Allogene Therapeutics, Inc. Stock

All right. Good morning. I'm Sam Semenkow, one of the senior biotech analysts here at Citi, and it's my pleasure to be hosting Allogene Therapeutics at Citi's 2026 Biopharma Back to School Summit. I'm joined this morning by -- with Zach Roberts, President and CEO of Allogene. Zach, welcome, and thank you so much for being here.

Thank you very much, Sam. Great to be here.

So, why don't we just start a little bit high level on the business. You've made a ton of progress this year on the pipeline. Could you just level set for the audience where the company stands today and what we can expect throughout the rest of the year?

Yes. So, it's been a very productive year in 2026 so far. Beginning with our leading program, we released some data in April from an interim futility analysis. We also are moving very briskly through enrollment in our Phase I program, which is a novel therapeutic CAR T cell product in autoimmune disease indications. And we'll have some data from that program later this year at an upcoming conference. And that's setting us up for a very exciting busy year of catalysts in 2027.

Yes, absolutely. And so you recently stepped into that CEO role. Congratulations. I'm wondering how you're thinking about the business from that perspective? What do you bring from the company in this new seat? And how should we think about how you're going to drive the business going forward, particularly through busy 2027 and also '28?

Yes. So, I took over as CEO on July 1 of this year. Before that, I spent 3.5 years as the Head of R&D and Chief Medical Officer. So, the programs that we'll discuss today are programs that I launched, designed and launched as the Head of R&D. So, it's quite a natural transition for me to step into the CEO role.

So I have a very clear mandate from our Board and shareholders. And internally, the plan is to continue to execute on our main programs, the pivotal cema-cel program in ALPHA3 and then the RESOLUTION study with ALLO-329. And really, those are going to be the focus for the coming months and years.

We also have a very exciting preclinical pipeline. We've shared a little bit of data here and there at medical conferences this year. We've got some more coming up. So really, it's a focus on delivering on the lead programs and then continuing to build out the pipeline.

Perfect. Well, so then let's just dive right in on cema-cel and ALPHA3. You had impressive MRD clearance data earlier this year, where you demonstrated cema-cel is having that measurable effect on residual disease. And we know that MRD clearance is heavily predictive of EFS benefit. So how should that inform our thinking as we near the EFS analysis next year, as you mentioned, and then the final EFS analysis the year thereafter?

Yes. So the study itself is a randomized trial of cema-cel, which is an off-the-shelf anti-CD19 CAR T cell. And it's -- the study is designed in a novel way where we are looking to see whether patients who have completed first-line treatment for their non-Hodgkin's lymphoma, B-cell-related non-Hodgkin's lymphoma, but remain positive for minimal residual disease using an ultrasensitive MRD test at the end of first-line therapy.

Those patients who are MRD-positive come into the study and then they are randomized either to a dose of cema-cel, which is an off-the-shelf CAR T cell or the standard of care, which is just observation, surveillance program. And so the analysis that you just alluded to occurred in April. It was a preplanned safety and futility analysis where we looked at 12 patients in each of these 2 arms.

And rather than looking at the primary endpoint of the study, which is EFS, we looked at the ability for cema-cel to eradicate the residual disease. So patients -- everyone who comes into the study is MRD-positive and who went from MRD-positive to MRD-negative. So as you mentioned, we did have a positive outcome there.

We saw about a 42% differential between the 2 arms, 7 out of 12 patients in the MRD arm -- sorry, in the cema-cel arm cleared their MRD and 2 out of 12 in the observation arm cleared.

So when we revealed these data and we were internally examining them, we asked ourselves the same question that you just asked, what does this mean for the potential EFS analyses that are upcoming? So in 2027, we have a planned interim event-free survival analysis and then in 2028 is the primary. Overall, the study is designed to detect a 50% reduction in risk of EFS events. And so we have to allocate the alpha spend between the '27 and the '28 analysis.

So we actually have a very small amount of alpha allocated to the interim analysis in mid-'27 and the majority of the alpha is reserved for the primary. So when we saw this MRD differential back in April, first of all, we were overjoyed with the amount of signal that seemed to be coming from the cema-cel arm. And it gave us a great deal of confidence that this study was going to be positive when it was completed.

As it pertains to the interim EFS analysis next year, that is a TBD, right? Because it is a small amount of alpha, which means the effect size would need to be overwhelmingly positive, probably to a degree that's maybe even a little bit greater than what we saw at the interim futility. And honestly, that is an Independent Data Monitoring Committee review of that data.

So they have a decision to make whether stop the study for efficacy or continue the study. So we are focused solely on enrolling the trial, ensuring that we have an overall positive outcome because we believe that, that outcome would transform the way medicine is conducted for these patients.

So it's -- what is the disclosure plan for the interim EFS analysis? Is that something that you'll be sharing like that the study will continue or the study will stop? Is that the extent of what we'll probably hear from you?

Again, so we -- there are a few stakeholders here. Of course, it's -- the IDMC is going to perform the analysis and then also the FDA is going to be watching carefully here. And one of the things that we are committed to doing is ensuring that the data integrity remains fully intact so that we don't get to the end of the trial and there's a problem with bias that could have crept in from early disclosures.

So while the interim EFS analysis will occur, it's really up to the IDMC to make a recommendation on what to do with the study, either continue on as planned or potentially stop the study for efficacy if it turns out that enrolling additional patients would be considered unethical because of such an imbalance in outcomes.

And so it seems like a really high bar given the minimal alpha spend, but it's not a nonzero chance theoretically. So I'm wondering if there's any pre-commercial steps, if any, you're considering as we near that interim analysis in the event that you do have something that is overwhelming success, sufficient to stop the study? Or just maybe we could just talk more broadly as well just about any commercial preparations you're already starting to make now.

Yes. So we absolutely are beginning to sort of start thinking about what our commercial launch plan is going to look like. Again, we assume that this study will be positive. We are building it for success. It's a little bit of a different launch than really any other CAR T cell that's come before because of this being intertwined with the MRD test itself. And that's a very interesting sort of side story to the ALPHA3 program, just how rapidly MRD is becoming part of the standard of care in oncology.

So some of that work is being done outside of Allogene just by the natural evolution and really high degree of interest in MRD. So the concrete steps that we have taken already is we have hired our first commercial hire. It's someone who is going to be focused on market access and reimbursement because we think that this is going to be the area that requires the longest prep time. So that person will be on board very shortly. And that person will then begin to kind of figure out exactly what this launch plan would look like. The bulk of the commercial team would come later and really probably over the course of 2027.

Okay. And I guess if that interim is positive, you have the ability to step up and accelerate any pre-commercial activities at that time?

Yes. So I mean if that interim is positive, of course, then we would approach the FDA to try to ascertain is this suitable for a BLA on its own? Do we need more follow-up that those sorts of pre-BLA conversations would begin. And then if a BLA is submitted, of course, then there's a review interval as well. So that's going to push us into 2028. So we will have at least a year, if not 18 months of time to build out a commercial team and get ready for launch.

Makes sense. Okay. And so then you did mention the uptake of MRD testing. And if you follow those companies, they're all telling a very similar story where the uptake has just been growing at a very strong place -- I'm sorry, pace. So what does that tell you about physicians' overall appetite to adopt MRD testing in large B-cell lymphoma, but also just more broadly across oncology?

I think we are witnessing nothing short of a revolution in how we think about management of patients with cancer. And we're now -- within the last 3 months, there have been major events from a regulatory approval perspective in -- with MRD. So beginning in May when we had the approval of the IMvigor011 study, which is atezolizumab study in completely resected bladder cancer, very analogous to the ALPHA3 trial. Patients with MRD, got a year of atezolizumab versus placebo, very positive from a disease-free survival and overall survival benefit.

Just last week, we saw the SERENA-6 data set approved, which was a little bit of a surprise, a good surprise because the ODAC that they had back in April suggested that maybe the FDA would not approve that drug based on the use of the MRD test in that context. So this is -- we're absolutely starting to see a sea change in how people are thinking about these molecular tests to first understand prognosis and then eventually to make treatment decisions.

And so internally, we have heard from our investigators that this is the future. We've heard that since the day we designed ALPHA3, and that momentum has grown really consistently, almost sort of exponentially actually in the last couple of years. And to cap it all off, we recently conducted a quantitative market research analysis internally here at Allogene and asked many questions, one of which being exactly this, what percentage of your patients are you currently testing for MRD, and in the hypothetical context of a cema-cel approval, what percentage of your patients would you test?

And already, it was sort of in that 25% to 30% currently being tested, which was a large number. But then in the context of an approved agent for use in the context of an MRD-positive result, that number jumped to about 80%. So we see the world is really building quite an appetite to start to utilize these advanced diagnostics, particularly when it allows them to make a treatment decision for their patients.

Yes. And that's a measurable already, which I think is a bit surprising based on what maybe you had guided several years ago when you started ALPHA3. Can you just talk about like -- I mean, is it just excitement around the potential for a therapy that's really driving the use even though there's nothing to be done for these patients if they're MRD-positive right now?

So it's both, Sam. And right now, you're absolutely correct. There is no -- there is no treatment option for an MRD-positive result that doctors can offer their patients. And that's actually really the niche that cema-cel will fill eventually. And right now, we're the only one that's really focusing on this area. So that is great for us from a competitive standpoint.

But in the current moment, most of the patients with large B-cell lymphoma are cured with their front line therapy and about 2/3 or so. So people are ordering these tests now, which are commercially available because they're hoping to get a negative result because that does significantly enhance their prognosis.

So right now, PET/CT is the standard of care. Its false negative rate is quite high. Its false positive rate is even higher. So it gives you a hint about what might happen with your disease. But if you have an MRD test, particularly when it's used in conjunction with the PET/CT, that is a much stronger prognostic sign that your disease is cured.

And so that is the reason that these tests are starting to take off. It's just a useful tool for prognosis. That will be further accelerated overnight once there is an opportunity to treat in response to an MRD-positive result, which is unfortunately kind of an awkward conversation that doctors have to have with their patients at this point.

Right. Okay. That makes a lot of sense. And so then when you think about, I guess, how the commercial potential for cema-cel is in the context of the MRD testing background being quite positive. One of the things that you've made a big push on is moving into community centers for adopting cema-cel. Like what feedback have you received from the community physicians and their comfort with prescribing cema-cel?

It's been...

Potentially...

Universally positive. And this is coming from primarily the community oncologists who are part of our trial and about 50% of our sites are community centers, many of which don't have CAR T or transplant or any kind of cell therapy available. So this is their first cellular therapeutic that they're administering in their clinics. And all of them are really overjoyed to have access to CAR T, some of them for the first time in their career. But even outside the sort of folks who are on the front lines in the trial, we are hearing really quite positive feedback that this would constitute a revolution in how they -- the services that they can offer their patients, the ability to offer these potentially curative therapies when those patients generally are not actually receiving those.

So that's one of the biggest conundrums that these community practices face is if they have a patient who relapses, as I said, about 1 in 3 will relapse, that's really a difficult moment because many of these patients, frankly, are not interested in being referred to an advanced care center where they can receive CAR T even if they live in the same city. So this is -- there is such a demand for CAR T throughout the spectrum of treatment centers.

And in a world where only 15% to 20% of patients who could benefit from autologous CAR T actually receive autologous CAR T, we are going to bridge that 80% gap in our view with the cema-cel strategy with the consolidation, the safety profile that we showed at that interim futility, no cases of CRS, no cases of ICANS, fully outpatient regimen. This is really going to allow us to maximize that commercial opportunity, which is, in our estimate, about $2.5 billion to $3.5 billion annually.

And my understanding is that activating these treatment centers, whether they're community or academic is a bit simpler than autologous CAR T. I guess how do you think about initially choosing which centers to launch in? And how quickly are you capable of expanding from there to really maximize across the country and then globally as well?

When I was at Kite and we were completing the ZUMA studies and then planning for launch, there was just an awful lot of work, and I understand that work is ongoing about what are the basic requirements, the training, the facilities, the personnel, the beds that are needed to onboard an autologous CAR T. And it is an awful lot of work -- it's an awful lot of investment by the company, and it's an awful lot of investment by the hospitals.

And I think you see that those challenges, financial and logistical reflected in the restricted access footprint that exists today for autologous products. For -- and there's an accreditation process known as FACT that's also involved. These centers have to be accredited by FACT in order to offer commercial and clinical CAR T.

In ALPHA3 with cema-cel, we are currently treating patients at centers that do not have FACT accreditation. They do not have any of the infrastructure build-out that is required for autologous. These are research personnel, nurses and physicians who have never given CAR T, who are thawing our product at the bedside and infusing it in their outpatient infusion centers and the patients are being sent home.

This is the vision that we would want to carry forward into a commercial launch where the onboarding process is straightforward. This is what the product looks like when you receive it. This is how you handle it. This is -- if you need to ship it back, this is how you ship it back, right? On-site storage is not something that we envision as being necessary because these products are shipped on liquid nitrogen.

This is how you thaw and infuse. So while all those steps are yet to be built out and will be under the purview of the future commercial leader, it is undoubtedly going to be significantly more straightforward than it is for an autologous product, and that really is key to our vision of increasing access to these products.

Right. Okay. That makes sense. And then I think that that's a good segue perhaps into the competition question I have since it is maybe easier for an allogeneic CAR T here. Why -- I've heard some concerns about bispecifics also easily moving into the space. I've heard some concerns about CAR Ts in the first-line setting, taking some of the share that cema-cel could have in the consolidation space. I just would love your thoughts on the landscape where it stands today, anything potentially coming down the line? And how you envision maintaining that niche that you are actively building for cema-cel where it has the ability to maintain that market share?

