Great. Thank you again. And again to all those folks that make this so easy for us and provide us all the information, in case there's ever, you know, backup is needed. We have David Chang, founder and CEO of Allogene, here with us. David will be doing a slide presentation at the end of which we'll have some Q&A. We've been covering the Allogeneic CAR T space courtesy of Cellectis for a while, just started covering Allogene. We are big fans of Allogeneic CAR T, and we're looking forward to David giving us a quick update and then launching into some Q&A towards the end. So David, please take it away.
Well, Hartaj, first of all, thank you very much for giving me an opportunity to present and talk about what we are doing at Allogene. I'm the CEO and President of Allogene. As some of you may know, Allogene has been focusing on advancing and commercializing Allogeneic CAR T products for hematology-oncology indications, and more recently, adding to that is also our foray into the autoimmune indications. We are essentially taking unique advantages of what AlloCAR T can do to, as the title of this slide shows, doing what no autologous treatment has done before. This is the disclaimer. Earlier this year we outlined our vision for 2024 and going forward, essentially trying to shift the paradigm in terms of how we are developing the Allogeneic CAR T therapy.
you know, the most important aspect of this paradigm vision is the cema-cel in first line consolidation in large B-cell lymphoma, essentially to boost the cure rates in the front line and render later line treatment obsolete. We'll talk more about our cema-cel in the first line consolidation. Adding to that is advancing the cema-cel in the relapse and recurrent Chronic Lymphocytic Leukemia setting, capturing the growing medical need in CLL patients who have previously been treated with BTK inhibitors and/or BCL2 inhibitors. Adding to that is ALLO-329, which is our next generation Allogeneic CAR T products to address both B-cell and T-cell dysfunctions in autoimmune disorders. Also, the product attribute of ALLO-329 creates an opportunity to reduce and potentially eliminate the lymphodepletion to remove the key barriers of CAR T therapy in autoimmune indications.
And last, and also important, is, you know, our continued effort in advancing Allogeneic CAR T in solid tumor indication, ALLO-316 in renal cell carcinoma. Underpinning all this effort is the fact that we have our own fully owned and operational GMP manufacturing facility that is providing the clinical supply, and also essentially, you know, being ready in the manufacturing facility for commercial launch, upon the success of our clinical programs. So, let's talk about the ALPHA3 trial, you know, which is really advancing the cema-cel into the first-line consolidation. Why? I think this is the right time, on-demand products with potential to safely and powerfully consolidate remission, thereby reducing the need for the subsequent lines of therapy, and also the fact that we are employing very sensitive and specific MRD assays to identify the right patients.
These 2 elements really bring the, you know, the right time to advance the Allogeneic CART into the large B cell in the front line setting. And, you know, the fact that this is an Allogeneic really makes the therapy very, this approach very attractive. It, you know, treatment is immediately available as an off-the-shelf without any, you know, complicated logistics. They can potentially delay the start of the treatment. And also it significantly reduces the patient burden as well as burden to caregivers. And, you know, and the approach is really, you know, a, you know, one of a consolidation where we will provide the cema-cel treatment immediately after completion of the front line R-CHOP treatment, on patients who remain MRD positive after completion of the front line treatment.
So, what's really making us very excited about the frontline consolidation is the data that we have already generated in harder-to-treat, recurrent treatment setting. What's shown here is, you know, our phase 1 data coming from patients who relapse, who have relapsed-refractory large B-cell lymphoma. We have shown overall response rate in this difficult-to-treat disease setting anywhere between 58%-67%, of which, you know, 42%-58% complete remission that are quite durable. Another thing that we have noticed as we gain more experience in the relapse-recurrent setting is that overall safety profile numerically indicates that the cema-cel can be given very safely without incurring grade 3 cytokine release syndrome or neurotoxicity.
In fact, in the lymph depletion regimen and the manufacturing process that we have tested in the phase one setting, we had not seen any cytokine release syndrome or neurotoxicity, grade 3 plus event. Also, you know, with the lymph depletion, especially the one that we are using, FCA, there has been a lot of concerns about infection. But when you actually look at the infection rate, as the table shows, it also compares very favorably to other, approved Autologous CAR T treatment. Also, to be noticed, notable is that almost everybody who was enrolled in the study was able to receive the cema-cel treatment with a median time from enrollment to treatment of less than 3 days.
Now, you know, what is really enabling us to move into the front line, you know, MRD positive consolidation setting is availability of highly sensitive assay called PhasED-Seq, PhasED-Seq assay, which is coming to us through our partner, Foresight. This is exquisitely sensitive, and also comes with a highly, you know, high positive predictive value, as well as negative predictive value, which is essentially, you know, giving us a way to identify patients, not just who are at risk, you know, essentially patients who are destined to recur after the completion of the front line treatment, as shown on the right side, which is a Kaplan-Meier curve, you know, from the time of MRD assay, which is really based on the, you know, completion of the the the front line treatment.
