Allogene Therapeutics Inc (ALLO) 2024 Q4 法說會逐字稿

Hello. Thank you for standing by, and welcome to Allogene Therapeutics' fourth-quarter and full-year 2024 conference call. (Operator Instructions) Please be aware that today's conference call is being recorded.

I would like to turn the call over to Christine Cassiano, Chief Corporate Affairs and Brand Strategy Officer. Ms. Cassiano, please go ahead.

Thank you, operator, and thanks to all of you for joining this call. After the market closed, Allogene issued a press release that provided a business update and financial results for the fourth quarter and full year 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 an hour. I'm joined today by 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 forecast 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.

Thank you, and welcome, everyone. It's a pleasure to be speaking with you today. At the start of 2024, we set forth a bold strategy that some viewed as merely words on PowerPoint with a distant horizon. A year later, we stand on the brink of a transformative year at Allogene. Pioneering allogeneic CAR T therapy was never expected to be easy. It demands vision, rigorous science, relentless persistence, and operational excellence. Today, all three of our key programs are approaching critical milestones, marking the tangible progress of our dedication.

We enter 2025 stronger than ever with a differentiated pipeline and a clear path to shaping the future of allogeneic CAR T. Our programs in large B-cell lymphoma, autoimmune disease, and renal cell carcinoma are breaking new ground, reinforcing our commitment to making off-the-shelf cell therapy a new standard of care. Our pivotal Phase 2 ALPHA3 trial for cema-cel in first-line consolidation large B-cell lymphoma is widely considered to be groundbreaking.

We are immensely proud of the innovation behind this trial. The enthusiasm from both community cancer centers and leading academic institutions has been truly energizing, and momentum continues to build with 40 sites now activated. We anticipate reaching a critical milestone with the lymphodepletion selection and futility analysis around mid-2025. This interim analysis will provide essential insight into whether our approach is on track to meet its objectives, providing a clear signal of progress when we select our lymphodepletion regimen.

Beyond oncology, 2024 also marks our official expansion into autoimmune disease with ALLO-329, the first-of-its-kind CD19/CD70 dual targeting allogeneic CAR T product candidate, powered by our proprietary Dagger technology. Earlier this year, we secured FDA clearance for our Phase 1 RESOLUTION basket trial in rheumatology, an important step towards delivering a scalable off-the-shelf CAR T options to the vast number of patients who stand to benefit.

The IND clearance for ALLO-329 cements Allogene as a true innovator in the autoimmune disease space. We did not follow the crowd. We deliberately took the time to ensure our approach was differentiated, developing both an investigational product and trial specifically to address the unique challenges of autoimmune disease. ALLO-329 is designed to induce lasting remission by targeting both B-cells and activated T-cells.

An equally important design feature is incorporation of our Dagger technology, which has the potential to reduce or even eliminate the need for lymphodepletion. If successful, this breakthrough could fundamentally change how CAR T therapy is deployed in autoimmune diseases. With the RESOLUTION trial slated to launch in mid-2025 and proof-of-concept data expected by year end, we believe ALLO-329 represents a new frontier in allogeneic cell therapy that will showcase the power of our platform to redefine treatment paradigms beyond oncology.

In solid tumors, ALLO-316 is emerging as a promising and potentially groundbreaking asset in renal cell carcinoma. The Phase 1 data we presented last year underscores the potential of allogeneic CAR T therapy to drive meaningful responses in solid tumors, an area where cell therapies have historically faced immense challenges. With our Regenerative Medicine Advanced Therapy designation, ALLO-316 has the potential to redefine treatment for advanced renal cell carcinoma, bringing a much-needed innovation to patients with limited options.

In mid-2025, we plan to share an update from our Phase 1b cohort focusing on durability, a key factor in improving long-term patient outcome. From a broader perspective, the momentum across our programs highlights the potential of allogeneic CAR T therapy to disrupt multiple disease areas. We aim to not just compete with autologous therapies. We are demonstrating that allogeneic approaches can surpass them in accessibility and scalability. Our bold pivot in 2024, coupled with our relentless execution affirms that we have the right team, science, and strategy to make 2025 a breakthrough year for Allogene, one that defines the future of allogeneic CAR T therapy.