I expect that anybody with a drug or a product that is active in large B-cell lymphoma is going to be strongly considering moving into the MRD space for many reasons, some of which we touched on earlier, this is just a very natural place for us to be doing drug development and regulators have clearly signaled that their willingness to use MRD as a treatment decision point.

So I think that the desire to get into this space is probably universal. What makes an off-the-shelf 1-time infusion like cema-cel so attractive is that, is that it's off the shelf and it's a 1-time infusion. And you can give it right on the heels of the completed 6 cycles of first-line therapy. This is -- we sometimes call it the seventh cycle of treatment.

And so in our vision, what will happen is a patient completes their chemo, they come in for their MRD test and their PET scan on the same day. They get the results the same day. And then a decision is made, do you need cema-cel or do you not need cema-cel? And if they need cema-cel, they can write for it and the patient can come in literally the next day to get their lymphodepleting chemotherapy and then get their cells and they're done. If you look at bispecifics, which have the advantage of being off the shelf, so you can prescribe them quickly, there's going to be a treatment interval here, a period of time where these patients are likely going to need multiple infusions that maybe last 6 months or maybe even 12 months. This is going to be something that clearly is going to need to be thought out.

And that is just not going to be, in my view, speaking as an oncologist, very attractive to a patient who's been told from day 1 that they have a curable malignancy, perhaps they've been told that they're in a complete PET remission. And then this blood test tells them that they need another 6 to 12 months of treatment. That is not going to go very well, in my view. On the other hand of the -- on the autologous side, the autologous CAR T, there are some real challenges there. For example, patients who have just completed 6 cycles of R-CHOP generally don't have a lot of T cells floating around.

So manufacturing these products that close to the completion of therapy is going to be probably more difficult than it is in a patient who's got a few months since their last dose of chemo. So I think the manufacturing failure rate is going to take a hit.

And then the other problem is that most of the patients are being treated in the community for their front line, and that would still require a referral to an advanced treatment center to be considered for CAR T. And recent publications from real-world data have shown that, that often takes 3 to 4 months from the time that the patient is referred to the time of CAR T infusion in the real world. That interval of time, we'll see a good 1/3 to maybe as many as half of the patients who are MRD-positive, their disease will progress during that 3- to 4-month interval. So all this to say is, obviously, there is clearly a growing desire to get into this space, but the product profile is going to be really dominant in determining who is the most successful here and really cema-cel has the best profile.

And you're well in the lead as well.

Yes, at least 2 years ahead.

Right. Okay. One more MRD question, actually. So you said that the PET scan and the MRD testing can be done on the same day. I mean, have payers embraced paying for the MRD testing? Has there been any pushback that you can see in your market research there?

We are still somewhat in the early days. I will say that Medicare covers the commercial MRD test for large B-cell lymphoma. So that's been the case for a couple of years now, and we're seeing really impressive growth from Adaptive Biotechnologies, who makes clonoSEQ. Natera also has a marketed product called Signatera for lymphoma. Both of them report the growth of their MRD business on their quarterly calls, and it's been astonishing how fast these products have grown in market share. So I think the commercial payer story is still evolving. But I think as acceptance of the prognostic value of MRD grows with pros -- more and more prospective data sets being published.

There was just another paper that came out a few weeks ago with the Signatera showing very prognostic information for the MRD test at the end of therapy. I think incrementally, those commercial payers will begin to pick up the cost. And then, of course, when the MRD result is tied to a treatment decision as would be the case for a cema-cel approval, I think in that case, as the NCCN, as other guidelines come out with Category 1 recommendations for MRD testing, those -- that will be the real catalyst to make sure that all of those tests are covered. But we're already making strides towards universal coverage now.

Right. Okay. And then maybe a bigger picture question for you. You're pioneers in leveraging MRD testing across the business. I think we can all agree that. Is it possible this becomes your niche set aside 329, which we're going to talk about in a minute. But could you consider leveraging MRD testing to replicate the success that you've already had with cema-cel, but in different settings, whether that's other blood cancers or solid tumors? Is there an appetite at Allogene for that direction?

At the risk of sounding like a broken record, 100%, yes. I believe strongly that any opportunity that we have communally, not just Allogene, but as in general, to treat patients when they have the smallest disease burden that you can measure, whether that's with CAR T or really anything else, that's what we should be doing. We know outcomes are better. Safety outcomes are better, efficacy outcomes are better.

So at Allogene, absolutely. I think we're validating this strategy in ALPHA3. There are other non-Hodgkin's lymphoma B-cell malignancies that -- where MRD plays a role as well. So those are clear next potential steps for us.

But I'm also thinking about it for solid tumors. And we don't talk about it as much anymore, but we recently published the Phase I experience from our metastatic renal cell carcinoma trial just in July of this year in JCO, where we showed a 31% durable response rate in patients with metastatic solid tumors using a different CAR, CD70 CAR.

There is emerging data now showing that MRD is prognostic in RCC. Very early days for that yet, but that data is out there. So one could easily envision an adjuvant study where patients who undergo a complete resection for early-stage RCC. They undergo an MRD test to see if there's residual micrometastatic disease. And then they receive a dose of ALLO-316 in the adjuvant setting. That's a study that I would love to do. So the short answer is yes. The long answer is we're looking for ways to do that.

Excellent. Looking forward to hearing more about that as we go on. Well that's a good segue, I think, to start talking about 329. So ALLO-329 is your CD19/CD70 for autoimmune diseases. And I think one of the last updates you gave us with concrete numbers said you had at least 9 patients dosed. I think this was in May. And you're guiding to the first interim data readout by the end of this year. What should we be looking for in that data set and recognizing that you'll still be in the dose escalation phase?

Yes. So with any first-in-human study, you have to be cautious and first and foremost is to ensure the safety of the product, ensure the safety of the patients that are coming into your trial. And I think with recent events in the news, that has, I think, shown to be a patient decision and strategy of Allogene.

And so we started at a very low dose, 20 million cells, flat dose, which is really low dose in the world of CAR T, much lower than the autologous doses that are being given and far lower than those for the allogeneic peer companies. And then we've been quite methodical. And as you may recall, we've got 2 parallel dose escalations. It's a standard 3+3 design, but 1 is without lymphodepletion and 1 is includes Cytoxan-only lymphodepletion.

And then just recently, we added a third arm that was already in the protocol. We just opened it to include Flu and Cy conditioning for these patients. Now technically, we have 3 parallel dose escalation arms. And that decision was primarily made because there is such a backlog of patients waiting to get into our study that this allowed us a third option to kind of decompress that waiting list a little bit. So what that means for us in terms of the Q4 update is that we will have some patients with quite a long amount of follow-up, presuming that they're still being followed in the study.

Those were patients with the 20 million cells that dosed towards the end of last year. And then as we have picked up steam over the course of 2027 (sic) [ 2026 ], we have reached 40 million and then 80 million and beyond for a cell dose across those 3 different LD arms. So we should actually have a reasonable number of patients that we share in Q4 with varying degrees of follow-up, but across all 3 of these different lymphodepletions and up to 80 million cells and probably a dose level higher.

And it's a basket study across a couple of different rheumatology indications. Do you expect that -- or looking at the enrollment that you have so far, will we have representation from each of those indications in the basket sufficient that we can start to get a feel for efficacy, again, be it at a dose escalation phase here?

We will have patients from all 3 indications. Those 3 indications are systemic sclerosis or scleroderma, inflammatory myopathies and lupus. So we will have patients across all 3. It is a true basket study, meaning it is a first come, first serve. There are no targets or quotas or thresholds that we have instituted for individual disease types. So it is expected that we will have not a perfect balance between those 3, but we will have some patients in each of these 3 arms.

Got it. Okay. And then you've alluded to some of the safety concerns that have been in the headlines recently, specifically IEC-HS. And you also talked a little bit about 316, which you had some experience that was your renal cell carcinoma asset, where you had some experience seeing that safety adverse event in that study. And 329 leverages that same CD70 CAR.

So how should we think about the safety profile of 329? I know that you started very low and that was on purpose and you're prioritizing safety. But how should we think about the potential safety profile over time as you look for that ideal dose for 329?

When we designed ALLO-329, we were sort of well on our way with ALLO-316. So we were getting familiar with the toxicity profile that was unique to these Dagger endowed products like ALLO-316 and ALLO-329. Dagger is our nickname for the CD70 CAR that drives very robust cell expansion and persistence in an allogeneic setting. So we did a couple of things from the outset. First is we modified the CD70 CAR in ALLO-329, so we removed its co-stimulatory domain.

So it is technically a first-generation CAR. And the reason that we did that is we saw a high degree of tonic signaling in vivo -- sorry, in vitro in -- as we were designing these different CAR constructs, which suggested that this product, if both the CD19 and the CD70 CAR both had co-stimulatory domains, that it may be an overly hyperactive CAR.

So we tuned back its activity a little bit by removing that co-stimulatory domain that turned out to make a much better product. So from a product design perspective, we've already kind of detuned a little bit from where we were with the CD70, ALLO-316. Secondly is we have all the experience that we could have gathered from that TRAVERSE trial with ALLO-316. We encountered quite frequent and even high-grade IEC-HS in that program. We learned very well how to manage that -- how to diagnose and manage that on the fly. So we've created customized algorithms for these Dagger products and really a very specific management and surveillance for this entity and then rapid therapy.

So those 2 tools, I think, are putting us in a good place. We train our physicians extensively on IEC-HS diagnosis and management. And in the wake of the news reports from last week, we pulled together an impromptu kind of refresher on IEC-HS, which was very well attended. So this is top of mind for everybody.

We have not seen any IEC-HS in the RESOLUTION study yet. The safety profile looks pretty good, and we continue to dose escalate. But we know that you don't have IEC-HS until you do. And so we want to be ready for if and when that does occur.

Right. And I think you've also said no high-grade CRS or ICANS in the study, too. Is that accurate?

In RESOLUTION?

Yes.

Yes. No. No high-grade CRS, no high-grade -- any IEC-HS. And yes, the safety profile is looking pretty good so far, and that's why we continue to go up on the dose.

Exactly. Okay. And then just from a commercial perspective, it's a little bit crowded, maybe a little bit less with some of the pauses in studies, but those could resume. But you have the potential for no lymphodepletion or a reduced lymphodepletion regimen, which would be a significant advantage commercially. So when you look at the overall landscape, where do you see 329 potentially positioned, assuming you require lymphodepletion or none?

That is a very good way to set up that question, Sam. It's kind of a fork in the road. And if no lymphodepletion is the selected regimen, which I hope will be the case. I think that substantially increases the opportunity for us to develop this drug in more indications and also more patients within a given indication because I think the risk tolerance will -- not the risk tolerance, but the risk will actually drop if you're not giving chemotherapy. The appetite for a chemo-free regimen will go up. I think we can make a strong argument to doctors and to regulators that maybe we treat patients earlier in their disease history. Maybe they don't have to fail 2 regimens, maybe it's just 1.

Perhaps we go into indications where chemo is something that would never be considered like type 1 diabetes, for example, and really start to brainstorm where we could go with a no -- a truly no lymphodepleting chemotherapy regimen.

Obviously, that's what we're hoping we see, and that's why we're running the experiment the way we are. That said, if we need to use Cytoxan, we've heard from many of our physicians and KOLs who are familiar with the program that, that is not really a barrier in patients with treatment-resistant rheumatologic disease.

In fact, we are using the very dose of Cytoxan that is used in rheumatology. It's 1,000 milligrams per meter squared times 1, so just a single dose. That's given, I wouldn't say routinely, but often in rheumatology clinics. So we did that with rheumatologists in mind. And so in the end, we're going to need to see what the safety is. We're going to need to see what the efficacy is, and I think either path is viable. But really, the promise of Dagger is to try to get away from the need for chemotherapy-based lymphodepletion.

Great. Well, looking forward to the data later this year. And so we're almost out of time, Zach. So I'm just wondering if you could just remind us your cash runway, perhaps recap us what we should expect over the next, call it, 12 months? And any other closing remarks you wanted to share?

Yes. So we raised some money back in April on the heels of the futility data that -- from cema-cel that we talked about earlier. We reported about a $420 million cash on hand at our last call, and that gets us into 2029, which should cover all of the main catalysts for cema-cel, the interim -- sorry, the interim EFS as well as the primary EFS and of course, all of the upcoming catalysts and data releases for ALLO-329. So beginning later this year and then throughout 2027, there's going to be opportunities for lots of news flow from Allogene both -- on both of our lead programs, and we think that this is going to be a very, very exciting 12 months or so for the company.

Looking forward to it. Well, thank you so much for being here. This has been wonderful. And thank you for your time.

Thanks, Sam.

Hello. Thank you for standing by and welcome to Allogene Therapeutics second quarter 2026 conference call. [Operator Instructions] 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.

Thank you, Operator, and welcome everyone to Allogene's conference call. After the market closed, Allogene issued a press release that provided a business update and financial results for the second quarter of 2026. This press release and today's webcast are available on our website. Following brief prepared remarks from Dr. Zachary Roberts, President and Chief Executive Officer, we will open the call for questions. Geoff Parker, Chief Financial Officer, will also join the Q&A. To help us conclude within 45 minutes, we ask that each analyst limit themselves to one question.

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, the potential treatment setting, 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'm going to turn the call over to Zach.

Thanks, Christine, and good afternoon, everyone. This is my first quarterly call as CEO, and it marks the beginning of a new chapter for Allogene, one made possible by the foundation David Chang helped build. David has been my mentor and one of the people who has most shaped how I think about cell therapy and drug development. More than that, he co-founded and built this company, led the field in the generation of clinical data in patients with relapsed cancer, and created the framework we needed to take Allogene into its next chapter.

