Allogene Therapeutics - Q3 2024

Transcript

Operator (participant)

Hello, thank you for standing by, and welcome to Allogene Therapeutics' Third Quarter 2024 conference call. After this speaker's presentation, there will be a question-and-answer session. To ask a question during this session, you'll need to press star 11 on your telephone. You will then hear an automated message advising your hand is raised. To withdraw your question, please press star 11 again. Please be aware that today's conference call is being recorded. I would now like to turn the call over to Christine Cassiano, Chief Corporate Affairs and Brand Strategy Officer. Ms. Cassiano, please go ahead.

Christine Cassiano (Chief Corporate Affairs and Brand Strategy Officer)

Thank you, Operator, and welcome to all who are joining this call. After the market closed today, Allogene issued a press release that provides a business update and financial results for the third quarter of 2024. This press release and today's webcast are available on our website. Following our prepared remarks, we will host a Q&A session. We recognize that historically questions have been multifaceted, but note that we will endeavor to keep this call to under one hour. Joining me today are Dr. David Chang, President and Chief Executive Officer; Dr. Zachary Roberts, Executive Vice President of Research and Development and Chief Medical Officer; and Geoff Parker, Chief Financial Officer. During today's call, we will be making certain forward-looking statements.

These may include statements regarding the success and timing of our ongoing and planned clinical trials, data presentations, regulatory filings, future research and development efforts, manufacturing capabilities, the safety and efficacy of our product candidates, commercial market forecasts, and financial guidance, among other things. These forward-looking statements are based on current information, assumptions, and expectations that are subject to change. A description of potential risks can be found in our press release and latest SEC disclosure documents. You are cautioned not to place undue reliance on these forward-looking statements, and Allogene disclaims any obligation to update these statements. I'll now turn the call over to David.

David Chang (CEO)

Thank you, Christine, and welcome to those on the call today. Today, I am excited to share our recent progress and upcoming milestones as we continue our mission to redefine cell therapy for both cancer and autoimmune disease. In the third quarter, our groundbreaking achievements include: one, in heme malignancy, we continue to activate sites and advance the pivotal phase 2 ALPHA3 trial of cema-cel for large B-cell lymphoma. This trial marks a significant step forward as cema-cel could become the first CAR T therapy integrated into the first-line treatment. With its focus on patients at high risk for relapse and the ability to potentially predict who those patients might be, this trial could transform first-line treatment and set a new standard for patient outcomes.

Solid tumor ALLO-316 is showing unprecedented efficacy in solid tumors through the phase I TRAVERSE trial for renal cell carcinoma, achieving a confirmed response rate of 33% and best overall response rate of 50% in heavily pretreated patients with high CD70 expression. We define high CD70 expression as tumor proportion score greater than 50%, which represents the majority of patients. This breakthrough led to the RMAT designation from the FDA, positioning ALLO-316 as a promising treatment for advanced renal cell carcinoma. Pipeline. Our pipeline innovation extends into autoimmune diseases with ALLO-329, the first dual CD19/CD70 CAR designed to target CD19 positive B cells and CD70 positive T cells, both key drivers of autoimmune dysfunction. By addressing both B cells and activated T cells, we are tackling a broader spectrum of autoimmune mechanisms, which could significantly enhance therapeutic outcomes and expand the range of autoimmune diseases we can address.

But what really differentiates ALLO-329 is our proprietary Dagger technology. This technology, now clinically validated via the ALLO-316 program, could enable ALLO-329 to overcome one of the biggest anticipated barriers to CAR T therapy in autoimmune disorders: lymphodepletion. We believe this unique feature of ALLO-329 will allow us to reduce or eliminate the need for lymphodepleting chemotherapy, which we believe is a significant barrier to advance CAR T beyond severe cases of autoimmune disorders. Beyond its technical strength, ALLO-329 is designed as an off-the-shelf and once-and-done solution, which differentiates ALLO-329 from autologous CAR T or bispecific T cell engagers and allows us to potentially reach these larger patient populations more efficiently. We anticipate an IND filing in first quarter 2025, with proof of concept data by year-end 2025.

A sneak peek at the potential of Allo-329 in preclinical models will be presented at the American College of Rheumatology Convergence on November 18, 2024. Looking ahead to 2025, these developments reflect a potential paradigm shift, highlighting the AlloCAR T platform's unique ability to address diverse patient needs. This journey is not without challenge, as each trial brings its own level of complexity in a highly competitive field. It's for this reason we crafted each program with a long-term vision in mind. As Wayne Gretzky famously said, "Skate to where a puck is going to be, not where it has been." That's precisely our approach. By pursuing what we believe are best-in-class therapies with differentiated development approaches to maximize the key attributes of AlloCAR T, we are confident that this strategy of anticipating future needs will yield remarkable outcomes.