If you follow these patients over a short period of time, those who are MRD negative, which is shown in the blue line, essentially remain in remission through the follow-up time. While those who are MRD positive, they recur relatively quickly, with a median time that we estimated to be somewhere between 8-12 months. This really sets us a way to identify patients that nobody else had been able to do before. Let me just illustrate this in the setting of how the frontline patients are managed. Once LBCL, large B-cell lymphoma, is diagnosed, the standard of care is undergoing Immunochemotherapy, whether it's R-CHOP or Pola-R-CHP, you know, anywhere between 6-8 cycles.
What we, and at the end of the treatment, the patients who are responding and the patients who remain refractory, and those who are refractory go straight to the second-line treatment. The responding patient that represents about 90% of the frontline large B-cell lymphoma patients. They are essentially, you know, left to watch and wait. Fortunately, with the Immunochemotherapy, 60% of those patients continue to be in remission. Essentially, their needs are addressed by the frontline Chemoimmunotherapy. But there are the other 30% of the patients whose disease relapse, and, you know, the only thing that you can offer them is just watching and waiting until there's evidence of disease progression, at which point the second-line treatment will be given.
What we intend to do is using the MRD PhasED-Seq assay to identify those patients who are destined to recur, and then offering the consolidation approach with cema-cel. The study design that we are envisioning is captured here. Patients upon completion of the frontline treatment, they will undergo MRD assay. If they are MRD positive, they'll be randomized initially into 3 arms. One, there is an observation that will be considered as a standard of care. The other 2 arms where they'll be receiving cema-cel, either after getting a lymph depletion with FCA or FC regimen. We intend to carry out a first interim analysis to decide which lymph depletion to move forward, in the beginning of 2025. Once that decision is made, thereafter, the randomization will be simplified to one to one, observation and the selected lymph depletion.
We will continue the enrollment till the target enrollment of approximately 110 patients in the observation arm and 110 patients in the test arm. So essentially, this is an extremely efficient study design where patients who are you know you know studied in the initial phase will be also used for the final data analysis. And here, the primary endpoint we intend to use will be event-free survival, which is a composite endpoint that consists of death, disease progression, or need for the subsequent treatment. And we expect the median time to event-free survival in the observation arm, you know, will be about eight months. So much of the endpoints will be driven in this study by the enrollment cadence. So let's talk about what that means in terms of overall front line setting.
We estimate that there are approximately 34,000 frontline, first-line drug-treated patients in the United States. As I've covered, about 30% of those patients, the need is not met with the frontline treatment, and they are destined to relapse. We have means to identify those patients using the MRD assay. Upon MRD testing, if we can capture 75% of those patients, we estimate the addressable patient number in the U.S market alone will be approximately 7,700 patients, which really represents over $3 billion in revenue potential. So how we foresee the, you know, market shaping in the frontline setting for the chimeric antigen receptor therapy is shown on the next slide.
On the left side is the historical information, as well as the estimated market penetration of the Autologous CAR T, which are currently approved in the second line and the third line setting. Most of the growth will be coming from the second line setting. With the success of the cema-cel frontline consolidation approach, we will be creating, you know, you know, more opportunities in the first line setting, essentially, you know, the revenue potential that will exceed $4 billion in large B-cell lymphoma. This is really taking full advantage of the advancement in the MRD assay and the Allogeneic CAR T therapy, which can be readily available and also safely to patients.
In fact, the planned study that I have just talked about, we intend to, you know, open up the study not just in the tertiary centers, but in the community, you know, you know, based cancer treatment centers as well, where most of the front line patients will be treated. The second part of our 2024 vision is advancing cema-cel into recurrent and relapsed chronic lymphocytic leukemia. The time is right. Because, despite the advances that have been made with BTK inhibitors and BCL2 inhibitors, these treatments are not curative, and patients will eventually recur. And now it's about, you know, 7-10 years after approval of these patients. There is a growing need for providing more effective treatment on those patients who progressing after BTK inhibitor and BCL2 inhibitor treatment. As an Allogeneic, we believe this is an right approach.