When I joined Allogene, my mandate was clear. Challenge the conventional thinking about how allogeneic CAR-T should be developed. That meant starting with the patient and working backward. Understand what patients and their care teams need, then design products and clinical programs that meet those needs. That work led to a deliberate strategic shift announced in 2024, designing programs and products that leverages features of the allogeneic cell therapy into a clinical advantage. We focused on settings that demand the unique attributes of off-the-shelf CAR T, ready availability, consistent product quality that is independent of the patient's immune status, and crucially, the ability to treat patients locally. Allogeneic CAR T is not a stepping stone between autologous therapy and whatever may come next. It is a distinct platform capable of filling gaps existing modalities cannot and progress across ALPHA3, ALLO-316 and ALLO-329 is beginning to demonstrate those advantages in practice.

I will start with ALPHA3 because it is the clearest expression of this strategy. ALPHA3 arose from a simple premise. Can we identify patients at high risk of relapse after first-line treatment and intervene with CAR-T before the disease returns clinically? By treating earlier, the study aims to prevent relapse while avoiding much of the toxicity associated with standard second-line therapies, including autologous CAR-T. The trial is also designed to prove that we can overcome longstanding access barriers by enabling patients to receive CAR-T where they already received their first-line care in the community with the same doctors who gave them their first-line treatment.

Testing this required a more precise way to identify patients at high risk of relapse. Standard methods used at diagnosis, such as disease stage and IPI, lack sufficient specificity because many patients classified as high risk by those methods are still cured with R-CHOP. That new tool emerged just weeks before I joined Allogene. When I saw the Foresight now Natera CLARITY data presented at ASH 2022, the design of ALPHA3 came into focus.

When ALPHA3 began, MRD in large B-cell lymphoma was viewed largely as an academic research tool. We believed it could become far more a standard marker patient's prognosis and, if properly validated, a new treatment decision point. That view is gaining traction not only in LBCL but across oncology. In May, the FDA approved Tecentriq as adjuvant therapy for patients with bladder cancer who are in radiographic remission but remain MRD positive by circulating tumor DNA. The approval, based on the IMvigor011 study, is the first where patient selection was based solely on a ctDNA MRD test. IMvigor011 closely parallels ALPHA3's design and this approval, as well as a new Category 1 NCCN recommendation, signals a broader shift toward using MRD as a treatment decision trigger rather than waiting for clinical relapse.

Fast forward to our first look at data from the ALPHA3 trial in April, the interim futility analysis, which provided an important early test of ALPHA3's hypothesis. Cema-Cel drove rapid MRD clearance in a majority of patients and did so with no treatment-related hospitalizations. Most patients were treated and followed entirely in the outpatient setting. And importantly, Cema-Cel was successfully delivered in community practices with no prior CAR-T experience. Together, those findings support ALPHA3's potential to change the lymphoma landscape by offering CAR-T earlier with less logistical burden and greater access across more treatment settings.

At the end of July, the FDA granted both RMAT and Fast Track designations for Cema-Cel in first-line consolidation. These designations are based on two critical points. First, FDA acknowledges that MRD positivity at the end of first-line treatment is an unmet medical need. And second, Cema-Cel has the potential to meet that need. need. We interpret this action by FDA as validation for the ALPHA3 program. Additionally, RMAT creates an important opportunity for more frequent and focused engagement as we advance the trial. That engagement will be central to how we move forward.

Our objective is clear. Execute the study well, protect its integrity, and work with the FDA toward the most efficient development and regulatory path. As enrollment continues, we expect opportunities in 2027 to update investors on the program, including enrollment progress and potential data such as the planned interim EFS analysis. The timing and scope of these updates will of course be guided by our regulatory discussions and the independent data monitoring committee. In the meantime, we will communicate meaningful operational and regulatory progress.

Today we are proud to provide one such operational update. We entered the year with a goal of activating over 80 clinical sites by year end. With strong execution by the team and increased investigator interest following the interim futility analysis, we reached that goal in July. New academic and community-based investigators have asked to join the trial, citing enthusiasm for the initial MRD clearance data and safety profile and growing momentum of MRD testing in lymphoma. As a result, we now expect to have approximately 100 sites active by year end with the significant majority in the United States and additional sites in Canada, Australia, and South Korea. This expansion reflects growing investigator conviction in MRD and the ALPHA3 strategy, supports enrollment momentum, and gives more sites hands-on experience with Cema-Cel's ease of use ahead of a potential commercial launch.

Turning to ALLO-316, the publication of the TRAVERSE results in the Journal of Clinical Oncology was an important milestone for the program and the Dagger platform. Solid tumors have been CAR T's hardest test. In patients with CD70 high renal cell carcinoma, ALLO-316 produced a 31% confirmed overall response rate the optimized regimen. At the data cutoff, none of the five confirmed responders had experienced disease progression, with follow-up ranging from eight months to more than 18 months after a single dose of ALLO-316. The data set is small, and the program has faced real safety challenges. We've been direct about both. But consistently, confirmed responses with this degree of durability in a solid tumor are notable. Just as important, the translational work gives us a much clearer view of the underlying biology of these responses using CAR T-cell expansion, persistence, tumor infiltration, and the contribution of Dagger.

TRAVERSE also demonstrates how we operate. There were moments when the conventional decision would have been to stop development of ALLO-316. When toxicity emerged, our team brought in outside experts, engaged with the FDA, developed the management algorithm and continued learning. That work gave us a pathway to manage the most serious events while advancing understanding of an increasingly recognized immunotherapy toxicity and allowed us to generate the foundational clinical evidence for our Dagger technology pipeline. We are still far from declaring victory in solid tumors, but these results provide encouragement to keep pushing. They move the field forward and reinforce the principle that is central to allergy. When the biology is sound, we stay focused, learn from the data, and continue advancing the science.

That same focus on thoughtful program design brings me to ALLO-329 and the RESOLUTION trial in autoimmune disease, where the core message is execution. Enrollment has moved quickly across cohorts, dose levels, and lymphodepletion strategies, even in a highly competitive field. We believe that momentum reflects a program designed with patients as the focus rather than one that asks them to adapt to the technology.

ALLO-329 was designed with Dagger from the outset. Rather than designing another CAR-T product that requires chemotherapy-based lymphodepletion to work, the product is designed to function better when confronted by the biology of allo rejection by targeting the activated host T cells that contribute to it. Our objective is to both identify the optimal dose regimen for ALLO-329 and to understand how its cell dose, lymphodepletion, and Dagger work together. Strong enrollment and execution are keeping us on track to report a clinical and translational update by year end.

Across all three programs, the through line is clear. We embrace the features of allogeneic CAR-T as unique strengths and have designed programs to allow us to meet the demands of patients when and where they arise. Over the next 12 months, we expect the value of that work to become increasingly visible, beginning with an ALLO-329 update by year-end and opportunities to update investors on ALPHA3 throughout 2027. Those milestones will help define our progress, but the standard we are working toward is simpler. Innovation only matters if patients can actually access it.

We'll now open the call for questions.

[Operator Instructions] Our first question comes from Michael Yee of UBS.

Hey, good afternoon, guys. This is Matt on for Mike. Thank you so much for taking your questions. I wanted to add, I saw you guys added an observational cohort to the ALPHA3 study, and I just wanted to ask about kind of the design of this cohort, maybe what the goal of it is, and kind of the questions you're helping to answer. It looks like it's an MRD negative patient. So just to kind of expand on kind of what the goals are. I'm wondering how we could just show what that observational cohort might be.

Thank you so much. Matt, thanks for the question. So it's pretty straightforward. We added this cohort to help provide context for the overall results of ALPHA3 looking at the MRD-positive patients. Of course, those are the ones that we randomized now into ALPHA3, so having a paired MRD-negative cohort using essentially the same patient population as this is coming into ALPHA3 itself, will give that ability to compare outcomes in the observational cohort of the MRD positive patients as ALPHA3 with the MRD negative patients as well. So really it will give us the ability to further characterize the test itself in a prospective manner.

Our next question comes from Tyler Van Buren of TD Cowen.

Congratulations on your first call as CEO, Zach, and I appreciate the efficient prepared remarks. I guess given the acceleration of site activation by six months, is it possible that the interim EFS analysis could occur earlier than the guided mid-2027 timeline?

Thanks for the question, Tyler, and thanks for the congratulations. It's a thrill to be CEO and it's an honor. So getting to your question, so we are currently maintaining guidance that the EFS should occur at roughly the same time as previously guided. We are just moving to try to accelerate the enrollment of the study and of course working very hard to bring on as many sites for the reasons stated in the prepared remarks. But at this time we're not making any adjustments to the expectation of data availability.

Our next question comes from Salveen Richter of Goldman Sachs.

Hey, this is Mark on for Salveen. Thanks so much for taking our question and congrats on the progress. It was good to see the enrollment for ALPHA3 post the interim data. Could you give us a breakdown of enrollment cadence across academic versus community sites? Is the expectation still that it's going to be 1/3 community and 2/3 academic and what feedback are you hearing from the community physicians?

Without getting too specific here, I would say that the interest continues to be very high and growing in both the academic corners as well as the community corners. I would say that, that the surge of interest that we did see after the interim data really was pretty balanced between the two. We had some pretty big names centers reach out to try to join. And then we've got quite a number of community practices that also ask to join.

So as far as how the patients break down in terms of where they come from, we actually have, I don't know if we've stated previously that it's about a third is expected. That's what we did see in the interim futility analysis. analysis, which was a very great outcome for us. I think that if we can maintain that or even bring it closer to parity in the final analysis, that would be something that we would be interested in doing. And that really does, I think, capture the last part of your question, which I believe was around what we're hearing from the various docs about the program.

I think everything that we heard early on when we launched the study and even before that when we were just talking about it with sites is that the community practices view this as really the best and first true opportunity to access CAR-T for their patient populations. And the academicians, on the other hand, you know, are very excited about, you know, cutting edge technologies, serving their patients in ways that improve the benefit-risk profile, ideally preventing relapse, which everybody universally agrees is a bad outcome.

So, across the board, we continue to hear very strong conviction that this strategy is excellent for patients, and then from the community practices specifically, enthusiasm around gaining access to CAR T, which has been out of their reach from the beginning.

Our next question comes from Samantha Semenkow of Citi.

Zach, let me add my congratulations on your first call as CEO. So just another one on ALPHA3. As we look forward to the interim EFS analysis mid-next year. Just wondering how we should think about that analysis in terms of the potential for overwhelming benefit to be demonstrated. If the interim MRD assessment that we saw is repeatable for with more patients. How likely is that to translate into a stat-sig benefit on EFS at the interim analysis? Thank you.

Thanks, Samantha, and it's a great question. So, as we went into some detail when we released the data in April, the strong MRD clearance data that we observed we did think was quite positive and gave us some very positive views on the potential outcome of the study, either at the interim EFS or at the primary analysis. We also detailed that because of the way that we've allocated the alpha between those two EFS analyses, that it would require overwhelming efficacy to achieve statistical significance at the midway point there at the EFS, the interim EFS analysis.

You know, we can't really go into further detail around, you know, whether about how we're thinking about the likelihood of that statistical significance, except I will reiterate that prior studies such as the, the TRANSFORM study of Breyanzi illustrated that a 24% MRD clearance differential between the CAR T and the transplant arm translated into a greater than 60% improvement in the EFS between those two arms. So a very, very positive outcome there on a comparatively lesser differential in the MRD clearance rate.

So we remain very excited about the potential for a positive outcome here, but going into any further detail around how that might play out at the EFS analysis that is currently planned for middle of next year. I don't want to get too far ahead of myself on that one.

Thank you. And our next question comes from Matt Phipps of William Blair.

Hey team, this is Josh on for Matt. Thanks for taking my question and congrats on such a good quarter. So I had a question on the RESOLUTION readout as it approaches. We were wondering what kind of data and the level of granularity that we should expect from the readout later this year.

Thanks, Josh. So for the RESOLUTION trial, the data that is -- the data readout that we're currently planning for quarter 4 of this year, we expect to share clinical and translational data. I'll reiterate what was contained in the prepared remarks that we continue to be very pleased with the way enrollment is going. At the last call last quarter, we announced that we had treated nine patients in both the LD and non-LD containing arms. We have continued to see very robust demands to put patients into the study, so we should have a nice number of patients by the time we share that data in quarter 4, and then that will feature, of course, safety and efficacy outcomes as well as the translational findings.

Thank you. And our next question comes from Cha Cha Yang of Jefferies.

This is Cha Cha on for Roger. Congrats on the quarter as well. Just a question on the 329 trial with the data coming in fourth quarter. Just wondering if your guidance has changed in terms of the dose groups that you're going to announce. Are we still expecting the 20 million, 40 million and 80 million doses or is there any change?

Thank you, Cha Cha. So those are indeed the first three dose levels or the first two dose levels. We also will be dosing patients with 80 million. And this, you know, there are additional doses above that are contemplated within the protocol. So as far as we get in that dose escalation, that will be the day. data that we share, but at least those three dose cohorts, 20 million, 40 million and 80 million, will be included.

Our next question comes from Jack Allen of Baird. Your line is open.

Congrats on the progress over the quarter. I want to extend my congratulations to Zach on the new role. Really great to see you on the quarterly call here. My question is around the RMAT and Fast Track designations that you were able to secure over the course of the quarter. My understanding is that for RMAT specifically, there's a need to share clinical data when available with the FDA, and I'm just curious if you could provide any more context around what data was shared with the FDA. Was it really the April MRD data? Or were there additional clinical data that were shared with the FDA? And then also kind of in the same vein, what aspects of the data set were most intriguing from the FDA's perspective? Was it the efficacy? Was it the safety? Or was it a combination of the two? Any context you can provide would be very helpful.