Each of these programs has the potential to revolutionize the application of CAR T therapy in treating disease and shaping the future of medical practice. Now, I would like to hand the call over to Zach to discuss the status of the ALPHA3 trial and provide a deeper dive into the latest data from our ALLO-316 program.

Zachary Roberts (EVP of Research and Development and CMO)

Thank you, David. This quarter, Allogene has made substantial progress, moving us closer to potentially redefining treatment options in both oncology and autoimmune diseases through our innovative AlloCAR T platform. Looking ahead to 2025, we're energized by the advancements in our pivotal cema-cel trial, the upcoming IND submission for Allo-329, and the promising data for Allo-316 in advanced renal cell carcinoma, recognized by the FDA as a potential breakthrough. While we won't have an update on the ALPHA3 first-line consolidation trial for cema-cel until mid-2025 when we finalize our go-forward lymphodepletion regimen, I want to recognize our exceptional clinical team. They are navigating a highly complex landscape to bring trial sites online amid intense competition, and I'm incredibly proud of their accomplishments to date. Since its launch in June, the trial has successfully activated 27 of the planned 50 sites, with approximately 60% of those at community centers.

Although the proportion will shift as more academic sites are activated, this early emphasis on community-based centers is essential to ensuring broad accessibility. If any CAR T therapy can make meaningful inroads into community settings, we believe it will be an allogeneic product like ours. Beyond the LD selection in mid-2025, we continue to anticipate primary event-free survival data by the end of 2026, with potential for a Biologics License Application submission in 2027. I'd like to now turn your attention to Allo-316 and the data we released this morning. We are excited to share groundbreaking phase I data on Allo-316, our first AlloCAR T product candidate for the treatment of advanced renal cell carcinoma, or RCC. This data showcases the encouraging responses found in heavily pretreated patients and underscores the potential for Allo-316 to become a pivotal off-the-shelf CAR T therapy for solid tumors. Let's dive into the details.

I'll first start with response rates. A single infusion of ALLO-316 demonstrated an impressive 50% best overall response rate and a 33% confirmed response rate in patients with metastatic kidney cancer with high CD70 target expression, defined as a tumor proportion score, or TPS, above 50%. Importantly, the majority of patients with advanced or metastatic RCC have CD70 TPS scores at or above this level. Given the number of previous therapies these patients have been on, most of which were in combination, I can't overstate how meaningful this data is: a single infusion that generates responses in patients with advanced disease and also yields what we would call a treatment break. This is part of the reason we believe our investigators are eager to enroll patients in this trial. Just as exciting as the response rates we've seen in TRAVERSE is the dose cohorts where we are seeing them.

The rates I just mentioned, 50% overall and 33% confirmed responses, occurred in our selected phase IB expansion dose cohort. This dose cohort featured a standard fludarabine and cyclophosphamide-based lymphodepletion regimen. We believe the unprecedented anti-tumor activity of this allogeneic CAR in a solid tumor setting is attributable in part to our proprietary CD70 Dagger technology. With this technology and our deepening understanding of its intrinsic ability to selectively deplete activated CD70-positive alloreactive host T cells, we have seen robust expansion and sustained activity of Allo316 even with standard Flu/Cy lymphodepleting chemotherapy regimens. This highlights the potential of the CD70 CAR as a next-generation allogeneic platform capable of producing meaningful clinical responses in solid tumors and, in the case of Allo329, which incorporates the Dagger technology, in autoimmune disorders as well.

Lastly, and something that has been much discussed, with the addition of another 20 patients enrolled since the last data update, we have gained significant experience handling the potent activity of ALLO-316 and have established a safety profile that could enable continued progress in a challenging field like CAR T therapy for solid tumors. Through our newly implemented diagnostic and management algorithm, we have been able to effectively recognize and treat immune effector cell-associated HLH-like syndrome known as IECHS. Much like what was done in the early days of CAR T development as the industry wrestled with CRS and neurotoxicity, developing and proactively utilizing tools to mitigate risk creates a pathway to maximizing potential efficacy and improving patient outcomes. The strength of our data has led to RMAT designation for ALLO-316, signifying the FDA's acknowledgment of ALLO-316 as a potential treatment for advanced RCC.

While we don't typically comment on FDA interactions, the speed with which this designation was received reflects the promising impact ALLO-316 may have for patients with advanced or metastatic RCC. The data will be featured in an oral presentation at the International Kidney Cancer Symposium, or IKCS, on November 8, followed by a poster presentation at the Society for Immunotherapy of Cancer, or SITC's, annual meeting on November 9. Both presentations will be accessible on our website. We continue to actively evaluate ALLO-316's safety and efficacy in the phase 1B expansion cohort. This will help define the optimal dose for phase 2 trials, setting the stage for development for our CAR T technology in solid tumors. We are deeply encouraged by these results and the opportunity to offer hope to patients in need of new options for managing their disease.

