Hey, good morning, everyone, and thank you very much for joining us at the 44th Annual Canaccord Genuity Growth Conference here in sunny Boston today. I'm John Newman, one of the biotech analysts here at the firm. We're very excited to have Allogene with us today. We have both the CFO, Dr. David Chang, as well as CFO, Geoff Parker. Welcome, gentlemen. So David, welcome, and perhaps we could jump in and discuss your lead asset, cema-cel. Wondering if you could discuss your first-line consolidation study in large B-cell lymphoma, known as the ALPHA3 trial. This is now the lead study, and just curious as to why you think cema-cel is very well suited for what's known as first-line consolidation there?
Okay, John, first of all, thank you very much for having us at this healthcare pharmacy conference, and also thanks for making sure that the weather is great outside. You know, important question. You know, before talking about why cema-cel is so well suited for the first-line consolidation, I think it's, you know, important to understand how the first-line patients are treated. Most first-line patients, the ones who are diagnosed with large B-cell lymphoma, the standard care for the past 30, 40 years in the United States and also globally, has been treating those patients with what we now call chemoimmunotherapy. The main regimen that most people talk about here is R-CHOP, but there has been some other regimen that has been introduced in the setting. The fact is that chemoimmunotherapy is very effective.
About 60% of the patients who get treated, essentially, their disease are cured. But there are the other 40 patients, some of them, they do not respond. These are called primary refractory large B-cell lymphoma. They need to go into a different treatment right away, but there are remaining 30% of the patients. They get treated quite well and achieve complete remission or what's considered as a very good partial response, where there is essentially no evidence of disease. But those two patients, if you follow them over a period of next 12 to 18 months, their disease will recur. The current standard practice is that you have to do periodic routine, you know, imaging studies to see whether their disease has recurred or not before you can act on it.
So what the cema-cel frontline consolidation trial is trying to do is capture those patients and treat them before their disease manifest and start causing problems with the well-beings of the patients. So why is this so attractive? I think it really starts with the fact that when you talk about CAR T, you're talking about potentially curative treatment, and using the curative treatment early on before the disease recurs, that's where you can maximize the potential of curative therapy. And this is something that the field has been talking around for a while, and Peter Marks at FDA has really been advocating, you know, CAR T treatment needs to move to the earlier line, you know, where you can maximize the benefit.
The second one, which is a little bit, you know, technical, is the fact that if you look at available data across, you know, all the indications that the CAR T has been treated, whether it's large B-cell lymphoma or multiple myeloma, CAR T treatment tends to be safer and more effective in a low disease volume setting. So here we're targeting patients who have minimal residual disease. I would argue that's the lowest disease burden that one can have, and those are the patients that we are going after. So it really adds on to what I've just said, maximizing the potential of CAR T and also puts the deck in favor of CAR T, treating low disease volume where the treatment can be safer and more effective.
And then, you know, the fact is, as I've alluded at the beginning, picking out, you know, selecting MRD positive patients, that really, you know, leads to treating only patients who needs the treatment.
Mm-hmm.
So I think all these are leading to what the investigators, and I also believe the regulatory bodies, felt likewise. This is really in a very innovative study design that's well suited for the current, you know, unmet need in the earlier line, large B-cell lymphoma, and that's the indication that we're going after. And also, you know, another thing, you know, we are, you know, a public company. We have to think about the potential of the indication that we are going after. Before we made a pivot earlier on, you know, we were trying to position cema-cel in the relapsed refractory setting. A lot of competition as well as, essentially, you know, diminishing market indication, versus now that we are moving into the earlier line, you know, the market opportunity is much greater.
We are potentially talking about close to 15,000 addressable patient population in the U.S. alone, creating a market opportunity of upwards of, you know, $5 billion in U.S. as well as Europe and U.K. combined.
Yeah, and David, if I could add a couple more elements to that. So, John, what's critical to remember is if you go back a year ago, we were doing sort of hand-to-hand combat in the third-line setting for LBCL, and with this ALPHA3 trial, of course, we're jumping ahead to the frontline consolidation, where we really have no competition right now, and is a very, very good application of allogeneic CAR T, because unlike autologous CAR T, we are off the shelf. So in that frontline consolidation setting, you've just come off six cycles of R-CHOP. Importantly, 80% of these patients are sitting at the community cancer centers.