Thanks, Jack. Yes, we were thrilled to receive those designations. RMAT, as you point out, is it does in fact require clinical data. It's very similar to breakthrough therapy designation. And so the clinical data that we provided was derived from that interim analysis that we shared back in April. And of course, what we share with regulators, generally speaking, is quite a bit more extensive than what is shared publicly outside of the company. And so this was a complete briefing package that went into all the information. available detail that we had. Again, EFS at the time, the actual events were blinded and they remained blinded to us. So this was really focused on the MRD results, but additional detail around the MRD was provided to the FDA and of course, an exhausted safety package also.

In the FDA's decision, to award RMAT or not, they generally don't go into details about which aspect of the package was most enticing to them or most influential in their decision, but just generally that number one, that the disease under study, in our case MRD-positive large B-cell lymphoma represents an unmet medical need, which I really want to highlight as a pretty important thing for them to have pointed out, that this trial and this data set was even eligible for RMAT designation was predicated on that very fact, that MRD positivity is an unmet need. And then critically, of course, that MRD... Based on the data that they reviewed, Cema-Cel has the potential to meet that unmet medical need. So for those reasons, they decided to give us RMAT, but any further granularity, they did not provide.

And our next question comes from John Newman of Canaccord, who line is open.

Congrats on the excellent progress. The question is, given the very impressive pace of enrollment for ALPHA3 and the increased target of enrollment sites to 100 by the end of the year. Are you open to the possibility of enrolling additional patients beyond the current target?

Thanks, John. The short answer is we are going to try to find as many ways that we can in the context of an ongoing study to offer enrollment to patients who meet the eligibility criteria for ALPHA3. Within the confines of ALPHA3 as written, the target is the target, 220 patients randomized into the two arms and generally speaking you don't want to go much above that until data is available to suggest a benefit-risk ratio that is permissive of over-enrollment. However, if additional opportunities along the way present themselves to add cohorts or explore other nuances within this broader field. those things will be considered in due time. But as the time sits right now, our target is 220.

Our next question comes from Luca Issi of RBCCM.

Adding our congrats to Zach and team on successful transition This is Cassie for Luca. Quick question on the 329. As Zach, you mentioned that dosing started for the lymphodepletion arm. Are you hearing any early anecdotes for CAR T expansion or persistence in patients treated with cyclophosphamide? And what positive signs are you looking for here at the 4Q update for this specific arm? Should we be thinking non-inferior or any specific benchmark. Any color, they're much appreciated.

Thanks, Cassie. So, you know, we were, as all phase one, first in human studies are, they are primarily a safety trial. So this is why we started a low dose and go up, and really we're monitoring most closely the safety outcomes and then making decisions about whether the dose escalate, dose expand. at additional cohorts, what have you.

So we are collecting all of the safety information and we meet as a team with outside advisors prior to dose escalation. So that is the most important and comprehensive data package that we review in real time. We obviously are in close contact with the investigators around the efficacy and so, you know, as in previous statements, we've talked about encouraging signs of activity in that program and so, you know, I'll reiterate that now here is that we continue to have very robust interest and demand from investigators and patients to come in. on what we're seeing so far.

As far as the translational data goes, those data are developed sort of in parallel and typically in batches. But so we do not, you know, we're not in a position to comment on the translational findings here today, just that we will be including those findings in the upcoming fourth quarter data release.

Our next question comes from Reni Benjamin of Citizens.

Zach, congratulations on the new role. I guess I jumped in late. I hope this hasn't already been asked, but I'm interested in the competitive landscape as it continues to evolve and how you guys are kind of thinking about things and managing it, in particular, you know, not just the frontline study for autology CAR-T's that are being evaluated but also the recent Legend in vivo CAR-T data. I would love to kind of get your thoughts as to how you manage these things.

Thanks, Reni, for the question and for the congrats. So, great question. Thanks for asking it. It had not been asked prior to you joining, so good opportunity for me to dive in a little bit on that. So, obviously, we monitor the competitive landscape across our portfolio very, very carefully. And one of the things that we've enjoyed and continue to enjoy, I believe, is a pretty well protected place within this first line consolidation for ALPHA3. Nobody else has entered this space explicitly in that way yet. And the upfront, the first line studies that are ongoing, you mentioned CAR-T, but of course there's other specific pivotal studies as well.

You know, we've looked at this very carefully both through conversations with PIs and investigators that are involved in the studies and those that are not. And then we've also performed some fairly extensive blinded market research. And our conclusion from that, those ongoing frontline studies is that they'll actually have a fairly minimal impact on the overall rate of MRD positivity in the immediate post-frontline setting. And that's primarily because both the CAR T cells and the bispecifics tend to carry a fairly significant toxicity profile. They're a bit cumbersome. some for patients and with some of them needing step-up dosing and even prospective hospitalization just to administer the therapy.

So this is largely, in my view and in the view of the respondents to our study, will probably be reserved for select patients and select centers. So by and large, being that most patients, 80% or more, are treated in the community practices, the MRD rate is likely to stay pretty much where it is, primarily driven by outcomes following R-CHOP and R-Pola-CHP.

With respect to the question around in vivo, And my view on this, and I think this has been validated through several conversations I've had, is that obviously an extremely exciting platform for the field and for patients, but likely I believe it will primarily suffice to replace autologous CAR T in the relapsed refractory setting, again pointing primarily to the toxicity profile, at least in the early days here, unless that gets markedly better, most community oncologists are not going to be enthusiastic about administering a large dose of active viral particles into patients during a busy clinic afternoon.

So, it feels like this is an opportunity for really, an off the shelf CAR T being available to community oncologists. They can give it in their infusion clinics over five minutes and the patients can be reasonably assured to go home without having much toxicity. At least that's the intention of ALPHA3. So clearly a lot of activity both upstream from us as well as downstream from us with the in vivo, but we think we're pretty well protected here right in the middle.

Thank you. That concludes our question-and-answer session. 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.

Hello. Thank you for standing by, and welcome to Allogene Therapeutics First Quarter 2026 Conference Call. [Operator Instructions] 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.

Thank you, operator, and welcome, everyone, to Allogene's conference call. After the market closed, Allogene issued a press release that provided a business update and financial results for the first quarter of 2026. This press release and today's webcast are available on our website.

Following our prepared remarks, we will host a Q&A session and we will aim to keep the 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, potential treatment settings 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, Christine. As we move through 2026, next-generation cell therapy is shifting from promise to proof. The field is increasingly being defined by differentiated clinical evidence rather than platform ambition alone. At Allogene, our lead program, cema-cel is built around the clear objective to establish a differentiated development path. That strategy is now translating into data that provides support for our approach.

Our second program, ALLO-329 in autoimmune indications is built on the same principle of product differentiation, enabled by our understanding of CAR-T design and the biology of allogeneic rejection. While these 2 programs are at different stages of development, the evidence emerging to date is consistent and aligned with the design principles behind each.

Starting with ALPHA3, we have taken an innovative approach of treating patients with cema-cel in the first-line consolidation setting for large B-cell lymphoma with a primary goal of improving the cure rates. A key to achieving this goal is democratizing access by breaking the barriers that have historically limited the use of CAR-T therapy and by enabling cema-cel to be delivered in the outpatient setting. We are very pleased with what we've seen in the recently announced interim futility analysis from the ALPHA3 trial.

In this 24-patient analysis, cema-cel achieved a 58.3% MRD clearance rate compared with 16.7% in the observation arm, representing a 41.6% absolute difference. While preliminary, this differential exceeded threshold of MRD clearance reported in other trials that led to groundbreaking clinical outcomes. We also observed a rapid and substantial reduction in circulating tumor DNA or ctDNA in the cema-cel arm, while the opposite trend was seen in the observation arm where the ctDNA levels increased.

Together, these early findings provide evidence consistent with the biological activity of cema-cel in the first-line consolidation setting as we advance ALPHA3 towards the next key milestone, the interim EFS analysis in mid-2027. Importantly, as we consider use in the outpatient community setting, this early biomarker efficacy signal was accompanied by a favorable safety profile. We observed no CRS, ICANS or treatment-related hospitalization, enabling the majority of patients to be managed in the outpatient setting. These results reflect the trial that was designed to lead, not follow.

Under Zach's leadership, ALPHA3 was built around MRD testing as a point of intervention rather than passive observation, an approach that moves beyond conventional trial design. We set out to test a forward-looking thesis and these early data reaffirm my conviction that we are not only on the right path, but ahead of the curve. Taken together, we believe these data provide compelling support for a different paradigm, one where cema-cel can be used earlier, made readily available, delivered broadly and potentially integrated into routine care beyond specialized centers.

Turning to ALLO-329. The program is progressing through early clinical development in autoimmune indications with the RESOLUTION basket trial advancing efficiently through dose escalation. This progress embodies the same disciplined and forward-looking development approach that underpins ALPHA3. ALLO-329 incorporates the Dagger technology, which is designed to overcome premature rejection of allogeneic CAR T cells. This technology has previously been validated as part of our ALLO-316 program in the metastatic solid tumor setting. However, autoimmune disease represents a fundamentally different clinical context with distinct biology and the different threshold for safety and tolerability.

With that in mind, we designed a structured and stepwise clinical approach, beginning at a conservative dose level to establish clear understanding of tolerability before progressing to therapeutic dose levels. Patients treated to date are within this initial dosing range as we evaluate both dose and lymphodepletion strategy. Our focus is on characterizing how the therapy behaves in patients by establishing a tolerability profile that supports continued development while also assessing early signs of activity.

Within this framework, we are very pleased with the pace of enrollment and are beginning to observe initial signs of clinical activity, coupled with favorable tolerability. While still early, these findings are highly encouraging and have important implications for the overall dosing paradigm, which includes not only the dose of Dagger-enabled ALLO-329, but also the required lymphodepletion regimen.

As the program progresses, we expect continued dose escalation and patient follow-up to further establish the activity, tolerability and mechanistic profile of ALLO-329. We look forward to providing a further update in the fourth quarter.

With that, I will turn it over to Zach to walk through the data in more detail.

Thanks, David. I'll start with ALPHA3 and then turn to ALLO-329.

ALPHA3 was designed around a clear clinical hypothesis that intervening at the point of molecularly detectable disease before clinical relapse can meaningfully alter the course of disease. When we initiated the study, MRD was emerging as a prognostic tool in LBCL. Our objective was to move MRD beyond risk assessment and into a treatment decision point. Across oncology, we are now seeing the shift is approaching a potential breakout moment. A case in point is the IMvigor011 trial, which evaluated Tecentriq in muscle-invasive bladder cancer.

In the trial, patients who are in remission but remained MRD positive after the standard first-line procedure of complete surgical resection were randomized to Tecentriq or placebo with Tecentriq demonstrating improvement in both disease-free and overall survival. The results of this trial could establish MRD as a clinically actionable endpoint following standard first-line treatment. If approved for this indication, Tecentriq would become the first therapy for which treatment initiation is guided by an ultrasensitive ctDNA MRD assay rather than clinical progression, a defining moment for the field.

Against this backdrop, ALPHA3 is positioned at the forefront of how this new paradigm could evolve in large B-cell lymphoma as the first pivotal trial designed to use MRD positivity as the trigger for CAR-T therapy. The ALPHA3 study is enrolling patients who have responded to first-line therapy but remain MRD positive and therefore, at high risk of relapse. Patients are randomized to treatment with cema-cel or observation. We partnered with Foresight, now a wholly-owned subsidiary of Natera, to utilize their CLARITY MRD assay, enabling a highly sensitive and dynamic view of disease burden over time. This enhanced sensitivity, detecting disease at or even below 1 in a million or 10 to the minus 6 is central to the design of ALPHA3 study and how we interpreted our interim futility data.

At the interim analysis, we evaluated the first 24 patients enrolled in the ongoing 2 arms, a single dose of cema-cel versus observation. We observed a 58.3% MRD clearance rate in the cema-cel arm compared to a 16.7% in the observation arm, representing a 41.6 percentage point absolute difference. We also saw a rapid and substantial reduction in circulating tumor DNA. At the day 45 time point, the median ctDNA level decreased by nearly 98% in the cema-cel arm, while the median ctDNA level increased by more than 26% in the observation arm. The ALPHA3 interim futility analysis rests on the assumption that MRD clearance foreshadows clinical benefit. This hypothesis is supported by a growing body of evidence in various clinical settings, including in LBCL, linking MRD clearance in the range of 25% to 30% with meaningful reductions in EFS events. The magnitude of the difference we just announced exceeds that range. While these external data sets support the relationship between MRD clearance and clinical outcomes, the impact on EFS and durability will ultimately be determined through our planned interim and primary EFS analysis.

From a safety and treatment administration perspective, we observed no CRS, ICANS or treatment-related hospitalizations, enabling the majority of patients to be managed entirely in the outpatient setting. We believe this encouraging tolerability profile is a function of treating patients earlier when disease burden is low, which is inherent to the ALPHA3 design. If the safety profile observed in the interim futility analysis bears out in the study overall, it could mark an important shift towards outpatient CAR-T administration and enable cema-cel treatment in community practices where most patients with LBCL receive care.

As ALPHA3 progresses, interest in the study is growing. First and foremost, we are seeing robust engagement from existing clinical sites, resulting in high rates of patient screening. At the same time, new sites are expressing significant interest in joining the study, further reinforcing its momentum.