I would like to now hand the call over to Zach to provide further details on our clinical programs.

Thank you, David. We take great pride in our clinical progress across our R&D organization and the company as a whole. All three of our cutting-edge programs demonstrate significant promise, reinforcing the strength of our science and execution. We are energized by the momentum in our pivotal cema-cel trial in first-line consolidation LBCL, the upcoming launch of the RESOLUTION basket trial with ALLO-329 in rheumatology, and the compelling data emerging from ALLO-316 in advanced renal cell carcinoma.

Let's start with the foundation of our programs. The field has questioned for years whether an allogeneic CAR T could deliver durable responses. With multiple patients with relapsed/refractory LBCL in ongoing complete remissions beyond four years, we now have proof that our products can achieve that. The Journal of Clinical Oncology's recent publication of our Phase 1 ALPHA/ALPHA2 trial results in relapsed/refractory large B-cell lymphoma marks a defining moment for the field.

These findings represent the most comprehensive allogeneic CAR T data set to date. The study showed efficacy comparable to approved autologous CAR-Ts with an overall response rate of 58% and a complete response rate of 42% across the study, increasing to 67% and 58%, respectively, with the pivotal study regimen. Importantly, treatment delivered exceptional durability with a median duration of response of 23.1 months and median overall survival not reached in patients who attained CR.

We also observed a potentially best-in-class safety profile with no cases of graft-versus-host disease, immune effector cell-associated neurotoxicity syndrome, or high-grade cytokine release syndrome. The median time to treatment was just two days, significantly shorter than the weeks-long wait times required for autologous CAR T.

Moreover, these results provide compelling evidence supporting the use of CAR T therapy in patients with low disease burden. A growing body of research indicates that earlier intervention with CAR T when the disease burden is minimal can lead to improved safety and efficacy outcomes, and this study reinforces that premise. Among patients with baseline tumor burden of less than 1,000 millimeter squared or normal LDH levels, a key biomarker of low disease activity, the complete response rates were 100% and 82%, respectively.

These findings strongly support cema-cel as a breakthrough therapeutic option for patients with minimal residual disease, which is the population studied in ALPHA3, the first randomized trial evaluating CAR T as first-line consolidation therapy for MRD-positive patients. With cema-cel's 100% CR rate in patients with low but still radiographically evident disease burden in these earlier trials, ALPHA3 presents an unprecedented opportunity to both predict relapse and intervene before it occurs.

If successful, ALPHA3 stands to upend the standard of care in first-line LBCL, potentially marking the first significant advance to the treatment paradigm in the last 25 years. Since the trial's launch in June, we have made steady progress. Today, we have successfully activated 40 of the planned approximately 50 sites with roughly a 50-50 split between community cancer centers and academia, and we are progressing towards the first key milestone in ALPHA3 trial, the lymphodepletion regimen selection anticipated around mid-2025.

Beyond signaling progress in accrual, the lymphodepletion selection step is paired with a futility analysis, and thus, our decision to proceed will be a critical indicator that the trial is on track to meet its objectives based on early data. Moreover, this milestone will help map the registrational path forward, further solidifying our confidence in cema-cel's potential to redefine the standard of care.

Due to the seamless pivotal design, these early patients results count towards the pivotal analysis, and therefore, we will not be releasing detailed efficacy or safety outcomes to protect trial integrity. Beyond LD selection, we plan to conduct an interim EFS analysis, which will be overseen by the independent Data Safety Monitoring Board in the first half of 2026. The primary EFS analysis data readout is expected around year-end 2026 with a potential BLA submission in 2027.

None of this would be possible without the great partnership of Foresight Diagnostics and their ultra-sensitive ctDNA-based CLARITY assay powered by PhasED-Seq. For this reason, we expanded our strategic collaboration with Foresight to support the development of their MRD assay as a companion diagnostic in the EU, UK, Canada, and Australia to support Allogene's clinical development of cema-cel.