They can now use CAR T at the community cancer center instead of being referred to an academic center where you would get your autologous CAR T. You can stay with your oncologist in your community center, get the allogeneic CAR T, which is a much simpler delivery and logistics issue, and we think that's a big step forward in helping patients and building a larger market. If you look at some of the recent releases with the autologous CAR T manufacturers, probably the two biggest issues they identify that are a limiter on their revenue growth, one is their manufacturing pipeline, and the second is getting the patients appropriately referred from their community centers to those academic centers. We just announced in our last release that we've already initiated 10 of our estimated 50 centers that we have in the ALPHA3 study.
Of those 10, the vast majority are already community centers. So you can see this, this huge amount of interest and enthusiasm to be in our study, because before now, these academ. these community, oncologists hadn't had the opportunity to deliver important CAR T therapy to their patients. And as David said, we went from probably a few hundred million dollar market opportunity in the third line, where we were making a very viable but increasingly difficult case against autologous, because autologous works very, very well, thanks to the work David and, and members of our team did at Kite. That product is very, very good.
But we've leapfrogged now to frontline consolidation, where being in the community center, being able to deliver the therapy quickly after they're diagnosed with MRD positive setting is very, very important and a place where autologous can't compete, given the time it takes to deliver that therapy. At that point, most of those patients will have relapsed.
Mm-hmm. That's a great point. Wondered if you could also describe the design of the ALPHA3 study. So we get questions from investors and other parties, about things like the control arm, why Allogene thinks that's appropriate, and also just what patients currently receive now in this setting?
Yeah. Hmm. You know, so study design, you know, this is something that our team has worked very closely with the investigators, and obviously, as I've said earlier, the study design has been well vetted with FDA, with the idea that if the study is successful, the outcome of the study could be used for the BLA submission and potential approval. So in terms of design, you know, the important part is, you know, the patient population. So the patient population that we are going after are the patients who have completed first-line chemo immunotherapy and their first, you know, follow-up visit. That's when the MRD testing is done.
If MRD is negative and the data supports that those patients, you know, will continue to have remission that lasts for a long time, those are not the patient population that will be eligible for the ALPHA3 study. On the other hand, if you are MRD positive, the chances are that your disease will recur within relatively short period of time. You know, I can't say exactly how, I mean, we estimate that the median time to disease recurrence can be, about 6 months. But essentially, you know, if you look at the field, about, you know, 90% of the patients who have a recurrence, those recurrence will occur within first 18 months after completing the first-line chemo immunotherapy. So that's the patient population. Study design is a randomized study.
We will be testing a single infusion of cema-cel versus what would be considered as a standard care, and the current standard care is following these patients radiographically and clinically every three to six months after completing the chemo immunotherapy. So there is no approved treatment, and to my knowledge, there isn't any ongoing trials that are targeting this patient population. So this is a really unique situation where we will be testing an active treatment of cema-cel to what essentially would be considered as a, you know, just observation. So that's number one. The study design, as I said, it's a randomized study. We expect to enroll about 240 patients for the ALPHA3 study. Currently, we are expecting the study enrollment to, you know, last till the first half of 2026.
So we expect the study to enroll pretty quickly. Study has one interesting twist, is that early on in the beginning, we will be testing two different lymphodepletion: FC, so that's fludarabine and cyclophosphamide. That's commonly used for the autologous, you know, CAR T treatment. And the second chemotherapy regimen, lymphodepletion regimen we'll be testing is what we call as FCA. FC plus ALLO-647, which is our proprietary anti-CD52 antibody that we have used and demonstrated as important for the allogeneic CAR T therapy in the relapse, recurrent setting. And the primary endpoint we will be using is event-free survival, and key secondary endpoint includes PFS and overall survival, and there's also other exploratory endpoints, such as, you know, MRD conversion rate that we will be testing in this study.
Mm-hmm. Okay, great. Also wonder, do you expect that most of the ALPHA3 patients will come from the academic centers or from the community?
So very important question. I mean, we are, you know, targeting both academic as well as community-based cancer centers for ALPHA3 study. So if you look at, you know, how the frontline patients are treated, I mean, the demographics of, you know, where they receive the care, about 80% of the patient cares are done in the community-based cancer centers. And when their disease recurs, sometimes they continue to be treated in the community-based cancer centers. If they elect to go, you know, for the CAR T therapy, at that point, they have to refer to so-called treatment certified centers. And there are about, you know, 100 or, you know, about 150 in that range of where the CAR T can be administered commercially.