From an execution standpoint, the trial continues to scale. We are now enrolling across more than 60 sites with global expansion underway. We recently announced regulatory approval in Australia and South Korea, where site activations and patient screening have begun. We anticipate the Asia Pacific region to expand the study footprint to over 80 sites worldwide. These are not incremental additions. Australia and South Korea offer established clinical research infrastructure, experienced investigators and highly efficient health care systems.

This expansion reflects both strong global investigator interest and the operational discipline required to execute at scale. We are also seeing meaningful participation from community cancer centers, which contributed approximately 1/3 of screening and cema-cel treatments in our interim futility analysis. This is an important early proof point for the feasibility of broader administration as we look to move beyond specialized centers and into broader clinical practice.

Let me now turn to ALLO-329, which as a first-in-human Phase I trial has a different objective at this stage of development. The program is supported by robust preclinical data recently published in Nature Communications, supporting the design of ALLO-329. These data demonstrated an optimized CD70 CAR engineered to protect allogeneic CAR T cells from rejection by eliminating alloreactive host T cells.

In those studies, co-expression of CD70 and CD19 CARs drove sustained CAR T cell persistence, elimination of pathogenic B cells and activated CD70 positive T cells in humanized SLE models and corresponding reductions in autoantibody production.

Importantly, the Dagger technology, which eliminates alloreactive host T cells, has been clinically validated by our third clinical program and first CD70 targeting program, ALLO-316, with recently reported outcome data further supporting the approach and reinforcing our plans to advance the program in the near future. At this stage of development, our focus for ALLO-329 is to define a tolerability profile that supports continued dose escalation while generating early evidence that ALLO-329 can achieve meaningful biological activity in autoimmune disease, consistent with its differentiated dual targeting mechanism.

The resolution basket trial, which includes patients with systemic lupus erythematosus with and without nephritis, scleroderma and inflammatory myositis continues to progress through dose escalation. 9 patients have already been treated since the study started enrollment in November 2025, with 3 patients at dose level 1 of 20 million cells and 3 patients at dose level 2 of 40 million cells, both following lymphodepletion with cyclophosphamide and 3 patients at dose level 1 with no lymphodepletion. Importantly, the doses evaluated so far are substantially lower than those being explored in other CAR-T approaches in autoimmune disease, including autologous programs testing approximately 100 million cells and some allogeneic approaches evaluating doses above 1 billion cells.

Even at these lower doses of ALLO-329, both with and without cyclophosphamide, investigators have reported signs of clinical activity. While these observations are preliminary and dose exploration continues, investigators have been very encouraged by these early signals, facilitating strong patient interest in participating in the study. This reflects a consistent approach across our programs. In ALPHA3, we designed the study to intervene earlier in disease treatment based on MRD. With ALLO-329, we are applying that same forward-looking discipline to autoimmune disease, prioritizing mechanism, durability, scalability and long-term usability from the outset.

As we continue dose escalation and patient follow-up, our goal is to build the data set that integrates clinical activity with mechanistic understanding and supports a path towards durable outcomes. We expect to provide a comprehensive update in the fourth quarter. Across both programs, our focus remains consistent, designing studies with clear hypotheses, executing with discipline and allowing the data to define the role of allogeneic CAR T.

With that, I'll turn it over to Geoff.

Thank you, Zach. As we execute against our key clinical milestones in 2026, we remain focused on maintaining a strong financial position that supports continued progress across our portfolio.

As of March 31, we had $266.9 million in cash, cash equivalents and investments. In April, we strengthened that position through a public offering that generated approximately $200.4 million in gross proceeds, extending our cash runway into the first quarter of 2029. R&D expenses for the first quarter were $32 million, including $2.7 million of noncash stock-based compensation, reflecting continued investment in our clinical programs. G&A expenses for the first quarter were $14.1 million, including $5.6 million in noncash stock-based compensation. Net loss for the first quarter was $42.6 million or $0.18 per share, including noncash stock-based compensation expense of $8.3 million.

Based upon our current forecast for the overall timing of the ALPHA3 program, we are modestly increasing our guidance for operating cash expense in 2026 from approximately $150 million to $165 million. GAAP operating expenses are also expected to slightly increase from approximately $210 million to $225 million, including estimated noncash stock-based compensation expense of approximately $35 million. These estimates exclude any impact from potential business development activities.

Overall, we believe we are well positioned to execute on our strategy with the capital and flexibility needed to reach our next set of milestones.

We'll now open the call for questions.

[Operator Instructions] And our first question comes from Michael Yee of UBS.

Congrats on the progress to date and the updated autoimmune color. Maybe two quick ones. One is, can you talk a little bit more specifically about some of the initial signs of activity or B-cell reductions? What does that mean? And to what degree maybe there are differences in B-cell reductions for the lymphodepletion cohort compared to any of the different cohorts with different lymphodepletion?

And if I may get a question on, obviously, the lead DLBCL program. Since the announcement of your MRD negativity interim, how have you seen perhaps enrollment engagement and feedback and things of that nature? Maybe just talk a little bit about how things have progressed since that positive interim.

Mike, this is Zach here. Thanks for the questions. So on the 329 question, we'll be saving the details sort of pertinent to your question until the Q4 update other than to say that the encouraging signs that we referred to are coming from the cohorts that we've highlighted, both with and without LD. So we will be continuing to enroll patients according to the protocol design with and without cyclophosphamide and expect to show a more complete update in Q4. But so far, so good, and we're really thrilled with the patients coming into the study very briskly.

The second question around has the IA1A results stimulated increased activity in ALPHA3, I will say that they have. In these early days, these first couple of weeks since the announcement went out, that has come in the form of new sites coming and asking to participate in ALPHA3, even sites that said early on that they didn't have room in their portfolio before the IA1A data was available. Now they're coming back and saying that they really do want to participate. So that kind of qualitative change is already underway. We will be watching very carefully for a quantitative uptick in the screening and enrollment pace, except to -- I will say that, that has been going very well in the last few months. So we're optimistic. But so far, we're pretty happy with the way things are going.

And our next question comes from Tyler Van Buren of TD Cowen.

Congrats on the progress. I have a couple of 329 questions as well. Since you mentioned favorable tolerability, can you discuss conceptually what sort of safety profile you hope to achieve with ALLO-329 over the long term?

And then with respect to the update in the fourth quarter, can you give us any sense of what that might entail and kind of help put goalposts around what we should expect with that update?

Tyler, thanks for those questions. The safety profile in autoimmune indications, I mean, we want this to be as clean as one can get to. I mean I think that's really the patient population that we're dealing with. I mean, we have seen in ALPHA3 study, even in oncology in the right clinical setting, CAR-T therapy can be well tolerated. And that's kind of profile that we are trying to mirror where the treatment can be given as an outpatient and patient can be managed as an outpatient. So that's really the safety profile that we're looking for. And so far, after completing both 20 million and 40 million dose cell dose levels with cyclophosphamide lymphodepletion, I feel very encouraged that if the safety profile holds out, this can be very interesting finding.

With respect to your second question about how to set up the expectations for the fourth quarter. I mean, so far, let's keep in mind in terms of the pace of enrollment that Zach had talked about. We dosed first patient back in November of last year and May. So within 6 months, dose escalation study, where we have to wait about a month after first patient is dosed before we can fill up the rest of the cohort with -- even with that kind of preset barriers in how fast we can enroll, we enrolled 9 patients. That is a pretty remarkable support that we are getting from various physicians involved in the autoimmune trial. So we are highly encouraged.

And this autoimmune, obviously, the way that the clinical responses are being measured is different than in oncology. But when the investigators are calling us and telling us that they are seeing that they would not have expected to see in any setting, I mean, that I would view as a highly encouraging early signs.

And our next question comes from Biren Amin of Piper Sandler.

Maybe just to stay on ALLO-329. Given you're reporting data in Q4, should we expect data across the 20 million and 40 million cell doses in the fourth quarter? Or could we get higher cell doses? So that's the first question.

Second question, what would be the patient composition across SLE myositis and sclerosis in the Q4 update? And then lastly, on the trial itself, recently in April, I think there was a change that was recorded on ct.gov where you increased target enrollment to 66 patients from 54 patients. Could you maybe just talk about that change and what drove that?

Yes, Biren, as to your first question, I'm also realizing that was Tyler's last question, which I did not fully answer. So in the fourth quarter, obviously, at this point, we have completed 20 million and 40 million, and we are continuing the dose escalation. By the fourth quarter update comes, included patients in that will be more than just 20 million and 40 million. We're hoping that we can include certainly the next dose level and possibly even a higher dose depending on how the pace of enrollment is maintained. And also, when I'm talking about the cell dose levels, certainly, I'm talking about both with and without cyclophosphamide. And Zach, maybe you can cover the patient composition.

Yes. So Biren, we're seeing patients come from all of the indications that I listed previously. So lupus, inflammatory myopathies and scleroderma. It's still too early to say whether the early signs of efficacy that we are seeing is segregated to one patient group or another. So we're not going to be making any changes to the basket style design of the protocol. So as we continue to enroll patients, we expect a mix and that mix will be presented in Q4. And then the ct.gov change that occurred, I actually have to say I don't know why we made...

It's an administrative change.

Yes, administrative change, sometimes we have to go through and we have to make little clerical changes to the ct.gov. There's not been any changes to the study design that would have warranted that change.

And our next question comes from Salveen Richter of Goldman Sachs.

For cema-cel, could you speak to the feedback you're hearing from the community practices to date post the recent data?

And then for the ongoing ALLO-329 resolution study, can you expand upon progress on site activation and patient enrollment and how that's playing out just given some competition in the field for other autoimmune CAR-T programs?

Salveen, it's Zach. So as far as how the community practices are reacting to the interim data from cema-cel, I would echo what I said a moment ago that the feedback has been really overwhelmingly and uniformly positive. Just to give another little anecdote on that, in the couple of literal days after that announcement was made that same week, we were on the phone with a couple of large community network practices that have already a couple of sites on the study seeking to expand their footprint within their practices and add additional sites. So we believe that the interim analysis data is being viewed by the community practices and academic practices alike as potentially something very, very interesting [indiscernible].

And also, I would say it makes a lot of sense. And when you think about this is giving the community physicians something to offer to patients rather than referring them to a tertiary or cell therapy centers. And then two, I think during the course of treating patients, they are realizing that treatment is relatively hassle-free. And what we have shared with the interim futility findings is the early safety profile, it was very clean, which also makes managing patients after the CAR-T infusion extremely smooth. I mean these are definitely early findings, but these are the things that I believe is making the community physicians being quite interested in participating in the ALPHA3 study.

And then your second question, Salveen, about site activation and enrollment in 329. We are approaching the target number of sites that we sought to activate for ALLO-329. I can't say exactly what the number is on ct.gov, but we expect that to be completed here very shortly within the next few weeks, maybe a couple of months. That's gone very well. We've actually ended up getting quite a bit more traction even in that competitive space that you highlighted. We've got some really excellent marquee sites already listed on ct.gov and a few more in the can, ready to come out. And then they are really being super productive on the patient screening and enrollment as we highlighted previously. So we could not be happier with how ALLO-329 is going operationally.

And the mixture of the patients in this basket study is actually -- is excellent.

And our next question comes from Samantha Semenkow of Citi.

Another one on 329. I'm wondering if you could just talk a little bit about your thoughts on dosing going forward. You mentioned some early clinical signals that you're seeing in these first 9 patients. I'm wondering, do you think the 20 million dose is too low or subtherapeutic? Curious your thoughts there. And how are you thinking about dosing going forward? Are there any adjustments you're planning to make to the dose escalation?

Sam, so with respect to the question around the doses that we've tried so far, in the tenet of a Phase I dose escalation study, you're really gated by safety. And I want to echo what David said a moment ago that safety is paramount here. We want to make sure that we maintain the safety profile that would make this therapy attractive to patients and doctors with autoimmune disease. And so we're going to keep going up until we start to bump up against that, the toxicity that we think would be prohibited. So whether you call it subtherapeutic or room to go, I'm more of a room to go type of guy. And so we're going to keep dose escalating.

And then your other question is, do we see any need to make any adjustments? At this point, we do not. We still have some doses to go up. And we're hopeful that we'll start to see really compelling activity here in the next dose or the dose after that, and we can maintain that safety profile. So look forward to that Q4 update.

And our next question comes from Roger Song of Jefferies.

This is [indiscernible] on for Roger. I have two. So one is, can you just give us some more color on what your current cash runway covers?

And then my second question is on also ALLO-329. Can you tell us more about the decision factors that are driving the optionality for the fludarabine addition? I know you mentioned with the option of adding this. Can you just explain the gating factors for why we add or why we don't?

This is Geoff. On the cash runway, as we discussed in the script, our current cash runway based on the addition of the capital added and the recent financing, the $200 million financing, takes us into the first quarter of 2029. And during that time, we intend to complete the ALPHA3 study. So as you know, we anticipate finishing enrollment at the end of 2027. We anticipate an interim analysis on EFS in mid-'27, primary analysis in mid-'28 with the filing of the BLA as quickly as possible based on the results of those interim or final analysis. So it really is focused on covering ALPHA3 as well as completing this Phase I resolution study for 329, as we indicated, having the comprehensive data set in the fourth quarter of this year.

Yes. And let me take the question on the optionality of fludarabine. I think this is just how we try to make the protocol as flexible as possible without a predefined idea about when to kick in this optionality. I mean it's really looking at the data and then making the decision. And right now, based on the data, our primary focus is continuing the dose escalation.