Shifting gears to autoimmune diseases, in January 2025, the FDA cleared the IND for the Phase 1 RESOLUTION basket trial, a first-of-its-kind study evaluating ALLO-329 in systemic lupus erythematosus, lupus nephritis, idiopathic inflammatory myopathies, and systemic sclerosis. This true basket design brings significant operational efficiencies, allowing enrollment access to a broad patient pool with a single IRB approval. This is one of several differentiating factors that may prove advantageous in this competitive space.

The strategy behind ALLO-329 stems from two key observations. First, autologous CAR T data suggests that short-term CAR T persistence is sufficient to reset the immune system in autoimmune diseases, contrasting with the months to even years-long persistence needed in oncology. Since B-cell depletion lasts around 100 days in autologous studies, allogeneic CAR T's natural two- to four-month persistence makes it uniquely suited for autoimmune therapy.

Second, data from our Phase 1 ALLO-316 program in kidney cancer demonstrated that our Dagger technology intrinsically enhances cell expansion and persistence, allowing us to significantly reduce the intensity of lymphodepletion without sacrificing efficacy. These insights shaped ALLO-329, which includes the Dagger technology and is intended to enable reduction or even elimination of lymphodepletion, a major differentiator in autoimmune treatment.

The RESOLUTION trial will immediately test the requirement for lymphodepletion in parallel cell dose escalation pathways. In one, we will use a single infusion of cyclophosphamide at a dose used in rheumatology; and in the other, a CAR T-only arm with no lymphodepletion, relying entirely on the Dagger effect. This trial is set to launch midyear with proof-of-concept data expected around year-end.

With extensive preclinical validation, published data, and an optimized design, ALLO-329 is positioned to be the most rigorously designed allogeneic CAR T program for autoimmune disease to date. Beyond rheumatology, its potential extends to nephrology, neurology, hematology, and even inflammatory bowel disease, paving the way for a new era of CAR T therapy in immune-driven conditions.

Last quarter, I highlighted ALLO-316 and its remarkable potential following data that showcased encouraging responses from a single infusion with an impressive 50% best overall response rate and a 33% confirmed response rate in heavily pretreated metastatic kidney cancer patients whose tumors expressed high levels of CD70.

Given that update, I'll keep it brief today with just a reminder of the next steps for this promising program. We have completed enrollment in the Phase 1b expansion cohort, which is assessing safety, efficacy, and durability of ALLO-316 at dose level 2 or 80 million CAR T cells following standard lymphodepletion with fludarabine and cyclophosphamide. As we continue to evaluate outcomes, we will determine the best path forward, including the potential to pursue a strategic partnership. We expect to share data from this cohort in mid-2025.

I'll now turn the call over to Geoff.

Thank you, Zach. I'll focus my remarks on our financials. Our financial position is strong, and we continue to operate with capital discipline, ensuring we are well positioned to advance our pipeline and pursue our strategic objectives. As of December 31, 2024, we had $373.1 million in cash, cash equivalents, and investments with our cash runway extending into the second half of 2026.

Research and development expenses for Q4 2024 were $45 million, including $5.6 million in non-cash stock-based compensation expense. For the full year of 2024, R&D expenses totaled $192.3 million, including $20.4 million in non-cash stock-based compensation. General and administrative expenses for Q4 2024 were $15.5 million, including $7.3 million in non-cash stock-based compensation.

For the full year, G&A expenses were $65.2 million, including $31.3 million in non-cash stock-based compensation. Net loss for Q4 2024 was $59.9 million, or $0.28 per share, including $12.9 million in non-cash stock-based compensation. For the full year, net loss was $257.6 million, or $1.32 per share, including $51.7 million in non-cash stock-based compensation and $15.7 million in non-cash impairment of long-lived asset expense.

Turning to guidance for 2025, we expect a cash burn of approximately $170 million. We expect full-year 2025 GAAP operating expenses to be approximately $250 million, which includes an estimated non-cash stock-based compensation expense of approximately $50 million. This guidance excludes any impact from potential business development activities.

We'll now open the call for questions.

(Operator Instructions) Tyler Van Buren, TD Cowen.

Hey, guys, thanks very much and congratulations on all the progress. My question was just following up on the recent JCO publication that you highlighted and thinking about the read-through as to the ongoing ALPHA3 trial. How do patients with low disease burden in the publication compared to those being enrolled in ALPHA3 as we think about the high complete response rate holding up in ALPHA3?