Today's data is a testament to the potential of Allo-316 and, ultimately, Allogene's commitment to advancing the field of CAR T cell therapy. We look forward to providing further updates as we move into the next stages of development across all of our programs. I'll now turn the call over to Geoff.

Geoffrey Parker (CFO)

Thank you, Zach. As I noted last quarter, Allogene is in an enviable position. We control the only clinically validated allogeneic CD19 CAR T product in a pivotal trial, positioned to transform how and where CAR Ts are used in heme malignancies. We control the only allogeneic CAR T that has shown real potential in solid tumors. And we control the only CD19/CD70 dual CAR that has been specifically designed to treat autoimmune disease. To continue with David's hockey analogy, these three shots on goal all have the potential to be transformative. Let me now turn to our financial highlights. Our cash balance as of the end of Q3 2024 was $403.4 million in cash, cash equivalents, and investments, and our cash runway continues to extend into the second half of 2026.

Q3 2024 research and development expenses were $44.7 million, which includes $5.6 million in expenses associated with non-cash stock-based compensation. General and administrative expenses in Q3 were $16.3 million, which includes $7.8 million of non-cash stock-based compensation expense. For Q3 2024, our net loss was $66.3 million, or $0.32 per share, including non-cash stock-based compensation expense of $13.4 million and $10.7 million in non-cash impairment of long-lived asset expense. For 2024, we continue to expect a cash burn of approximately $200 million. We continue to expect full year 2024 GAAP operating expenses to be approximately $300 million, which includes estimated non-cash stock-based compensation expense of approximately $60 million. This guidance excludes any impact from potential business development activities. We'll now open the call for questions.

Operator (participant)

Thank you. At this time, we'll conduct a question-and-answer session. As a reminder to ask the question, you'll need to press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Tyler Van Buren of TD Cowen. Your line is now open.

Tyler Van Buren (Managing Director & Senior Biotechnology Equity Research Analyst)

Hey, guys. Good afternoon and congratulations on all the progress. I have a couple for you. The first one is just on the RCC data, the 30% confirmed response rate in these late-line patients is, of course, pretty impressive. So can you give us insight into when you might be done with the expansion cohort and be able to start a pivotal for potential approval? And then the second is just regarding the read-throughs of the 316 data to your 329 autoimmune program. I agree that the data with FCA is impressive as we think about reducing or removing lymphodepletion, but can you discuss your confidence in safety in autoimmune specifically and why the 316 data might not be the best read-through?

David Chang (CEO)

Hi, Tyler. This is Dave Chang. Thanks for very insightful questions. The first one, in terms of the status of ongoing TRAVERSE study, let me turn it over to Zach to answer the questions that you had.

Zachary Roberts (EVP of Research and Development and CMO)

Thanks, David. And thanks, Tyler. Great questions. So the first one, how many patients do we expect to enroll into this expansion cohort? So we're aiming for approximately 20. We think that that will give us the sort of adequate number of patients to really ascertain response rate as well as durability, which, of course, we'll have to wait for some of that information to come in into next year. So we expect to be able to give a program update next year. As for the second question on 329, so we continue to be quite encouraged by the Dagger effect in the 316 program. And we have some additional data in the poster that will kind of illustrate that even further. And with additional patients having been treated, we have more and more confidence that this is real.

In fact, we have selected a phase 1B expansion lymphodepletion regimen that does not include ALL-647. So we've already been able to demonstrate efficacy with a reduced, substantially reduced lymphodepletion regimen. So we have pretty high confidence, actually, that that will carry forward into the 329 program. We don't intend to use 647 in the autoimmune setting. We'll be dealing with chemotherapy alone. And while we haven't disclosed exactly the plan to really pressure test the ability to reduce or eliminate lymphodepletion, that is definitely one of the key objectives of the early phase of that study. And then finally, just a comment quickly on the safety piece. So we know that patients with advanced malignancies are fundamentally different from an inflammatory milieu from patients with autoimmune disease.

Secondly, it's pretty obvious from the existing data that the duration of CAR T persistence and functional activity, namely the duration of, say, B-cell aplasia as a biomarker of CAR T cell activity, we know that that is substantially lower in the autoimmune setting than it is in somebody who's got very, very bulky tumors, as many of the patients in the 316 program did. Overall, we think that the intensity of the therapy that will be required in an autoimmune patient will be comparatively lower. That said, we have built a lot of experience dealing with the toxicity associated with Allo-316 through management of infections, the details around IECHS. We have a really good handle on how to diagnose and manage these. We think that, number one, lower intensity therapy in AID. Number two, we will be absolutely ready for any toxicity that does crop up.