When we look at, you know, sort of the projection of, you know, what we are trying to achieve and potential, you know, commercial utility of the cell if this study is successful, we feel that we have to go to the community centers where the patients are being treated. Not only that's where the patients are, you know, being managed, and also that eliminates the need for the referring patients from the community-based cancer centers to the, to academic or, cell therapy-certified, centers. So, you know, from that kind of logistics perspective, you know, we are targeting the community-based cancer centers pretty heavily, as potential clinical sites for the ALPHA3 study.
Mm-hmm. Okay. You know, David, minimal residual disease, or MRD, has been used in other cancers, such as multiple myeloma, for some time, but it's somewhat new in large B-cell lymphoma. You're developing a molecular diagnostic specifically to test for this. I wondered if you could talk about that.
So the concept of minimum residual disease to hematology, that's a very familiar concept. In leukemia as well as in multiple myeloma, MRD has been, you know, used, pretty extensively. You know, what's different about the, the large B-cell lymphoma is, you know, in this setting, you know, cell-based, you know, MRD assay, which is sometimes used for the lymphoma and, multiple myeloma and leukemia, is not really cannot be used. It has to be a circulating DNA-based, test. So the—for the patients to undergo MRD testing in large B-cell lymphoma, what's needed is couple tubes of blood collection, and the sample then undergoes, you know, some next-generation sequencing, plus, a proprietary algorithm to decide whether the patient has a circulating DNA or not.
So we are working with a diagnostic partner, Foresight Diagnostics, that has been, you know, developing this, Clarity test. This at this point is an investigational use-only test, and so far, the published data suggests that it brings a, you know, exquisite level of sensitivity and specificity. We're talking about sensitivity, you know, being able to identify MRD at about 90% and also sensitivity in the, you know, upwards of 97%+. That means that if you are MRD negative, you know, your disease does not recur. So, Foresight has published, you know, Kaplan-Meier curve of outcome of patients who are tested MRD positive versus MRD negative at the end of frontline chemoimmunotherapy, and that curve diverges, you know, clearly as one can see from, you know, immediately. So if you are MRD negative, essentially your disease will not recur.
On the other hand, if you are MRD positive, your disease will recur with a minimum, you know, time of about 4-6 months. So that's the beauty of going after this MRD-positive patient population for ALPHA3 study.
Mm-hmm.
And I would, I would add to that, that having Foresight as a partner, there are other LBCL MRD tests, but they didn't have the sensitivity and specificity that Foresight has. They were more in the 40%-60% area, which, as you can imagine, as a, as an oncologist and as a patient, it's a bit of a coin flip as to whether that test has a false positive, false negative. Not a great test to give your patient. With Foresight, it is so accurate now that it's actually been a huge driver in sites wanting to be involved with our study. Because you can imagine that a patient's coming off R-CHOP, you give them a scan, and as David talked about earlier, R-CHOP is very, very effective.
So 90% of your patients are going to show a complete or very good partial response off R-CHOP. 10% are going to be refractory; they're going to go right to second line. But of those 90%, again, it's divided: 60% are really cured, and 30% are going to relapse, and it's those 30% that are MRD positive. And so the physician's ability to provide that knowledge to their patient removes what they call scanxiety. This is the recur-- coming back for every scan, three months, six months later, "Doctor, am I still clear?
Am I still clear?" They now know with this Foresight test that they're either MRD negative and likely don't have to return to the physician, or if they are MRD positive, that's new information, and you have the opportunity to go on the ALPHA3 study, get cema-cel, one dose, and hopefully put you onto that MRD negative curve, which is effectively cured.
Okay, great. Maybe we can pivot just a little bit to ALO-329 in autoimmune indications, where we've seen a lot of interest here following an academic autologous CAR T study that was conducted by a physician in Germany, Dr. Schett, and also some initial readouts from a few biotech companies this year in autoimmune. Could you talk to us about how you view ALLO-329 as differentiated versus other players, and also some of the specific aspects of the molecule itself? Thank you.
Yeah. You know, first, you know, when we think about, you know, CAR T treatment in the autoimmune indication, the growing body of the evidence suggests that it brings a different value to the, you know, patients with autoimmune disease. There are a lot of effective treatments that are out there. However, it is a chronic treatment. Somebody has to be on it for the rest of their life. So if you are in your 20s and 30s and diagnosed with rheumatoid arthritis or lupus, you're talking about lifelong treatment. What the early evidence of CAR T is showing is really a paradigm-shifting approach to managing patients with autoimmune disease. Instead of the chronic treatment, one-time treatment that can potentially reset, which means essentially with a CAR T treatment, you push back the disease to the point that, you know, putting the patient in remission.