Hi, Tyler, excellent question. I think one thing that we highlighted in our JCO paper, and this is, in fact, something that we have been saying for some time based on what has been seen in autologous CAR T therapies. When you look across patients who have been treated with CAR T, I think this extends not just CD19 but with other BCMA or other antigen-targeted CAR T in heme malignancies.

There is a very strong correlation of likelihood of response as well as likelihood of experiencing adverse events, serious adverse events. I mean, actually, it's an inverse relationship in the latter case. When the disease volume goes down, the likelihood of response is much higher. At the same time, the probability of having a serious adverse event goes down. That has been seen numerous times, and there are many publications on that.

And essentially, in the JCO paper, we were showing that essentially the same holds true for the allogeneic CAR T, probably not that surprising. And I think this really bodes well for what we are doing, not only in the ALPHA3 study but also as we think forward into the autoimmune program with ALLO-329. Specifically about your question, in terms of estimating the disease volume of MRD compared to patients who's starting the frontline study -- I'm sorry, second-line study, there is some information that we have done together with Foresight Diagnostics.

MRD positivity is about 200-fold less disease volume than patients who are presenting with the disease for the start of the second-line treatment. Your particular question about how that compares with the low volume -- the two categories of low disease volume that we have published in JCO, LDH, or the tumor measurement, I would more or less extrapolate to about the same degree of lower disease volume as we have previously reported together with Foresight in the second-line setting versus MRD positive.

Michael Yee, Jefferies.

Hey, good afternoon. Congrats on all the progress. As we are thinking about the mid '25 futility and lymphodepletion decision, I wanted to get your affirmation that you believe that 647 is extremely likely to not be needed, and that should be the general Wall Street expectation. And I believe that would be a positive for a number of reasons. And then as we get to the first half of '26, which will be around the corner, it does say that there's an interim DSMB efficacy analysis. What is the criteria number of events? Or is there a very high p-value bar on that? What do you expect, and what should we expect of that interim? Thank you.

Mike, I'm going to defer your questions to Zach. Zach, can you take those two questions?

Of course. Thanks, Mike, for the great question. So our opinion on the lymphodepletion selection is sort of agnostic. I think you raised a fair point that not needing 647 brings some attractive attributes. It would be simpler for us. We're registering one entity instead of two. It certainly would be cheaper for us to do it that way.

However, we see requiring 647 is actually potentially beneficial as well, because that's part of our proprietary regimen. So it would help kind of protect our status here as the only therapy that is optional in this particular clinical setting. So we have designed this clinical trial to give us a solid answer to that question. Is 647 needed in this unique clinical trial, or is it not? And I think we can work with either independently, both has upside for us. Sorry, Mike, will you repeat the second question? I've forgotten that one.

Yes. Right around the corner within 12 months or so is the interim by DSMB. Well, what is the criteria? Is it a high bar, because you don't want to spend ALPHA there? But obviously, investors have had great discussions with you about how if the drug is clearly going to be working here. You could definitely have a chance of hitting there. Thank you.

Yes, so we haven't disclosed a lot of the specifics around the nature of that analysis, such as some of the specifics that you're requesting, except to say that it is a formal efficacy test where we will be testing the hypothesis with the primary endpoint of event-free survival. There will be some minimal ALPHA spend.

So it is quite possible, just given the way this study is designed that we could end up with a statistically significant finding there, which would, of course, allow us to initiate conversations with the FDA, begin to kind of move more briskly across the other elements that need to fall into place to launch the program in the coming months after that. So we are looking forward to that analysis. And in either case, whether it meets statistical significance or it doesn't, we look towards that as a very significant sort of milestone in the delivery of this program.

Thank you.

Salveen Richter, Goldman Sachs.

Hey, this is Mark on for Salveen. Thanks for taking our question. For ALLO-329 and the trial starting soon in autoimmune disease, what data are you looking to show by year end to demonstrate proof-of-concept? And maybe more importantly, since there are many CD19 players and also allogeneic players showing data this year, how do you think your approach is differentiated? And could your year-end data support said differentiation? Thanks.