David Chang (CEO)

Tyler, let me just add. I mean, I think over the years, we have learned that the patient population and indications and the tumor burden or the target burden greatly influences safety as well as efficacy. So yes, we know a lot from our experience in 316 and also through the course of developing 316, we learned to manage the adverse event a lot better. To your specific question about the read-through into the autoimmune program, my view is that this is something that we have to clinically test. I don't think there is a much read-through that you can make because of the indication target burden are so different between advanced kidney cancer versus autoimmune disease.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Brian Cheng of JPMorgan. Your line is now open.

Brian Cheng (Equity Research Analyst)

Hi. Thanks for taking our question. This is Shauna for Brian. Could you give us a better sense of the Grade 5 events that you reported in the data today? Were there any confounding effects that led to those cases? And on the IECHS case, could you walk through how the management algorithm is implemented? How easy will it be for doctors to monitor potential IECHS events?

David Chang (CEO)

Yeah. Shauna, thanks for those great questions. I mean, we disclose all the adverse event findings from the 316, and especially in oncology, in patients with advanced metastatic disease. In my experience, there is never a simple adverse event. It's very much confounded by the underlying disease. And also, a lot of times in phase 1, the doses that we use as well as different lymphodepletion that we have tested. So I can simply say that every case of the adverse events that we see in the 316, especially the grade five events that you mentioned, are very confounded. And I'll ask Zach to answer the second question.

Zachary Roberts (EVP of Research and Development and CMO)

Yes. Thanks, Shauna and David. So as far as management of IECHS, the algorithm that we've developed and is detailed in the upcoming SITC materials is pretty clear. It's very analogous, in fact, to the algorithms that were developed in the early days for CRS and ICANS. So it's sort of a two-step process. You monitor signs and symptoms and lab values carefully. And if you are convinced that there is an inflammatory process ongoing based on the diagnostic criteria, which are very, very clear, then you institute first-line therapy. And then you escalate quickly if you don't see a very rapid response to that first-line therapy. So this is a tried-and-true methodology for managing CAR T-related toxins. This one is just a slightly different flavor, given that it's IECHS. So it should be pretty clear and pretty easy to implement.

And in fact, it has been easy to implement in the study when we've needed it.

David Chang (CEO)

And Shauna, I would also add this entity, IECHS, now that it's more widely recognized and based on the publications over the last couple of years, there's a much better understanding. And in fact, as people better understand this entity, it is being recognized as a spectrum of cytokine release syndrome, but time course is a little bit different. And I think all these nuanced understanding is making the management of these hyper-inflammatory events a lot easier.

Brian Cheng (Equity Research Analyst)

Great. Thank you, David. Thank you.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Michael Yee of Jefferies. Your line is now open.

Michael Yee (Managing Director)

Hey, guys. Thanks for the updates. We had two questions. One was on your first-line lymphoma study. I know it's early, but maybe just comment a little bit about what you're seeing out there in terms of the screening rate for MRD positivity. How are things in terms of execution going? And how are you thinking about the pace of enrollment as you are getting that underway? And then the second question is back to autoimmune. Obviously, that has been a big focus point for a lot of different companies. And actually, we're seeing a lot of dynamics around CAR T versus T-cell engagers and now a battle around that. Maybe just comment about how you see CAR T there versus T-cell engagers and talk a little bit about your perspective there given what we're seeing out there. Thank you.

David Chang (CEO)

Mike, nice to hear from you. Always fantastic questions. I'm going to reverse the order. I'm going to talk about the AID and different modality that's going into, and I'll ask Zach to get back to the front-line study. I think what we all have to recognize is that through the experience of autologous CAR T over the last two to three years, people are sort of looking at the autoimmune disease as well as other diseases that are caused by overreactive B-cells or antibody productions. We can think how to manage these diseases in a totally different way. B-cell depletion, which is really the underlying mechanism behind whether using T-cell engagement or CAR T, I mean, that is being targeted, and people are realizing that this can bring a substantial so-called drug-free and disease-free interval to patients.

When I think about autoimmune indications, I mean, there are so many different diseases and so many opportunities. With respect to the modality, the way we view about different modalities, there are more than one modalities that can coexist. And even within one particular modality, I think there can be multiple successful stories. And if you look at the history of autoimmune drug development, that's exactly the case. So I just want to emphasize the opportunities, the great opportunities that there is. Obviously, even in that context, our team thinks about how are different modalities different. And everything comes with a different twist. But for the allogeneic CAR T, I mean, one is this is off the shelf. The convenience and all those things factor in. And also, CAR T usually is being viewed as a once-and-done, one-time treatment.