And I'll just add one other piece of color on that. And honestly, in part, this would be driven by the demand to come into the study. By opening additional cohorts, it would allow us to park some patients and to allow patients into the trial. So that is another factor that could come into it. But nothing has changed at all about our belief in the [indiscernible] possibility here. So we are continuing with that primary goal.

And our next question comes from Matthew Phipps of William Blair.

It's going to be on 329 as well. There's obviously been a lot made about B-cell reset after CAR-T with CD19. I was wondering if from your experience with ALLO-316, what the T cell kind of repopulation might have looked like after treatment if you looked at that? And I guess, do you expect maybe some ability to have an immune autoreactive T cell reset following 329 treatment when you have the data on that by Q4?

Matt, great question, really insightful and I think right on point in terms of our understanding of the mechanism of action of ALLO-329. We are really focused on how the B cell and the T cell repertoires will change and whether we achieve the reset as defined as just absolute B cells going all the way down to 0 or whether there's some editing of the repertoire on both the B cell and the T cell side. Now obviously, B cells, we expect the chances of those cells going very lower to 0 to be higher because we're targeting a pan B-cell marker.

In the case of CD70, you're absolutely correct. It's only a subset that are going to be CD70 positive. Of course, there's going to be a population of alloreactive cells that we expect to be depleted through the Dagger effect. But there is also known to be CD70 positive pathogenic AID causing T cells, so clonal populations with specific TCRs that also express CD70. And that has actually been one of the main reasons that we designed 329 the way we did was try to wipe out that set -- that clone or set of clones that may be driving the pathogenesis. And so we will be analyzing the T cell repertoire as part of the ALLO-329 study. And if we've got something to share in Q4, we'll share it.

And our next question comes from Jack Allen of Baird.

Congrats on the progress. I'll keep the theme going with the 329 question to start, and then I have one on cema-cel as well. On 329, I was just hoping you could provide some additional color as it relates to how many doses you could escalate the study in and what the next step up might be? I guess, logically, it looks like 60 million would be a realistic target for the next dose, but how high could you go in that trial?

And then on cema-cel, I just wanted to ask about the interim EFS look in mid-'27 and any additional color you can provide around the powering there.

So Jack, great question. The next dose level that we're going to be looking at is not 60 million, it's actually 80 million, 80 million cells. So that cohort is enrolling now following [indiscernible] and then the [indiscernible] cohort is close behind. I'm going to hold off on saying exactly how many cell doses that we plan to go up, and we'll sort of reveal that at Q4 because I do think that we'll be in that zone by the time we give that update. So stay tuned. But 80 million is the next dose cohort that we're working on now.

As far as cema-cel, we talked quite a bit about this with the fundraising and the alpha allocation for the IA2. We have not gone into specific detail. The method that we use to allocate the alpha with the O'Brien-Fleming spending function. So that will give you some general understanding of the fraction of alpha that's allocated to the IA2. I will take the opportunity now to reiterate though that the results of the interim analysis 1 does give us the possibility of having a positive outcome in IA2 and so that is something we are looking forward to and, of course, working feverishly to enroll the study and deliver on those time lines.

And our next question comes from John Newman of Canaccord Genuity.

Also have one on ALLO-329. The question is, do you expect that the Dagger technology that's targeting CD70 positive T cells could actually give you maybe differential efficacy in some of the cohorts that you're enrolling versus lupus, for example, scleroderma and myositis where it's sort of theorized that there's more T cell activity.

John, great question. As usual, thank you for the insight. And the answer is yes. So not just within these rheumatologic disorders, where T cells are known to play a role and there's literature on it. But of course, there are lots and lots of papers and understanding about other therapeutic areas, which are even thought to be more dependent on T cell biology. Just to throw out a couple, multiple sclerosis and type 1 diabetes are thought to be primarily driven by pathogenic T cells. And so not only within this initial set do we think we could have some differential efficacy, as you put it, but we also believe it will give us a more plausible pathway into other therapeutic areas where T cells are known to play a larger role than just a straight CD19 product.

And our next question comes from Reni Benjamin of Citizens.

Maybe just starting off with the interim analysis. Now that you've been able to kind of sit on the data with the futility analysis, do you feel that this delta that you're seeing increases the chances of a successful interim mid-2027 versus what you were thinking when you first started the study? And if so, does it make sense to potentially modify the trial design to allocate a little bit more alpha and increase your chances of success there?

And then regarding 329, as we kind of look at the landscape, look at autologous therapies and bispecifics, can you maybe just guide us as to what is the clinical sort of efficacy and safety benchmarks you're hoping to hit, hoping to meet so that you can move this program forward? And does this program move forward ideally with a partner? Or do you think you do this on your own?

Ren, on the interim analysis, EFS analysis, we had a question after looking at the MRD clearance differential, we believe the probability or the powering for the interim analysis has gone up quite a bit. I mean that really goes down to -- we have said that the study was designed to demonstrate the hazard ratio of 0.5, but the MRD clearance, as we extrapolate, based on the existing data leads us to a potential the hazard ratio being much lower than 0.5. If that turns out to be true as we continue to enroll the study, the probability of interim analysis, as Zach has pointed out, leading to a statistical significance is very significant. So we'll just have to wait and see.

And your second question about would we consider amending the protocol. I think that probably is not something that would be -- that's needed or that will be good to do at this point. I mean, I think the best course is just sticking with the original study plan.

And then the question around where does this fit in the evolving landscape. We actually feel really good about that. And right now, that landscape in the front line has really been focused for a long time on increasing intensity of those regimens and looking directly at the bispecific-based regimens that are being studied that really do add a lot of complexity and toxicity to those newly diagnosed regimen -- the patient regimens. So we actually feel really good that no matter what happens upfront, an MRD-positive result at the end of frontline treatment could trigger a cema-cel infusion and to be able to administer that even in centers that we believe actually may not ever engage fully in frontline bispecific regimens because of the complexity and toxicity that those centers could administer cema-cel in a consolidation setting. So we actually feel like we have threaded the needle very well with ALPHA3 and are somewhat insulated from all of that competition in the early lines.

So Ren, does that answer your question? Or was the question on 329?

That last one that Zach answered was on 329 in particular, just -- sorry about that.

Let me just answer the question on the 329. The profile that we are looking for is something that can be administered as an outpatient and patient managed as an outpatient and also -- and plus that on top of that, the nature of the CAR-T is that this will be a onetime treatment with a possibility of redosing several years down the line if the symptoms were to come back. So that is the profile that we believe will remain very competitive when you think about other emerging modalities that's coming in the T cell approach towards the autoimmune indications.

And our next question comes from Brian Cheng of JPMorgan.

Just a quick one from us. Can you talk about the rationale of updating the autoimmune resolution data update from June to 4Q? Is that decision data driven? Or are there other considerations?

Brian, let me take the question. I think our intent is to provide a data update in a very meaningful way. In terms of the maturity of the data and what we have now, I think what we can say is enrollment is very robust. And also there is very sort of interesting signs of clinical activity. I don't think -- definitely, I think this is for now. And as we dose escalate, I mean, keep in mind, we intentionally started the study with very conservative dose to ensure the patient safety. So 20 million, I think there was an earlier question about whether that may be low. In my view, it probably was lower than what was necessary. And as we dose escalate and certainly, we are going to the dose levels that in other programs that we have done, 80 million or 120 million is sort of the range that we have seen activities in programs like ALLO-316 or cema-cel. So we're getting to that dose range. And as we update the data in fourth quarter, we will have patients treated at the dose that may be more in the right range, but definitely, we are enrolling this study rather briskly, and we'll have a lot to talk about in fourth quarter.

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. We said at the onset that this will be a year of defining proof and the ALPHA3 interim analysis represents an important first step. The signal we see today must be validated through EFS, but it provides early support for a fundamentally different approach to CAR-T, one that is earlier, more accessible and potentially scalable. Our focus now is execution, completing ALPHA3 enrollment, advancing ALLO-329 through dose escalation and continue to generate the data needed to define the role of allogeneic CAR T across oncology and autoimmune disease. We believe we are well positioned to do that.

Thank you for your continued support. 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 log off and disconnect.

Hello, and thank you for standing by, and welcome to Allogene Therapeutics Business Update Conference Call. [Operator Instructions] 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.

Thank you, operator, and welcome to Allogene's conference call. This morning, Allogene issued a press release announcing data from our interim futility analysis from the pivotal Phase II ALPHA3 trial in first-line consolidation large B-cell lymphoma. This press release, webcast and accompanying slides are available on our website.

Following our prepared remarks, we will host a Q&A session, and we'll keep the call to 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; Jeff Parker, Chief Financial Officer; and Dr. Jeff Sharman, Chair of the Lymphoma Research Executive Committees SCRI at Willamette Valley Cancer Institute & Research Center. After opening remarks by Dr. Chang, Dr. Roberts will walk you through the key highlights of the interim futility analysis before introducing Dr. Sharman.

Afterwards, I will present findings from our recent market research. 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, Christine. At Allogene, our mission is to unlock the transformative potential of CAR T through our allogeneic platform. At its core, that mission is about democratizing cell therapy, expanding patient access, simplifying delivery for physicians and treatment centers and ultimately moving CAR T earlier in the treatment paradigm, where it may have the greatest impact.

That is why today's announcement is so important. We are excited to share the interim futility analysis from our pivotal randomized Phase II ALPHA3 trial, evaluating cema-cel as first-line consolidation in Large B-cell Lymphoma. Cema-cel achieved a 58.3% MRD clearance rate versus 16.7% in the observation arm, a 41.6% absolute difference, exceeding the clinical meaningful benchmark of 25% to 30% reported in the literature.

Just as importantly, this early efficacy signal is accompanied by an encouraging early safety profile. These early results represent an important step towards redefining first-line Large B-cell Lymphoma management. Today, many patients are simply observed after first-line therapy despite remaining at high risk of relapse. And by the time relapse occurs, disease may be more difficult to control and patients may be less able to benefit.

By bringing an off-the-shelf allogeneic CAR T approach into the first-line setting, we believe cema-cel has the potential to intervene earlier, reduce the risk of relapse and advance our broader vision of making CAR T more available, more practical and more impactful for patients.

On Slide 5, we outline what it takes to make this real. To unlock the full potential of CAR T, it must deliver across 5 key dimensions: safety, supporting use across broader care setting, including outpatient, speed being available when and where patient needs it, scalability, enabling consistent real-world adoption, simplicity, reducing the burden of treatment with a onetime therapy and ultimately, efficacy because outcomes determine benefit for the patients.

The first will determine whether a therapy can reach patients. The fifth determines whether it should. What we are seeing with allogeneic CAR T, specifically with cema-cel is the potential to address these dimensions in a way that enables that shift.

Slide 6 frames the market opportunity at high level. If ALPHA3 is successful, we believe it has potential to open a significant new market in the first-line Large B-cell Lymphoma consolidation. On the left is estimated total addressable market, approximately $5 billion, representing more than 14,700 patients annually across the U.S. and EU5.

On the right is the estimated potential cema-cel opportunity within that market, approximately $2.5 billion to $3.5 billion or roughly 7,000 to 10,000 patients per year. Later, we will walk you through the assumptions behind that opportunity. The next several slides addresses the obvious question that follows. What would need to be true for that market to open? And that comes down to physicians' willingness to test, identify and treat patients earlier, supported by a profile that can fit into real-world practice.

That brings us to Slide 7. ctDNA-based MRD has emerged as one of the strongest predictor of treatment outcome in Large B-cell Lymphoma. Patients who do not see MRD at the end of first-line therapy, shown in red line in this Kaplan-Meier curve are at high risk of relapse. Most of these patients experience progression within the first 24 months.

In contrast, those who achieved MRD negativity have significantly better outcomes with a greater majority remaining progression-free at 3 years. So MRD testing gives us a window into treatment effectiveness and future risk of relapse. And it raises fundamental question. If we can identify those patients earlier, can we intervene before relapse occurs.

Slide 8 shows how that could translate into practice. Today, patients with large B-cell lymphoma, who respond to first-line therapy, typically, 6 factors of chemoimmunotherapy are observed after treatment. While available first-line therapies are effective, approximately 30% will relapse and require second-line treatment where the chance of cure diminishes greatly.

ALPHA3 proposes a different approach, identify patients who are MRD positive at the end of first-line therapy and intervene at that point. This is not about disrupting how physicians practice. Instead, it is about integrating into the existing paradigm by incorporating cema-cel as a seventh cycle of treatment for patients not cured by the first-line therapy.

The reason this approach is compelling is timing, treatment earlier in the disease course, when tumor volume is low with a onetime dose of cema-cel to potentially clear MRD and prevent recurrence. It is all about the right product for the right patient at the right time in the right place.

Turning to Slide 9. We have a framework for interpreting today's data. Across multiple studies, a 25 to 30 percentage point difference in MRD clearance has been associated with meaningful clinical benefit. The first study TRANSFORM, which compared Breyanzi against autologous stem cell transplant.

A retrospective MRD analysis using the same Clarity assay being used in ALPHA3 demonstrated that a 24% improvement in the MRD clearance led to a 63% reduction in the risk of EFS event, corresponding to a hazard ratio of 0.375. The second illustration is IMvigor-11 trial, which randomized patients with bladder cancer who remained MRD positive after curative resection to adjuvant treatment with Tecentriq or observation. Again, a relatively small difference in MRD clearance was sufficient to reduce the risk of recurrence by 36%.

Slide 10 visualizes that relationship with a focus on durability. Here, we see that an MRD clearance improvement of 24% correlates with durable benefit, including a 27% improvement in 3-year EFS. Putting that in perspective, Polivy, which is approved for the first-line treatment of large B-cell lymphoma showed only a 6.5% improvement in 2-year PFS. These trials, along with other published data illustrate that MRD clearance strongly correlates with clinical benefit.