Hi, Mark, this is Dave Chang. Let me take on that question. So 329, we have cleared IND, and we expect to initiate the clinical study mid-2025. And we have been guiding towards the proof-of-concept data towards the year end. The number of patients that we expect to treat in 2025, because this is a dose escalation Phase 1 study, will be somewhat limited, but it will be handful. And what we are looking for is biomarker-based proof-of-concept.

One, do allogeneic -- ALLO-329, do they expand well? I think those are very important information. And second, do we achieve the B-cell depletion while also allowing some of the B-cell recovery to occur? These are some of the important information that will lead to the proof-of-concept. And also, in some of the patients that we treat, we expect them to have autoantibodies and the measurement of autoantibodies before and after the treatment that could also give a lot of insight into what the program is doing.

In terms of differentiation of ALLO-329 to many other programs that are currently in the autoimmune space, I think the key is that one, this is an allogeneic program; and two, this has ability to not only deplete the B-cells, but also activate the T-cells, which contributes to the overall pathogenesis of autoimmune disorders.

How the latter would translate, I think we will have to see the clinical data, but possibilities of being able to address the T-cells can allow us to go to indications that CD19 B-cell targeting therapies may not necessarily be sufficient. And another potential benefit of targeting T-cells is that the remission could be much longer because you are eliminating not just the B-cells, but also T-cells.

Thank you.

Brian Cheng, JPMorgan.

Hey, guys, thanks for taking our questions this afternoon. David, I'm just curious if you can provide a little bit more comments around your latest thinking around incorporating potentially other milder lymphodepleting agent or even completely removing the standard cy/flu that you're using? Any color on timeline? And what is really the fastest and the best way to kind of sort that out? Thank you.

Yes. I mean, Brian, excellent question. These are the things that we hope to address in the Phase 1 study. In the planned study, first of all, the lymphodepletion that we will be deploying is a milder lymphodepletion. We have taken out fludarabine. So one cohort will be treated with cyclophosphamide alone as a lymphodepletion.

And the second one, we have also clarified when we announced the clearance of IND is that in parallel, there will be a second cohort where we will be testing without any lymphodepletion. So a little bit to your question as well to the previous question about Mark -- from Mark is really the Phase 1 study already is built in to address the key questions about 329, whether it can achieve the objective with milder, which will be a fantastic news or even without any lymphodepletion, which will be phenomenal for this program.

Sami Corwin, William Blair.

Hey there, congrats on making the progress this quarter. Thanks for taking my questions. I was curious what increase or difference in event-free survival ALPHA3 is powered to show? And then I noticed in your 10-K that it said that if both treatment arms look better than the control of futility analysis, but they don't look any different than each other that additional patients could be enrolled and analyzed. So I guess what kind of difference are you looking to see between the two treatment arms? And if they do look similar, would you pursue the lymphodepletion arm without 647? Thank you.

Yes. Sami, I mean, the question about the powering of our ALPHA3 study, I mean, the primary endpoint is event-free survival. We haven't gone into the depth specifics about the powering of the study other than saying with the targeted about 110 patients each arm for comparison, this study is very well powered. And this also goes back to the earlier question around -- from Mike about what could be possible at the interim analysis, which will happen early 2026.

Yes, we are spending some ALPHA. And obviously, we believe that there is some possibility, which may be not so small that the statistical boundary may have crossed at the time. And frankly, if you look at what has happened with the CAR T studies in the second-line study, whether it's the YESCARTA or BREYANZI study, the sample size, number of patients that were treated in the second-line study, which was comparing CAR T with the active treatment, it's around 260 to some mid-300, not so dissimilar.

So those studies obviously will show the statistical significance in the midyear. So I think that is probably some good reference to think about how ALPHA3 study may have been powered. And your second question about what we have disclosed in the 10-K, we have provided a little more guidance about how many number of patients that we'll be looking at as we start looking at the futility as well as selecting the lymphodepletion.

Here, obviously, if we don't see any difference, there are possibilities that we may want to have some more patients to see whether the difference is more significant or not. Another possibility is that at the time of reviewing of our 36 patient data, that may provide the sufficient information for us to make the lymphodepletion. We will get there, and this will be very much data driven. So probably, it's best that we wait to that time point rather than speculating too much.