I think these are very attractive propositions to the physicians who are managing the autoimmune disorders, and lastly, the focus of our Allo-329 development program is really to address one of the sort of perceived challenges of CAR T, which is the lymphodepleting chemotherapy. The way that the 329 is designed is to really address this head-on with a built-in Dagger technology that's coming from the CD70 portion of our dual CAR T, and like anything else, we are really accelerating this program, and some of the key questions that you are asking, as the data matures, data emerges, I think we will know a lot better, but we feel very excited about our Allo-329 and the potential benefits that it can bring to the patients with autoimmune disorders. Zach, on the first question.

Zachary Roberts (EVP of Research and Development and CMO)

Yep. Thanks, Mike, for the question. So what I can say is that the enthusiasm and the engagement from our clinical trial sites has really been through the roof. I am, on a daily basis, extremely excited by the pace at which we're able to onboard sites, the activity of the sites that have been onboarded. I would say in these early days of the trial, things are sort of unfolding in a standard way. And especially as we pointed out in the prepared remarks and in the press release, the earliest sites to activate here have been predominantly community sites. And some of them, in fact, some of the more active sites don't have CAR T experience. So they're requiring a little extra hand-holding, but there is absolutely no shortage of engagement and enthusiasm.

Even the patients that are screening MRD negative, they're deriving a nice benefit, right, because they're getting access to something a little bit more prognostic than what is out there already. Very, very, very encouraging launch to the trial.

David Chang (CEO)

Yeah. I would say that, I mean, the study is progressing as planned. There are certain things that we are finding out. I mean, compared to pre-COVID days, site activation requires a lot more hands-on approach to get all the documents taken care of and also get the site ready. And that's where I really recognize our clinical operations team to be so reactive and handling that very effective. And I'm very proud of what they have done with the site activation, which is, as Zach had said, going very smoothly.

Michael Yee (Managing Director)

Very good. Thank you.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Salveen Richter of Goldman Sachs. Your line is now open.

Marc Nachmann (Global Head of Asset & Wealth Management)

Hey, guys. This is Marc on for Salveen. Congrats on the quarter, and thank you for taking our question. I have two quick ones on Allo-316 and the data that was released today. It seems that for the FC lymphodepletion without the CD52, that group performed a little bit better than the FCA group that did have the CD52. I realize the ends are small here, but can you speculate as to why there's that difference? And also, can you discuss what you are looking for in the phase one B expansion cohort data that's planned for 2025? What threshold of data would give you confidence on the forward regulatory path?

David Chang (CEO)

Yeah. Mark, great to hear from you. I mean, let me just quickly respond to the first question. It's a small number. We are seeing responders both with FCA and FC. But the fact that we are seeing the responses in FC is probably the most interesting finding from our SITC, the poster presentation. As an allogeneic CAR T program, we foresee that this program moving forward with a standard fludarabine cyclophosphamide lymphodepletion would not need for any kind of enhancement in the lymphodepletion. And that's really coming from the underlying Dagger biology that's intrinsic from the CD70. And the differences that you're seeing, I think with the small numbers, I would not read too much into that. And Zach, do you want to take the second question?

Zachary Roberts (EVP of Research and Development and CMO)

Yeah. So I think, as I mentioned a moment ago, we're shooting for 20 patients at this phase 1 B regimen and then sort of awaiting for that durability. So I think if you just look numerically at where we sit right now from a confirmed response rate, I think we are numerically better than the third-line options that are currently approved in this context. So we're pretty happy with that. Of course, it's always nice to see even more responses. But the question, I think, is that we'll just need to wait a little bit longer on is the durability. We've got a couple of nice ongoing remissions out several months in the patients treated with the phase 1 B regimen. So I think stay tuned for that program update next year.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Jack Allen of Baird. Your line is now open.

Jack Allen (Senior Research Analyst)

All right. Thanks so much for taking the question, and congratulations to the team on the progress. I guess the first question I had was, I didn't see a mention of the ALPHA2 study and the CLL cohort in your release, so maybe I missed it on the call, but is that still planned and ongoing, and then, Zach, I think you just touched on it quite a bit on the 316 program and the bar for durability. I was hoping you could just elaborate how you think about the existing standard of care and what you're looking to see for durability from 316 and RCC. Thanks so much.

David Chang (CEO)

Hi, Jack. Well, I'll take the first question, and I'll have Zach answer the second one. The CLL study is ongoing, and we are currently in the process of prioritizing different programs. When I look at the overall pipeline, without question, the ALPHA3 study in the front-line consolidation is our top priority. And as we have sort of advanced the 329, we are realizing that this could potentially be a very important program for Allogene and perhaps even for the entire field. So we are spending a lot of time to accelerate as much as we can with the 329 program. And certainly, the solid tumor program, it's also giving us sort of pause about what to do. So in all this context, yeah, the CLL study is ongoing, but it will be part of the prioritization, and we will be providing a program update next year.