It eliminates the need for Leukapheresis and complex delivery logistics. Also, you know, provides accessibility or a scale that can reach patients where they are treated, where they are treated to address a large patient. Also, because the Allogeneic products are made from the healthy donor lymphocytes. The product does not have to rely on patient cells where T cell dysfunction and the high levels of circulating leukemic cells pose manufacturing and potential safety challenges. Opportunities in the recurrent relapse CLL, we estimated to be approximately 7,500 patients, that can create a revenue potential in excess of $3 billion. We have already begun the phase 1 study in CLL, targeting patients who have relapsed after BTK inhibitor and/or BCL2 inhibitor treatment. Treatment will consist of lymph depletion of FCA, followed by the cema-cel treatment.
After the completion of the phase 1 study, which we expect the data will become available towards the end of 2024. We will have opportunity, pending the data review, to advance this program into a potential pivotal study, phase 2 study in 2025. In terms of the market opportunity, in the U.S. alone, drug-treated incidence for CLL is approximately 24,000 patients. The second-line relapse, recurrent CLL represents about 13,000 patients. Third line, as the number indicates on the table, 9,500. We do believe, based on the target patient that we are enrolling in the phase 1B study, approximately 75 patients will be eligible for cema-cel. As I've said, that creates a big market potential. The third one that we are very excited about is advancing very differentiated product ALLO-329 into autoimmune indications.
I think, you know, over the last 2 years, we have seen a lot of exciting data about using Autologous CAR T therapy that is directed against CD19 to essentially reset the immune system in patients with advanced and very refractory lupus nephritis patients. This is really changing the paradigm of how these patients are managed, you know, from, you know, trying to modify the disease to trying to essentially reset the disease where we can maintain the patients in remission for a long period of time. And we believe the Allogeneic CAR T provides a very differentiated approach in this setting. And especially with ALLO-329, we have opportunity not to go after pathogenic B cells, but also pathogenic T cells.
Also, using the underlying biology of the ALLO-329, we do believe that we have opportunity to eliminate, if not significantly reduce, the lymph depletion requirement, which is a big barrier in advancing CAR T therapy into the autoimmune indications. This is only data that I'll be showing, you know, in this presentation. What's shown on the left is the flow cytometry pattern, shortly after CD70-targeted CAR T are given in patients. On day 4, you start seeing CD70-positive CD8 cells. By day 10, as the CAR T cells get expanded, the CD8-positive CD70-positive T cells essentially disappear. I think that's really, you know, giving the indication that with ALLO-329, not only can we go after CD19-expressing B cells, but also CD70-expressing pathogenic T cells.
The ability to go after CD70-expressing T cells also creates an opportunity to reduce the lymph depletion, which is shown on the next, on the right panel. What's shown is the T cell expansion, CAR T cell expansion kinetics. You know, after giving different lymph depletion using ALLO-316, which is CD70-targeted CAR T cells. With the standard, the lymph depletion that was used in our study, which is shown in green, that's number 2, we get fantastic cell expansion that also persists for a long time. In this case, even if we reduce the lymph depletion by simplifying FCA 30 to FC, we still get a very robust cell expansion, which essentially is much greater than what we have seen with the CD19 using the FCA 90 regimen.
This is the unique attributes of the CD70 CAR T cells, and the underlying biology, which we have coined the term Dagger. Being able to go after CD70 expressing T cells allows Allogeneic CAR T cells to expand much better, and thereby creating opportunity to reduce the lymph depletion and potentially eliminate the lymph depletion altogether. So with this product, we believe, you know, it creates, many different opportunities, not only in, autoimmune disease indications that are primarily driven by the B cells, such as lupus, myasthenia gravis, and systemic sclerosis, but also, the autoimmune indications that has a, you know, a, you know, pretty, big T cell components. Essentially, all the indications that are listed here.
The primary indication that we'll be targeting with ALLO-329, obviously, you know, we will go with what the Autologous CAR T data is showing, you know, which is really going after the Lupus Nephritis as the primary indication. But we also believe there's a great opportunity to go after indications such as Systemic Sclerosis or Multiple Sclerosis. And the way that we view the opportunity with the CAR T is really sort of captured here. What both Autologous and Allogeneic CAR T cells should be able to do is with a single infusion providing prolonged remission. After that, what Allogeneic can do is offer off-the-shelf, on-demand products that can be manufactured, you know, with scalability and economics.
and also, you know, being able to do multiple gene editing, thereby really engineering the, you know, the CAR T cells to do the right thing, to do the, you know, what's needed in autoimmune indications, such as what, how we have, you know, generated ALLO-329. And also, by, you know, reducing the lymph depletion, we have opportunity to advance the CAR T therapy as an outpatient treatment and management, and thereby further increasing the, you know, potential of the CAR T therapy in autoimmune indications. So with ALLO-329, this is currently preclinical stage products. We are in the process of completing the IND enabling manufacturing process and assay development, targeting the IND submission and the phase one trial initiation in the H1 of next year, 2025.
