I just had to ask it because it was autoimmune, and people are excited about it, but I promised you we'd get solid tumors. So 316 RCC, we're up on time, but maybe briefly, you could describe the update that we're expecting here by the end of June and what you need to see by year-end to make that go, no-go decision for phase 2.
Yeah, the update that we're doing for the 316, this is our CD70 CAR T program in the renal cell, is one providing additional clarity in how we believe that we can control the hyperinflammatory syndrome. And, you know, the publication that we are aiming is undergoing review, and it outlines a patient who developed hyperinflammatory syndrome and being managed with a commercially available drug. And this is almost like, you know, how the cytokine release syndrome was managed with the tocilizumab in the early days of CD19 autologous CAR T. So we're very excited about... Yes, you know, when you are going into a new area, sometimes you encounter a new adverse event, you know, you know, in a profile. We're very happy that, you know, we believe that there is a way to effectively control that.
The second update that we will do at the year-end is providing additional efficacy data on additional patients that we have treated since the last data update. Previously, we presented 11-patient efficacy analysis. Of the 11 patients, we had three responders, and by the year-end, the number that we will include in the efficacy analysis will be close to 20 patients.
Okay. Wonderful. With that, we'll go ahead and wrap up. David, thank you very much for your time and the interesting discussion.
Tyler, it's great to see you, and thanks for having me on your Innovation Summit.
My pleasure. Thanks to everyone for logging in.