Zachary Roberts (EVP of Research and Development and CMO)

And then, Jack, just to kind of elaborate a little bit more on efficacy, I'll broaden it a bit to sort of speak generally. So first, I want to point out again that FDA has recognized this program with the RMAT designation as a potential breakthrough for patients in relapsed/refractory post-TKI, post-checkpoint blocker. So if you look at that subset of patients that are in the third line, I think outcomes there, both from a response rate as well as a PFS, are fairly modest. And the other thing I'll point out there is that that's continuous therapy. So what we have to offer here is potentially an equivalent or improved response rate and then a period of treatment-free remission. And I think that's always been one of the key attributes and attractive points of CAR T therapy, generally speaking, and it's no different in this context.

So I think we have to take all of that together in mind. And nobody would be happier than I, well, except for potentially the patients themselves, if we were able to put these patients into very, very durable remissions. And that's, of course, what we're hoping to do. But we have to wait and see how that shakes out and how it lines up to the existing therapies, as I said, with the PFS on the order of a handful of months. So the bar is quite low here, and we hear that continuously from our investigators who are constantly looking to put patients on this trial. So we have a lot of support from the investigator community here to continue pushing forward, and they're seeing real benefits to their patients.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Edward Tenthoff of Piper Sandler. Your line is now open. Edward Tenthoff, your line is now open.

Edward Tenthoff (Managing Director and Senior Research Analyst)

Yeah. Hi, guys. Thanks for taking my question. Zach, for Allo316, what kind of a durability do you need to see to give you confidence to go meet with FDA on a pivotal design at the end of 2025? And then I guess on Allo329 with the IND planned imminently, what type of indications are you expecting to pursue in the phase one? Thanks.

David Chang (CEO)

Zach?

Zachary Roberts (EVP of Research and Development and CMO)

Yep. Thanks, David. Thanks, Biren. Good question. So on 316, I'll paraphrase what I've said so far, which is I think the bar is low here. We've got two of these patients who are in the confirmed responses in the first group and treated in the phase one B regimen who are in ongoing nice, deep partial remissions at four and six months. So they're continuing to deepen over time. We'll have to see how those and the subsequently treated patients develop. The fact that we have this RMAT designation, which is just nothing more than a few days old now, is. It does give us access to kind of more frequent and in-depth conversations with FDA. So I think they're, by virtue of having granted this designation, they're enthusiastic about the potential for this therapy.

I think we're just going to have to wait for that durability data to come in and then go and have that conversation when the time comes. As far as the second question on indications for 329, the preponderance of the data that's out there right now is in rheumatologic conditions. First and foremost is lupus. We have said all along this year that we're going to be starting our focus there in rheumatology. We haven't yet said exactly which indications we're going to pursue and in what order. Suffice it to say, we are watching the data develop in the field. We're very excited about rheumatology. We're watching to see how others are expanding beyond that. We're going to be taking a path that really follows that proof of concept data.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of John Newman of Canaccord Genuity. Your line is now open.

John Newman (Managing Director and Senior Equity Research Analyst)

Hi, guys. Great progress. Thank you for taking my question. David, I wondered if you could talk about the importance of breaking pathological B cell and T cell response in autoimmune disease. So we've heard a lot, and we've seen a lot of focus on B cell depletion levels, which seems very important. We've seen a lot of focus on the phenotype of the B cells when they recover. But not very many people have talked about how the T cells are involved. So I'm just curious as to how you think about that with your product.

David Chang (CEO)

Hey, John. Great question. That probably goes beyond even my scientific understanding. But if you go to the immunology literature, the interaction between different lymphocytes leading to the B cell development and B cell differentiation into the antibody-producing cells, I mean, that is complex. And still, one of the main contributors of that B cell, the maturation, is the T cells as well as some other cells. And by the way, these other sort of lymphocytes that are involved in enhancing the B cell response, they also express CD70. So from our perspective, yes, when the B cells get depleted, all the indications are the returning B cells have a naive phenotype. They will have to undergo some kind of maturation and to become pathogenic again.

And I think by going after both B cell and the activated T cell early on, they can potentially address the underlying pathology more fully rather than just going after a single B cell component. That's a hypothesis. And another thing that's very important to us is, in addition to what CD70 can bring in that equation, is that CD70 has the Dagger technology, which allows us to use Allo-329 with a minimum lymphodepletion. I mean, we have already shown in the 316 program, even as an allogeneic, when there is a Dagger technology incorporated into it, you don't need any enhancement. I think this is something that we can extrapolate into the autoimmune indications. And that underlies our plan to reduce or eliminate the lymphodepletion during the initial investigation of Allo-329 in patients with autoimmune disorders.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Luca Issi of RBC Capital Markets. Your line is now open.