With that context, Slide 11 outlines the key questions we have been aiming to answer in this Interim Futility Analysis. Do we see an early MRD clearance signal that if we produced in overall ALPHA3 study could lead to a meaningful clinical benefit. Does the safety profile support a path to outpatient use? And can we deliver cema-cel in the setting where patients are treated.

With that, I will turn it over to Zach to walk through the data from interim futility analysis.

Thanks, David. I'll start by grounding us in the ALPHA3 trial design, as shown on Slide 13. ALPHA3 is an open-label randomized Phase II study designed as a registrational trial and in alignment with FDA guidance. It is targeting enrollment of approximately 220 patients with Large B-cell Lymphoma, who are in response after first-line therapy, but remain MRD positive.

Patients are randomized 1:1 to receive a single dose of cema-cel following Standard Fludarabine and Cyclophosphamide Lymphodepletion or observation. The primary endpoint is event-free survival with progression-free survival, overall survival and MRD clearance as secondary endpoints. The study is powered to detect a 50% reduction in the risk of disease progression, new anti-lymphoma treatment or death from any cause, which together make up EFS, reflecting the intent to demonstrate meaningful clinical benefit.

Turning to Slide 14. Patients enrolled into ALPHA3 have traditional features of high-risk disease. While residual disease is not only found in high-risk lymphomas, these higher-risk tumors have historically been more likely to progress. As a result, the study population is expected to be enriched for poor prognostic features.

Across both arms, patients' baseline disease characteristics demonstrate features associated with increased risk of relapse, including bone marrow involvement, advanced stage disease, elevated IPI scores and high-risk genomic characteristics. These are the lymphomas that physicians worry about.

Slide 15 captures the first-line therapies these patients received as well as their responses to those regimens. In keeping with their high-risk disease features, the majority of patients received an intensified version of R-CHOP dose-adjusted EPOC-R. Consistent with what we estimated when we launched the study, 75% of patients entered ALPHA3 in a complete response by PET/CT and the remainder entered, while in a partial response for which the current standard of care would be observation.

Slide 16 shows the MRD clearance rate and kinetics. The protocol-defined cutoff occurred when the 24th patients in this analysis set had undergone their day 45 post-randomization MRD assessment. Depending on the timing of their enrollment, some patients had additional MRD samples collected at day 90, month 3 and every 3 months thereafter through the first year post randomization.

As of their last MRD assessment prior to the data cutoff, 58.3% of patients in the cema-cel arm were MRD negative compared to 16.7% in the observation arm, representing an absolute improvement of 41.6 percentage points favoring cema-cel. This exceeded the 25 to 30 percentage point benchmark David discussed earlier. Underscoring this encouraging treatment effect of cema-cel, the clearance of MRD occurred rapidly post infusion.

In the 12 patients in the treatment arm, we observed a decrease of 97.7% in the median circulating tumor DNA level at the day 45 assessment. In contrast, the median ctDNA level increased by 26.6% in the 12 patients in the observation arm. Taken together, we believe these data suggest that cema-cel is capable of rapidly eliminating residual disease in this high-risk population.

On Slide 17, we summarize the safety results observed as of the data cutoff. At the time of this analysis, cema-cel was generally well tolerated. We observed no cases of CRS, ICANS or graft-versus-host disease. While the absence of any reported CRS and ICANS is notable, it bears mentioning that ALPHA3 was designed to optimize all aspects of an allogeneic CAR T product, including its safety profile by treating patients early and when their disease volume is so low that it can only be measured by an ultrasensitive MRD test.

Even with this in mind, the absence of CRS and ICANS in this interim analysis exceeded our expectations. Low-grade infections were evenly balanced between the 2 arms. Low-grade neurological events were reported in 6 patients in the cema-cel arm, headache in 2 patients, dizziness in 4 patients, numbness or tingling in the hands of feet in 1 patient and altered taste in 1 patient.

The observation arm reported 1 patient with dizziness. There were no treatment-related serious adverse events and no hospitalizations for treatment-related adverse events. The majority of patients were managed entirely in the outpatient setting. A major limitation of CAR T treatment has been its toxicity, which requires patients to remain close to the treatment center for monitoring for up to 14 days post infusion and triggers frequent hospitalization to manage CRS or ICANS.

This has limited broader use and has restricted patient access. We are very pleased with cema-cel's early side effect profile. And if these early ALPHA3 results remain consistent in the study overall, we believe there could be potential to deliver CAR T entirely in outpatient settings.

Slide 18 dives a bit deeper into cema-cel's real-world feasibility. ALPHA3 is now being conducted across more than 60 sites with a balanced mix of academic and community centers. At the time of this interim futility analysis, approximately 33% of screening activity and cema-cel infusions were conducted in community cancer centers, including sites with limited or no prior CAR T experience.

We believe the results observed thus far demonstrate that cema-cel can be delivered in a broad range of care settings, which is critical to expanding access if cema-cel is ultimately approved. That is the key for moving CAR T earlier in the course of disease and has been a major goal of ALPHA3.

Having heard from the Allogene team, we'd now like to turn to one of our investigators, Dr. Jeff Sharman, to share his perspective. Dr. Sharman is the Director of Research at the Willamette Valley Cancer Institute and Chair of the Lymphoma Research Executive Committee for Sarah Cannon Research Institute, which includes a network of more than 200 community oncology locations.

Dr. Sharman is a renowned thought leader in the latest breakthroughs in hematologic oncology and has been instrumental in developing a number of important advances in the field. Dr. Sharman, you and several of your colleagues at U.S. Oncology SCRI have had a front row seat since the launch of ALPHA3, and you've been actively involved in screening and treating patients in ALPHA3 at Willamette Valley Cancer Institute. Can you tell us about your practice, your history with CAR T and your perspective on the data we've presented today to get us started?

Yes. Thank you so much for inviting me to be a part of this. That was a great introduction as well. My name is Jeff Sharman. I'm a community practice, hematologist, oncologist. I've been in community practice for about 18 years. In my practice, I actually take care of all types of cancer, including breast, colon, lung, prostate and so forth, although my interest is certainly in lymphoid malignancies, and that typically constitutes about 2/3 of my practice.

I've helped lead the research program for our broader network. Originally, that was the US Oncology network, and now we've merged with Sarah Cannon. We have not really been able to successfully deploy a commercial CAR T program to date, and that really just has to do with payer limitations, cost and many of the features that make it challenging to move forward with CAR T. We have treated 1 prior patient with liso-cel on a research study.

I helped design the outreach study for BMS and managed to treat a patient on that study. But that was, again, only in the context of a research study. So my engagement in this study has allowed me to screen a number of patients treated sort of under routine standard of care, and we've identified patients and went ahead and treated on study. So we'll go from there.

Thanks, Dr. Sharman. As someone who has long been at the forefront of community-based cancer research, please provide your perspective on some of the gaps and access to CAR T, specifically for patients, who receive care outside of academic settings?

Yes. I think the statistics -- and these are probably slightly older statistics, but something like 1 out of 5 patients, who is eligible for CAR T actually receives them. And that's because many of these are done. They really require academic centers. So in my state like Oregon, we live -- the only place you can get CAR T is in Portland, which is in the top left corner of a very large state.

And if you live in Eugene, where I do, it's a 2-hour drive up to Portland. And that induced a lot of barriers for patients to go up there. They need to have a caregiver. They need to be physically present up there. And that just presents a number of insurmountable challenges for some patients. And I have absolutely had more conversations than I wish I'd ever had about CAR T, where I present it to a patient, hey, I think this is what is appropriate and suitable for you. And I'm told by the patient, I can't do that. It unfortunately comes up more commonly than you would want.

So I think the ability to deliver something in the community has long been one of my goals. That was sort of the impetus behind the design of the BMS outreach study. And we proved that you can do it operationally with more traditional auto CAR T. But nonetheless, for a practice like mine, where we have to -- there's just a lot of commercial barriers and those commercial barriers are real.

And -- and unfortunately, that limits a lot of CAR T options really to university medical centers or centers that may have already had existing cellular therapy programs, be that auto transplant or allo transplant. And that's really the minority. 80% of cancer patients in the U.S. receive their care in the community setting. And so I think it's really essential that we're able to deliver therapy in those settings where patients are being treated.

Thank you. What are your thoughts on the safety and tolerability profile that we've seen so far in ALPHA3?

I think it's impressive. And of course, I hope it holds. I wouldn't necessarily call it surprising. And I guess my thought of that is the setting in which you treat a patient, not now I'm switching from geographic to actual clinical setting, the circumstances where a patient gets treated is significant to their side effect profile.

When a patient under traditional auto CAR T, when we're waiting for disease progression, oftentimes, these patients just because their disease are acutely ill relapsed large cell lymphoma is a disease where patients -- really their life hangs in the balance and differences of days or weeks can make a significant difference. It's not unusual for a patient with relapsed disease to really struggle to even get to their auto CAR T infusion because their disease may be so rapid or causing symptoms.

And then introducing a CAR T into that very unstable clinical situation really is dangerous because the sort of antigen drive, if you will, of the -- or I should say, the abundance of disease in that setting really drives an exuberant proliferation of the auto CAR T and that's then what leads to the cytokine release syndrome and potential ICANS.

And so when you treat somebody whose disease is much more controlled, it's much easier to do. And I've certainly observed that clinically in many patients, who I've referred for CAR T in the past, those with better controlled disease get through the procedure much more easily. And so taking somebody whose disease is restricted to the presence of MRD positivity is somebody whose disease is, frankly, quite well controlled.

And I think the statistic you gave or that you presented was that 75% of these patients were PET negative. And so these are patients with a comparatively modest burden of disease. And the consequence of that is that they really don't have the same overwhelming autologous cellular proliferation. This is something that occurs under much more controlled circumstances.

And so I guess you asked what's my impression, and I would say I'm pleased, but I'm not surprised, and that's the basis by which I form that opinion.

Great. So how might these early safety and efficacy data if they bear out in the overall study, change how you think about offering CAR T to your patients? And how do you think it might change to other patients and other community-based practices?

Look, if this is -- if this proves positive, it fundamentally changes the way we treat large cell lymphoma without a doubt. The idea of consolidation therapy is not new to oncology. We do it in acute myelogenous leukemia. We do it in other hematologic malignancies. So that concept is not foreign to the field. It's just not something done in large cell lymphoma currently.

But look, there's an unmet medical need in large cell lymphoma, which is that we cure about 2/3 of patients with frontline therapy. That leaves 1/3 that's not. And if we have to wait until they relapse, that's what limits the efficacy of auto CAR T is that you're pushed for all the sort of clinical social variables I outlined above.

On the other hand, if you finish therapy, we're all used to getting tests, we get -- currently, we get PET scans. But if that just means that shifts to get -- if that means that just shifts for us to get MRD, well, then we'll get MRD. And if they're MRD positive, that gives us a very actionable step, which would be to proceed with allo CAR T in this situation. And I imagine we'll probably talk about it, but my experience with the therapeutic administration of the products was really quite easy.

So I mean, with that kind of thought, how do you see the ability to integrate something like this an off-the-shelf product into your busy community practice?

Well, listen, I think I'll just sort of say my experience treating a patient on the study was very simple. The lymphodepletion chemotherapy with fludarabine and cyclophosphamide. And I do have enough gray hairs to say that, that's used to be how we treated patients with CLL all the time. That was a standard regimen for the management of chronic lymphocytic leukemia. And not hard to administer. It's really quite simple.

And then the cellular product was also really simple. It just came in a doer and just had to be thought out and administered. And in my own infusion room, I think a number of people kind of gathered around to see this because it seemed so cool to do, but it was really kind of anticlimactic. We just sort of infused the cells and patient was done and went home and then we sort of checked on him regularly several days. The protocol had several protocol mandated visits and sort of nothing exciting ever happened.

And to my own patients, when I refer to them as boring, that's sort of the highest praise I can give them because really you want to be boring in an oncology clinic, you never want to have drama. And this was very boring, which was ideal.

Well, for one, I'm good with boring when it comes to side effects. So that's awesome. Okay. Finally, what are your thoughts on how MRD can be used in everyday care of patients with LBCL?

I think Foresight's product really looks quite provocatively effective or I'm not sure what the right word is. It's really good at identifying those patients, who are likely to progress versus not. I mean, again, I come back to the notion that 75% of these patients were PET negative, yet they were MRD positive.

And I think that really speaks to the limitations of PET scan. If there's a better test out there, we'll use it. And particularly if there's a use case for it, right? So I think that sometimes diagnostics struggle a little bit when there's not sort of an action item on the other end of it, meaning if we get a test and it's purely for prognostic purposes or so forth, sometimes those are more difficult tests to get.

But if there's an obvious thing for us to do afterwards, which would be CAR T, then it's much easier for us to justify getting that. And so I think MRD is the company who bought Foresight, Natera, they are a very good company. I think a lot of oncology practices are comfortable and familiar with using them. They have a lot of products in solid tumors already.

And so there's -- they're a good partner for us to work with. And I think that they will help deploy this assay in an effective way as well. So look, I think all the pieces kind of line up right for this. And congratulations to you guys for having some really interesting early data and setting up a clinical study that I think operationally mirrors how the product could be used in the real world.

Okay. Great. Well, I'm going to let you take a break and grab a cup of coffee because we'll have Q&A here in a little bit. Thank you so much, Dr. Sharman, for your sharing your thoughts here.

You bet. Thanks.