Got it, thank you.

Jack Allen, Baird.

Awesome. Thank you so much for taking the questions and congrats on the progress. I just wanted to ask about the futility analysis as well. How should we be thinking about the futility analysis as it relates to the comparison? Is it a comparison against the control arm here, or is it against some sort of hurdle rate? And then on what metrics will you be looking at to evaluate futility? Would it be MRD conversion, response rates, or any early survival data? Thanks so much.

Yes, Jack, let me just take this question. We get asked about the futility question. There isn't anything unique about the futility analysis that we are doing. This is a very standard thing that many Phase 3 studies, sometimes even Phase 2 studies will be doing. What gets looked at in the futility analysis is really the totality of the data. You can look at the safety.

Obviously, we want the safety to be tracking close to our expectation based on what we have seen in the ALPHA3 study. And there isn't a significant imbalance in the safety between the observation control arm versus two treatment arms. And then the second one is sort of the signs of efficacy. And here, we will be relying primarily on the MRD conversion rate.

So every patient who gets enrolled in the ALPHA3 study starts with MRD-positive, both the control as well as the two treatment arms using different lymphodepletion. The expectation is MRD conversion will be heavily upgrading more, significantly more in the treatment arm compared to the observation. So that will be the -- essentially the futility that we'll be looking for. Then afterwards, once the futility has been crossed, we'll be looking at the two treatment arms, two lymphodepletion arms to see which one is better.

Thanks so much for the color.

Biren Amin, Piper Sandler.

Yes, hi, guys. Thanks for taking my question. I think for the ALPHA3, your prior guide has stated that patient enrollment would complete by first half of 2026. So I just want to see if you're continuing to track towards that timeline. And then I guess second question is, I think you mentioned that the split in the trial is 50-50 between community versus academic in terms of sites. How about the patient split? Is that 50-50 as well?

Biren, in terms of the overall trial guidance, we are now focusing more on the data readout, which has not changed. And obviously, your particular question around the trial completion, I think we are more or less tracking around that time. And obviously, as we progress with the study, we'll provide more information. With respect to your second question, can you just repeat the second question?

Yes. I think you mentioned in terms of the trial split, the site split is 50-50 across the 40 sites that you've activated between community and academic.

Yes, yes.

So I want to understand if the patient split similar as well.

Yes. Let me pass that question to Zach to provide more details on -- in terms of the site distribution across community versus academic centers.

Yes. Thanks, David, and thanks, Biren, for the question. David, yes, you are correct that it's about 50-50 split right now with about four -- four-fifths of the sites activated, community versus academic. As far as the patients coming in, what I can say is that we haven't seen a heavy skew in one direction or the other. I can't say it's exactly 50-50. But what I can say is that we are seeing robust activity in both the community centers as well as the academic centers.

Great, thank you.

John Newman, Canaccord Genuity.

Hi, guys, thanks for taking my question. Just wondered on the initial data for 329 at year-end '25, just curious if you know how much follow up you might have if you would be able to look at one month or maybe three. And then also, given the mechanism of action for 329, is there a way that you can look at not just the B-cell depletion but also potentially depletion of the active T-cells? Thanks.

Yes, John, great question. It's something that we constantly talk about internally. Let me pass off to Zach to answer the questions about the length of follow up that we may have and what else we're going to be looking at in the biomarker analysis.

Yes, so thanks, John. So we haven't said exactly how much follow up we expect to have. And we have said that with the trial starting middle of this year and us obviously moving as quickly as we can, we should have a handful of patients treated, hopefully, by the end of the year and a little bit of follow up. I mean, what we've guided towards in terms of proof of concept is, as David pointed out earlier, the biomarker data, so B-cell depletion as well as expansion of the CAR T cells.

And we'll have some early safety results, too. So we can gather that information in relative short order in a clinical trial. We won't really have a significant read on durable efficacy, of course, by the end of this year. Diving into your second question on the specific analyses that we plan to conduct, so obviously, B-cells is a must have. But the T-cells, as we have shown in the 316 program is going to be an area of focus as well.