Luca Issi (Senior Biotechnology Research Analyst)

Oh, great. Thanks so much for taking my question and congrats on the progress. Maybe Zach or David on RCC, do you have any tumor aspirates or renal biopsies here? Wondering if you have any evidence suggesting that the cells are actually able to infiltrate the tumor microenvironment here, which I think is something that has been kind of the main historical issue here for CAR T for solid tumors. So any color there much appreciated. And then maybe just to clarify, is it fair to assume that all the responses so far are PRs and not CRs? Thanks so much.

David Chang (CEO)

Zach, do you want to take that question?

Brian Cheng (Equity Research Analyst)

Sure. Luca, as always, great questions. So the first one, the answer is yes. We have actually quite a number of tumor aspirates and biopsies that we have collected within the first couple of weeks after infusion. And we do have a figure in the poster that really lays that out. In fact, there's a dozen contemporaneous biopsies and peripheral blood samples. And in that figure, it's quite convincing, actually, that the ability of ALLO-316 to get into the tumor bed itself is quite robust. And we see essentially in almost all of those 12 biopsies, equivalent CAR transgene in the tumor aspirate is in the peripheral blood drawn at the same time. So we find that to be extremely encouraging in terms of getting to where the cells need to be the site of pathology.

Regarding your second question about PRs and CRs, we did have one complete metabolic remission in a patient who had an antecedent confirmed PR. So it was a PR that deepened to a complete remission. Unfortunately, that patient contracted COVID and expired from that infection. So sort of an extremely unfortunate situation to die from an infection when you're in remission. But that patient was in a complete remission in addition to the other ongoing and deepening PRs.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Samantha Semenkow of Citi. Your line is now open.

Samantha Semenkow (Vice President and SMid Biotech Equity Research Analyst)

Hi. Good afternoon. Thanks for taking the question. I just wanted to follow up on some of the prior questions on the safety data for ALLO-316 and completely understanding that the underlying disease burden is a confounder here. But is there any rationale that targeting CD70 in the context of the Dagger technology could also be contributing to the grade 5 events and just overall safety profile? And what are your thoughts on how that could translate into your autoimmune program, particularly in the context of how you're thinking about choosing a dose for that program? Thank you.

David Chang (CEO)

Hi, Samantha. Let me take the question. We are looking, like in any drug development, all the safety findings very carefully. But especially in the 316 study, I do believe the poster will go online pretty soon. So it will be more detailed. I mean, these are very heavily pretreated patients, really running out of options. And usually in that kind of situation, they are pretty sick patients. And so yes, these events did occur. But trying to read through that to what may happen in autoimmune patients with autoimmune disorder, I don't think there is much that we can read through. And the second question is, does this have to do with the Dagger technology? Dagger technology, what it does is really enhance the pharmacodynamic effect of CAR T. So yes, to some extent. But at the end, this is really how you develop the ABCs of drug development.

We are dealing with active drugs, which is always a good place to start. And then we have to find the right cell dose. And for the CAR T, right lymphodepletion, that balances out the efficacy and the safety. So like anything else, as I said before, these are the things that will be part of the phase one study as we advance the Allo-329 program.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Matthew Biegler of Oppenheimer. Your line is now open.

Matthew Biegler (Senior Equity Research Analyst)

Great. Thanks. Hi, everyone. Just one from us. Can you talk about patient retention efforts in ALPHA3? Because the question we often get is why a patient randomized to watch and wait would choose to stay in the trial versus maybe some form of off-label consolidation treatment. I don't even know if that exists. But can you just kind of comment on that theory that we're hearing? Thanks.

David Chang (CEO)

Hi, Matt. Yeah. It's very soon. Let me take that question. Give Zach a little bit of break. The standard care in large B-cell lymphoma after they complete the treatment is watch and wait. And watch and wait, meaning that they undergo periodic radiographic scans to see what's happening to the disease. And it occurs at a different interval after the completion of the initial treatment. In terms of that particular question about patient retention, I mean, the patients who are enrolled in our study, they'll be getting the best standard care that is available to them. And in our discussions with the investigator, they feel that that is very sufficient for them to carry out the conversation with the patient and retain the patients on the study. And obviously, in this setting, when patient progresses, they can go on to any of the available treatment.

But when the patient progresses, I mean, they already had the primary event. The primary endpoint of the ALPHA3 study is the event-free survival. So when somebody starts the next treatment, I mean, that is an event in the event-free survival analysis.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Sami Corwin of William Blair. Your line is now open.

Samantha Corwin (Senior Equity Research Analyst)

Hi. Thanks for taking our question. This is Brooke on for Sammy. So we are wondering, going off on ALPHA3 again, how has physician interest been with the ALPHA3 trial? And what feedback have you received on what aspects of potential use of cema-cel in the first-line is most valuable? Is it community use, affordability, time to treat, or something else?