If all goes well, we have opportunity to generate the proof of concept data in autoimmune indications by year end, 2025. The H4 of our 2024 platform vision is continuing to advance the Allogeneic CAR T in solid tumor indications. You know, you know, the TRAVERSE study is a program that we have been running in renal cell carcinoma for some time. We have already shown proof of concept that Allogeneic CAR T can provide a meaningful clinical response in the patients with the renal cell carcinoma. And we believe that, you know, solid tumor is really an untapped area where the opportunity of CAR T can expand, exponentially. So the product that we have been studying in the renal cell carcinoma is ALLO-316. This is CD70 targeting CAR T products. And the patient population that we are targeting is post-immune checkpoint inhibitor and TKI patient population.
So far in the ongoing phase 1 study, we have shown very encouraging activity in CD70 positive renal cell carcinoma, where we have shown an overall response rate of 30% and disease control rate of essentially everybody who has been treated in the phase 1 study. And another thing that is very unique about ALLO-316 is its intrinsic Dagger activity that allows cell expansion to, you know, happen, you know, even, you know, much better than what has been reported in the autologous, you know, CAR T product. And, as we sort of push the expansion as well as lymph depletion, you know, we have seen hyperinflammatory responses in some patients, which, you know, we are at this point trying to come up with a management paradigm to effectively control the hyperinflammatory responses.
In terms of the efficacy shown on this slide, in the CD70-positive patient, we have seen 3 patients who have shown overall responses, and the other 7 patients had stable disease. Shown on the bottom is the tumor reduction in one of the patients with a stable disease. So this patient is not categorized as a partial response. But when you look at the kidney, which is shown on the right side as a large mass, we can see a significant reduction by day one, day 28, that continues to get reduced, you know, in the subsequent follow-up on day 56. This patient, you know, however, when you measure the overall tumor measurement, doesn't qualify as a partial response, but it really illustrates how effective ALLO-316 treatment can be in renal cell carcinoma.
So the next step for the TRAVERSE study is continuing to advance the innovation on the, you know, underlying Dagger technology. That's really trying to optimize the CAR T cell expansion and persistence to maximize the potential of the Allogeneic CAR T in solid tumors. And we expect to communicate the algorithm that we'll be using to control the hyperinflammatory response by Q2 of this year. And towards the end of this year, we will provide additional updates on the ongoing phase one program. And as we talked about, we have a fully operational GMP manufacturing facility that can handle multiple products, not just for the clinical studies, but also in the event that studies are successful, to commercially launch those products from this manufacturing facility.
The capacity of this manufacturing phase is pretty enormous, and we expect that this single facility can produce more than 20,000 patients' worth of CAR T product on an annual basis. Now, just to summarize, you know, the key milestone events. I'm just gonna, you know, focus on, you know, what's highlighted in orange, which is really the large B-cell lymphoma. We are already in the process of the startup activity. We expect the ALPHA3, the frontline LBCL study, to be initiated by mid-year 2024. And by mid-year 2025, we will make the lymphodepletion selection of the lymphodepletion regimen by next year. And also, another important milestone is, towards the end of 2024, Q4 , being able to provide an update on the cema-cel CLL program, phase 1 data.
So, you know, with that, I just want to end that in the advancement of CAR T, only competition is disease itself. And we believe with Allogeneic CAR T, we can redefine the future of CAR T, fully leveraging the enormous potential that the Allogeneic CAR T brings, can bring, not just on the efficacy perspective, but also scalability and the logistics, which can be greatly simplified with Allogeneic CAR T. With that, thank you very much. And, you know, Hathaj, back to you.
Yeah, no, no, David, this is great. And looks like 2024 is gonna be full of, you know, stuff you need to execute on. Allogene is, I think, one of the best executing companies I've ever kind of tracked or now cover. We got a, so, so really looking forward to this, you know, this coming year, and also, you know, getting to know you better, David, and the company.
Got a question from online. The question is, or is cema-cel restricted to the US only, David? And is that because of Servier?
Yes, you know, we have the rights, you know, in the U.S, the ex-US rights. We are currently in discussion with Servier about how to handle that. As some of you may know, Servier used to be our ex-US partner. But a couple of years ago, for strategic reasons, they decided to exit from the CAR T, and we are trying to sort out the, you know, how to exactly, separate the partnership.
Yep. That's fantastic, David. We look forward to keeping the conversation going. Thank you for taking the time to be here. And we'll chat soon.
All right. Thank you very much for hosting Allogene , Hathaj, and have a great day. You too. Give our best to the team.