And what I think we've elegantly shown such as in the SITC data just a few months ago is that we can really parse out the CD70 positive versus the CD70 negative cells in the patients. And really, that is what has given us the foundation to -- that has validated the Dagger effect in patients. So we'll be doing very similar analyses in 329 and seeing whether we are seeing that evidence of a strong dagger effect in these patients.

Okay, great. Thank you.

Asthika Goonewardene, Truist.

Hey, guys, thanks for taking my questions, and I appreciate all the color today. I want to follow up John's excellent question on the RESOLUTION study. It's great to see that you guys are aiming to explore the lymphodepletion-free strategy as well here. But I want to ask you this, how much follow up do you need to answer that question? And I ask because just in some of these indications you're going after, the KOLs out there would like to see maybe a treatment benefit after six months or even a year.

Do you think you'll need to do that all the way up to them to really answer that question of whether or not you can go with the lymphodepletion-free strategy? And then a second quick follow up. On the JCO publication, all the durable responses were CRs, and it also goes to say that all six patients with low disease burden had CRs. So I'd like to confirm, are those the six patients that are the ones that are still in response on the swimmer at the data cutoff on that paper? Thanks.

Yes, Asthika, so two questions. Let me take the 329 RESOLUTION question about whether we need to follow the patient for longer. That's probably without question, we will be following these patients longer than the initial biomarker data analysis. So the way we see it is a biomarker, especially T-cell depletion and cell expansion, autoantibody titer changes. I think these are very great telltale signs around whether the treatment is -- 329 is behaving as we have expected.

And obviously, as we follow these patients, we will get more information about the clinical outcome, including if some of these patients go into complete remission, how long they may last. I mean, those are much longer follow up, and that will not be the part of the initial data release that we are projecting year end. The second question I'll pass off to Zach to respond. Zach?

Yes. Thanks, Asthika. So the first thing to kind of keep in mind is, as you pointed out in your question, is most important outcome after any treatment at all, whether it's CAR T cells or anything else, is that you achieve a complete remission. That is obviously the number-one thing because if you don't get to a complete remission, your chance of durable cure is zero. So that's the first thing to keep in mind.

What we showed in our subgroup analysis is that if you had low disease burden as assessed by either the tumor measurements or by the serum LDH, you had an extremely high chance of achieving that must-have clinical scenario of a complete remission. That said, we want to also tout that the cema-cel product itself is a very potent product. Obviously, it's very active as the JCO paper indicated. And we've actually had plenty of patients that were -- had bulky disease that achieved durable CRs as well. So it was a little bit of mixing and matching.

Matthew Biegler, Oppenheimer.

Hey, guys, thanks for the question. I'll ask another one on RESOLUTION but maybe in a slightly different way, which is hypothetically, how much efficacy are you, I guess, potentially willing to leave on the table to get away with no-lympho conditioning, i.e., is no-lympho conditioning really a game changer? Or is it just a nice to have in your opinion? Thanks.

Yes, Matthew, excellent question. You are asking things that are highly debated internally. I mean, probably the best way that I can sort of describe is lymphodepletion is a potential barrier. And the lower -- I mean, if you can lower the lymphodepletion, that's a big plus. And if you can eliminate, that's really a big, big game changer.

But frankly, probably the best way to think about it is when it doesn't -- it doesn't have the burden of lymphodepletion, it can be used more widely. So it really creates the potential to treat not only autoimmune disorders with a high severity, but also moderate in severity. So it gives a lot more opportunity to address different patients. So it is -- yes, we would love to have no lymphodepletion, but I think even just lowering the lymphodepletion would be a significant win for the 329 program.

Appreciate it.

Luca Issi, RBC Capital Markets.

Hey, guys, this is Shelby on for Luca, and thanks for taking the question. On ALPHA3, it's our understanding that there is an option for inpatient or outpatient treatment. Is that decision left up to the investigator? And how should we think about the mix of patients who will be treated outpatient versus inpatient? Any color there, much appreciated. Thanks.

Yes, Shelby, I'm going to ask Zach to respond to your question. Zach?