The remission, I guess the big question right now is: how long does it go on? Certainly, some of the, you know, the available data suggests the remission can go on for many years, you know, up to about three years. You know, and we need to follow those patients for longer, but that is the really paradigm-shifting concept that has emerged since Dr. Georg Schett presented his data treating patients with autologous CD19 CAR T. Now, you know, you know, with the growing, you know, evidence, you know, we made a decision that, you know, you know, this field, especially in the autoimmune indications, you're talking about large patient population.
I mean, even, you know, the common indication that people have talked about, lupus nephritis, patients with SLE that has a kidney involvement, the number of addressable patient population for that indication exceeds, you know, the non-Hodgkin's lymphoma, you know, patient addressable patient population. So with that, you know, we had in mind that if you want to advance the CAR T, you have to address the patient need as well as the scalability. So we have designed ALLO-329, you know, with the autoimmune indications in mind. It's an allogeneic approach, and it goes after two different targets, CD19 and CD70. So essentially dual, you know, dual CAR. CD19 addresses the B cell component of the autoimmune indications, and the CD70, which can eliminate activated T cells.
We expect that to address the T cell component of the autoimmune disease, so it really addresses the underlying dysfunction of the autoimmunity. Very important point. Number two, the CD70, or this is the basis of our Dagger technology. So what the Dagger technology does is allows the allogeneic CAR T to work as well as autologous CAR T, perhaps sometimes a little bit better if you follow the CAR T cell expansion data that we have generated with the CD19-only CAR T program that we are studying in the renal cell carcinoma patients. So that really creates the potential to eliminate or simplify one of the biggest barrier that we see, which is the lymphodepletion that is required to administer the CAR T.
So the concept behind our ALLO-329 is allogeneic addresses the fundamental, you know, dysfunction of the autoimmunity, and it creates an opportunity to simplify or potentially even eliminate the need of lymphodepletion that is required for the CD19. So this is a program that we are advancing pretty quickly. I forgot to mention another thing. You know, we also changed how we introduced the transgene into the T cells. Instead of using lentivirus, where the concerns around the T cell leukemia and lymphoma has been raised, we moved to the site-specific integration to potentially further reduce the risk of T cell leukemia and lymphoma. So there are many different things that went in, but this is very differentiated approach, and we are moving with this program pretty quickly.
You know, we expect the IND to be filed first quarter of 2025, with a potential initial data readout by year-end 2025.
Mm-hmm. Great. And just to follow on the comment that you made on lymphodepletion, are you planning to test lymphodepletion in the study or perhaps planning to test with and without lymphodepletion?
Yeah, that's a great question. That's much in discussion. We do have a plan, but, you know, we will further clarify exactly how we're gonna do it as the IND gets cleared. I mean, I think, you know, before we file the IND, talking about exactly how we're gonna do it, and sometimes we get asked about, you know, how many different autoimmune indications that you will be going after. You get asked those questions, but, you know, those questions are better suited to respond to as we are about to file or after we clear the IND.
Okay, great. Just one last question. Different program, ALLO-316, which is your CD70 CAR T, in renal cell carcinoma. Just curious if you could talk about your plans there going forward?
Yeah. So ALLO-316, this is a CD70-only CAR T program that is being studied in the renal cell cancer indications. The last time we presented data was AACR 2023, where we covered about 18 patients, including 10 patients who are CD70 positive. And at that presentation, we demonstrated proof of concept. We showed objective response rate about 30%, 3 out of 10 patients who are CD70 positive. And also, you know, there was also tantalizing finding that everybody had a disease control. Nobody was progressing in the first assessment. What we plan to do at the year-end data update, you know, we will have more patients who are CD70 positive. We estimate it will be somewhere in the 20 patients, so essentially doubling the evaluable patient population.
The second one that we will be covering in the data update is a protocol amendment that we have introduced into the 316 study to address some of the adverse event findings that we have observed early on. This is hyperinflammatory syndrome, and we have amended protocols, so we will be covering the, you know, experience coming from how we are managing those hyperinflammatory syndromes that we have seen in this study.
Okay, great. Well, we are out of time, but I wanted to thank Allogene, David and Geoff, for joining us, and also thank you to the audience.