David Chang (CEO)

Great question, Zach. You want to take that?

Zachary Roberts (EVP of Research and Development and CMO)

Sure. Thanks, Brooke. So overall, the enthusiasm is extremely high. Honestly, having been part of the team at Kite that really led to the approval of Yescarta, I mean, I lived and breathed third-line LBCL for several years. I can say that the level of enthusiasm for ALPHA3 has been as high, if not higher, than those early days of the ZUMA-1 trial. So I think physicians broadly recognize that if ALPHA3 is successful, that this will usher in a new era of LBCL management and kind of fundamentally change the paradigm. As far as why they think that, which is the second part of your question, I think it's all of those features that you mentioned. I think first is being able to implement a new and novel and highly accurate prognostic tool in this MRD test, being able to respond immediately to the result.

That is something that is paradigm-shifting unto itself. And to be able to do that with an off-the-shelf therapy that literally within days of receiving the MRD positive result, you can initiate lymphodepletion and then deliver a potentially curative dose of CAR T cells. And to do that in community settings that have been on the sidelines of the CAR T revolution from the beginning. So we see enthusiasm coming from community sites that don't have a lot of CAR T experience or any CAR T experience because it's giving them access to this. We see enthusiasm from academic sites because they see how this could fundamentally alter the future of frontline LBCL management. So it's really kind of a grab bag of really exciting topics that we're hearing lots of positive feedback from.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of William Pickering of Bernstein. Your line is now open.

William Pickering (Senior Research Analyst focused on U.S. biotechnology equities)

Hi. Thank you for taking my question and congrats on the progress this quarter. I had a safety question about ALLO-316. It looks like you had multiple DLTs at the dose level 2 that you're using in the expansion cohort, including one of the grade 5 AEs. So could you just speak to how you see the acceptability of this safety profile if it's more or less unchanged once you have data in the full 20 patients you're targeting for the cohort? Thank you.

David Chang (CEO)

Zach, do you want to take that question?

Zachary Roberts (EVP of Research and Development and CMO)

Sure. So I'll point out that the DLTs were in it was the same cell dose. It was 80 million. But it was in patients who had received FCA conditioning, so the inclusion of ALLO-647. So we had reached the DLT limit in that cohort. So we did not advance dosing any further in the FCA arms beyond dose level 2. So because the overall treatment intensity is lower in the FC only arm, right, the elimination of one of the three-part lymphodepletion, we did not encounter DLTs in that cohort. And the efficacy seemed to be the best in the subsets that we were evaluating in the dose exploration phase. So that's why that was selected.

David Chang (CEO)

Yeah. And we never take any kind of safety findings lightly. But the two DLTs, the ALPHA2 DLTs, as our press release indicated, one was a DLT that we had previously disclosed back in 2023 when we presented at AACR. And that was a patient who had previous exposure to checkpoint inhibitor before going on to another study and autoimmune hepatitis. So again, it's somewhat confounded DLT, but it is a DLT from the protocol perspective. And the second one is the one that is described as a cardiogenic shock in this data communication.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Laura Prendergast of Raymond James. Your line is now open.

Laura Prendergast (biotech equity research analyst)

Hey, guys. Congrats on the progress. I was generally just curious. The rate of enrollment in these autoimmune indication studies for cell therapy has been pretty slow. As you think about 326 entering phase one, how were you guys planning on maneuvering these headwinds?

David Chang (CEO)

Laura, I mean, great question. I mean, that's a topic that we are following pretty closely as other companies present about the enrollment status. But the general sense I get is like six, nine months ago, every enrollment seemed to be pretty slow. But definitely, the enrollment into the autoimmune studies are picking up. And this is very typical. I mean, you're dealing with the investigators who have not had any CAR T experience in the beginning. I mean, we certainly learned that when we were involved in CD19 CAR T during the Yescarta development. But once they get somewhat familiar with the CAR T, things will speed up. And I think that's exactly what we are seeing.

And in our case, not only are we going into an area where physicians are getting some familiarity with the CAR T, but we are also going in with the allogeneic CAR T, which really takes away a lot of logistic complexity of administering the CAR T. So we are very hopeful that as we move into the autoimmune, we will be able to execute studies smoothly.

Operator (participant)

Thank you. That concludes our question-and-answer session. I'd like to turn the conference back over to management for any additional comments.

David Chang (CEO)

Yeah. I just want to end by saying that our commitment remains clear to bring transformative off-the-shelf therapies to patients with difficult-to-treat cancer or autoimmune diseases. With each new milestone, we move closer to realizing the potential of our CAR T products in ways that could reshape the treatment landscape across oncology and autoimmune diseases. And with that, thank you very much for joining us on this journey. And operator, you may now disconnect.

Operator (participant)

Thank you for participating in today's conference. This does conclude the program. You may now disconnect.