Yes. Thanks, David and Shelby. So indeed, there is no requirement at all for inpatient either LD or cell administration. It is entirely up to the investigator on a case-by-case basis. I will say that we are seeing -- as we've seen for a long time in our cema-cel programs, even in the ALPHA and ALPHA2, we are seeing a significant number of these patients being treated fully as an outpatient. And of course, that is the vision -- part of the vision for this product is that it's going to be easy to administer in the clinical settings where these patients receive frontline care.

As for sort of specific characteristics that would lead to a patient being treated inpatient versus outpatient, there's a host of them. I won't go into them now. But one of the great benefits of the ALPHA3 study is that all of these patients are going to be in remission when they receive their cema-cel and their lymphodepletion.

And as David pointed out earlier in the call, patients with low disease burden tend to have better safety outcomes than those with high disease burden. So on balance, we would expect a significantly greater fraction of these patients over the duration of the study to be managed fully as outpatients, and that is our expectation.

And also, if I can add one color to that response, Shelby, I mean, I think the important thing is that in ALPHA3 study, we do not require hospitalization. And in that way, in essence, what that's doing is this trial is just like any other trial. And whether physician does with that information -- whether they decide to treat as a fully outpatient or maybe put them in the hospital for a day or two, I mean, that's essentially how the practice is done in -- not just in the cell therapy but in any other cancer treatment. So it's really giving the patient and the physicians the option on how they want to receive the investigational therapy in the ALPHA3 study.

Samantha Semenkow, Citi.

Hi, good afternoon. Thanks very much for taking the question. Some of your autologous CAR T counterparts have spoken about a push to expand into large community oncology centers that could potentially overlap with your ALPHA3 trial sites. So I'm wondering, to what extent are you seeing this infrastructure being built at the community centers you interact with? How much of this groundwork do you think could be in place by the time you potentially launch cema-cel? And how are you thinking about your ability to leverage this infrastructure for the launch? Thanks very much.

Yes, Samantha, excellent question. I think the effort, not just by us, but also in the entire CAR T community to move into the sort of community-based cancer centers, I think that's just going to extend and expand the usage of the CAR T. I mean, that's a very important aspect of any product launch and product life cycle management.

I think, in many ways, here is where the allogeneic CAR T really plays favorably. I mean, not having the logistical challenge, just being able to ship the product when the patient needs a treatment. And also, in our case, as we are learning, as we improve the manufacturing, the scalability of the manufacturing, all these things are playing in our favor. So as the effort from the autologous CAR T companies to expand their use into the community cancer centers, we see that as a positive thing for the field, and we also see that as a positive thing for what we are doing with the ALPHA3 study.

Ben Burnett, Stifel.

Hi, this is Carolina Ibanez-Ventoso on for Ben. Thank you for taking our questions. First, on the interim analysis of cema-cel in mid-2025, can you remind us when you are measuring the MRD conversion? Is it at one month post cema-cel infusion or later? And I have a follow up.

Yes, we're trying to limit the questions to one. Zach, do you want to take the question about the timing of MRD test?

Yes, thanks, Carolina. We have not disclosed exactly the timing of that draw. And as David pointed out earlier, of course, there will be other elements that we're assessing to make that lymphodepletion decision in addition to the MRD conversion.

Okay, understood. Thank you.

Laura Prendergast, Raymond James.

Hey, guys, can you elaborate a bit more on the registrational path for the Foresight MRD test and how it relates to the registrational path for cema-cel in 1L lymphoma? Thanks.

Hey, Zach, do you want to take that question?

Yes, that will be an easy one. Thanks, Laura. The plan has been all along to have a concurrent launch of these products at the time of the FDA approval. The specifics around the path to registration of the MRD test, though, I would refer you to the Foresight management.

But you don't foresee it being an issue at all with getting cema-cel approved in first line?

No.

Got it, thanks.

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

All right. Thank you. I just want to reiterate, Allogene entered 2024 with a bold strategy. And today, we stand on the brink of a transformative year. With three pioneering programs each approaching critical milestones, we are proving that allogeneic CAR T has the potential to redefine patient care. So thank you for your ongoing belief in Allogene and the field of cell therapy. Operator, you may now disconnect.

Thank you. Ladies and gentlemen, thank you for your participation in today's conference. This does conclude the program, and you may now log off and disconnect.