As we look ahead, Slide 20 outlines the next milestones for the trial. ALPHA3 is expected to complete enrollment by the end of 2027. We anticipate an interim EFS analysis in mid-2027, followed by the primary EFS analysis in mid-2028. These future readouts will ultimately determine whether the MRD clearance observed here translates into meaningful improvements in clinical outcomes.

As we summarize the data presented on Slide 21, we are very pleased with the results that are emerging for cema-cel as part of first-line consolidation treatment for LBCL. From a patient perspective, we believe the key takeaway is straightforward a 58.3% MRD clearance rate with cema-cel treatment over half of patients versus 16.7% with observation.

While early and based on a small sample, these data provide initial support for the potential of cema-cel to intervene in high-risk patients before clinical relapse. Combined with a favorable interim safety profile and the potential to deliver in outpatient and community settings, we believe this supports a fundamentally different CAR T paradigm, one that could expand access, enable earlier use and position allogeneic therapy as a scalable go-to option.

I'll now turn the call over to Christine to discuss recent market research that highlights the potential opportunity for cema-cel.

Thank you, Zach, and Dr. Sharman. And frankly, a lot of what I'm going to be talking about, Dr. Sharman's already kind of illustrated. So before discussing where the field is going, it's important to start with where CAR T stands today, as shown on Slide 23. Despite strong clinical efficacy, current CAR T access remains highly constrained. Only about 15% of eligible second-line patients receive treatment, driven by structural limitations and concentration in roughly 200 academic centers.

However, we think -- we know about approximately 80% of first-line patients are treated in the community where autologous CAR T is not readily available. These barriers are well documented. For example, a recent article in target oncology and featuring an MD Anderson KOL, who highlighted key challenges with autologous CAR T in LBCL related to referral patterns, infrastructure and access. These challenges are exactly what ALPHA3 and cema-cel are designed to address.

On Slide 24, we shift to what we believe could ultimately drive adoption if cema-cel is approved. We conducted market research with approximately 30 physicians across academic and community settings, evaluating 3 blinded Target Product Profiles or TPPs, representing emerging regimens and autologous CAR T and bispecific in first-line induction and cema-cel in first-line consolidation.

For cema-cel, the TPP assumed a 50% MRD clearance rate with no Grade 3 CRS or ICANS and low rates of grade 3 or greater infections, all of which is somewhat conservative relative to our data today. In this market research, autologous CAR T was recognized for its efficacy, but physicians noted logistical complexity, where it's currently used, manufacturing constraints and a safety profile that may limit earlier line use when used in first-line regimens, which have demonstrated a strong benefit risk profile.

For bispecifics, physicians acknowledge that they may offer greater accessibility and ease of administration, but questions remain around durability, continuous dosing, safety and overall treatment burden. The cema-cel TPP was differentiated by its MRD-guided first-line consolidation approach as a onetime targeted treatment only for patients who need it, all while addressing the 5 dimensions David discussed earlier, efficacy, safety, speed, simplicity and scalability.

The feedback was clear. Physicians are no longer evaluating CAR T on efficacy alone. Adoption in earlier lines requires confidence and outcomes and safety that allows for deliverability outside the hospital, access through off-the-shelf availability and simplified logistics, including biologic-like reimbursement without back accreditation.

This aligns with what was conveyed by Dr. Bartlett and Dr. Sharman in our press release and from Dr. Sharman's comments today on the call, efficacy is required, but safety and deliverability could ultimately unlock use, particularly in earlier lines and in the community setting.

On Slide 25, we've highlighted what we heard in research, which is consistent with some of the questions were asked by investors. For some physicians in this research, perceptions of current CAR T were anchored in a legacy framework shaped by experience with autologous therapies or by lack of knowledge of prior cema-cel data.

We heard consistent legacy perceptions, waiting until relapse, which is the current standard of care, reserving CAR T for later lines, viewing it as limited to academic centers and questioning its role alongside emerging first-line alternatives. Recall earlier the TPP is reflecting potential first-line induction profiles for autologous CAR Ts with strong efficacy, but constrained logistics, where it fits in the treatment paradigm, manufacturing and safety, while bispecifics offer accessibility and ease of use but face uncertainties around durability, continuous dosing, safety and overall treatment burden. When presented with the cema-cel TPP, it became clear that these perceptions could become outdated and that cema-cel could address these perceived barriers.

Slide 26 starts at the beginning of this process with MRD testing. Today, MRD testing is used about 20% to 30%, primarily in academic settings. When paired with a potential product like the provided TPP for cema-cel, physicians projected that use could increase to 75% to 80% as it could create a clear point of action at the end of first-line therapy. This is especially notable as we consider future uptake with Natera's acquisition of Foresight, reinforcing the commercialization of this assay is well positioned for success.

Compelled by the cema-cel TPP, physicians projected that approximately 50% to 70% of MRD-positive patients would be treated in first-line consolidation. We believe these responses suggest a new decision point at the end of first-line treatment that fundamentally changes how CAR T could be used.

Slide 27 builds on a framework we've previously shared and highlights a key dynamic. In real-world settings, approximately 30% of patients who achieve a response after first-line therapy will ultimately relapse. While ALPHA3 enrolled patients, who are MRD-positive immediately at the end of first-line treatment, physicians in our research noted that in practice, serial MRD testing following first-line therapy could be used to identify patients at high risk of relapse beyond a single time point.

Today, any high-risk patient is managed with the watch and wait standard of care. ALPHA3 challenges that current standard of care with cema-cel, which has been designed for real-world use that combines earlier intervention, broader access and biologic scale delivery, allowing it to potentially leapfrog the competition.

Slide 28 translates our perspective on the cema-cel TPP and market research into a quantified opportunity. Across the U.S. and EU5, this represents more than 14,000 addressable patients annually and an estimated $5 billion market opportunity for first-line consolidation alone. Within this, cema-cel's share of the market could represent $2.5 billion to $3.5 billion based on projected physician utilization, MRD testing rates and expected treatment patterns.

Slide 29 shows how cema-cel could fundamentally change the future market for CAR T. Today, CAR T adoption is constrained by access infrastructure and delivery limitations. We believe ALPHA3 has the potential to change that. In LBCL, the projections for autologous CAR T represent a roughly $3.5 billion market in 2032.

With first-line consolidation, this could increase to approximately $7 billion, more than doubling the category and moving beyond simply a shift in the market share to true market expansion.

I'll now briefly turn it back to David before we begin our Q&A portion of the call.

Thank you, Christine. Importantly, for patients, what we have discussed today is about access to innovation and the possibility of earlier intervention to potentially prevent relapse and improve long-term outcomes. We believe cema-cel, pending a successful outcome of the ALPHA3 study and approval has the potential to deliver across the 5 dimensions required to unlock CAR T, efficacy, safety, speed, simplicity and scalability.

We believe this combination could enable a fundamental shift in how CAR T is used, translating into meaningful market expansion and a multibillion-dollar opportunity. We have potential -- we are positioned to execute with a wholly owned U.S. manufacturing facility built to support demand at scale.

Taken together, we believe the interim data presented today positions cema-cel as a potential inflection point for CAR T, supporting a shift from a complex capacity-constrained intervention to a scalable, broadly deployable platform that can reach patients earlier in their disease. We will now open the call for questions.

[Operator Instructions] Our first question comes from Salveen Richter with Goldman Sachs.

Congratulations on the data here. You touched on this before, but could you just speak to how the interim futility will translate to the primary EFS endpoint? And then help us understand the registrational strategy here in terms of whether you could file on the interim EFS analysis in mid-'27?

Salveen, thanks for those great questions. In terms of looking at the MRD clearance, there are a number of emerging data points that clearly indicates MRD clearance after the treatment strongly correlates with the clinical outcome that reduction in the EFS that we have outlined, that's also associated with a reduction in PFS.

And in some cases, even the overall survival has been associated with the MRD clearance. So I think we still have to show the correlation between MRD clearance and clinical outcome within ALPHA3 study. However, the existing data are very compelling.

On the second question about the regulatory strategy, it's a little bit premature for us to go in depth. But what you're referring to is our planned interim EFS analysis in mid-2027. Like any other interim EFS analysis or primary endpoint analysis, the intent of the interim analysis to change the course of the study, conduct of the study in the event of overwhelming efficacy.

And appropriately, we have set a so-called ALPHA. This is how the statisticians use the validity of the testing. We have set the bar relatively high, appropriate for what we are trying to do. However, if we are fortunate enough to cross the statistical boundary at the interim EFS analysis and when if our independent data monitoring committee recommended, we will take the appropriate action to accelerate the regulatory discussion with the FDA and potentially leading to the BLA submission. We believe that is the right thing to do for the patients.

Our next question comes from Tyler Van Buren with TD Cowen.

Congratulations on the sandwich of both the stellar efficacy and safety data. Maybe one for Dr. Sharman and one for management. For Dr. Sharman, the value proposition here seems so obvious, at least to me. So -- but it would be great to hear you walk us through how you present the opportunity for cema-cel treatment to patients when discussing potential enrollment in the ALPHA3 study or eventually in practice following the alternative post the frontline treatment?

And how might these data change the conversation with patients? And for management, just on MRD clearance, I know you said, obviously, a great result. And I know you said it was rapid, but are there any additional details you can provide around the time course of the MRD clearance, for example, how many achieved it with the first assessment versus later assessments?

I'll go first since the question was to me first, and then I'll hand it over to the Allogene team. The discussion is actually pretty easy. When somebody is coming to the end of therapy, there's a very natural interest on the part of the patient to know how well they've done. Patients are like, so am I cured and where am I?

And with our PET scans, we can say, hey, look, you have a PET negative result or sometimes there are PET findings where there's a very equivocal finding and maybe the [indiscernible] score isn't low enough, but it's not an easy place to biopsy and so forth. And really, the only thing we have to offer our patients is test of time to say, let's see how this goes over time and the longer you go without relapse, the more likely you are cured.

In terms of MRD testing, patients are pretty enthusiastic about it because what we're able to say to them instead is, hey, we think we have a better predictive test than PET scan. We have just a blood draw that we can follow. Patients prefer blood draws to scans, scans have radiation and PET scans are cumbersome. So the testing is not much of an issue.

You asked a second question, though, which was how is this data likely going to affect the conduct of the trial moving forward. I will tell you, it might make it a little bit more difficult as there's -- I think the hardest part of the discussion is the patient who's MRD positive, who gets randomized to the observation arm.

And I think the current standard of care is observation, and that's what this trial is trying to displace. But I think for the MRD-positive patient, who is randomized to observation, there's understandably apprehension that the disease is going to come back and what that means for them. So overall, I think that the testing and the therapeutic administration here, I think, is relatively straightforward. And you said that the value proposition is obvious. I agree with you.

And Tyler, I'll take the second question. This is Zach. So because this is an ongoing trial, obviously, we don't intend to provide any more detail on the timing of MRD clearance of individual patients. But I will say that the most important thing according to all the existing literature that David covered is that you achieve MRD negativity at any point following treatment. And so that is what we shared with you all.

Our next question comes from Samantha Semenkow with Citi.

Let me add my congratulations on the really excellent data presented this morning. One for Dr. Sharman. I'm just wondering, as you're thinking about integrating this into your practice, if it were to be approved with a similar profile that we're seeing today, how many of your patients that end up MRD positive would you offer this to? And what proportion do you think would actually end up receiving cema-cel in an ideal world data-wise?

Yes. Let me just make sure I understand the question. The question, as I understood it, was how many patients who are MRD positive would you subsequently treat? Is that accurate?

Yes, exactly.

Yes. I think most of them, almost all of them, right? I'm sort of trying to think of a circumstance, where I wouldn't treat them. I think that in large cell lymphoma, there is kind of a frailty consideration and a burden of treatment consideration. So some patients as they finish up therapy for large cell lymphoma had a number of complications.

I can think of a patient I took care of recently who had 3 or 4 admissions for febrile neutropenia. He ended up with a colectomy because he had terrible clostridium difficile and he really limped through the finish line. And even though he was young, he was a patient that didn't offer testing for because the idea of additional therapy in that situation seemed like it would be too much for him in that setting.

But I'll tell you, I think that's a significant minority of patients. Most patients get through therapy. It's hard therapy, but they want to know that it's worth something. So I think the question is maybe a little bit different, which is, are there patients I wouldn't test -- and yes, there probably are some. Maybe that number is 10%. The high octogenarian large cell lymphoma patients, who we had to do a lot of dose reductions to get them through therapy or the patients who have the significant burden of therapy.

Those patients do exist, but those are ones where I probably just simply might not test them or if I did test them and they turned up positive, maybe it just kind of influences how I follow them up. So I'm sure there are some. I'm trying to think through the question and sort of clinical practicalities as I'm going to answer at the same time. So I would acknowledge that there probably are some, but I don't think it's a huge number.

Our next question comes from Michael Yee with UBS.

I have 2 questions. One was to the company around the confidence or agreement with FDA around the primary endpoint on EFS and thinking about positive around the understanding of MRD negativity as it relates to myeloma now and to others, but obviously, here within CAR T, specifically therapeutically and with the endpoint, what discussions you've had with the agency around that endpoint?

And then the second question is for the doctor. I know that you said overwhelmingly the majority of patients you would seek to treat with that. Can you speak to your comfort around this, particularly as an outpatient therapy and to what degree because you are, as you said, not in Portland, the degree that you can just treat and then send people home? Or how do you think about that logistically? Is that really a key part here?

Michael, this is David Chang. Let me take the first question, and I'm going to make my answer brief given that we have about 8 minutes left. In terms of the FDA and EFS as an endpoint, first of all, this is an established endpoint in the second-line setting, and there is an ample precedent for using EFS as a primary endpoint. And we have a full agreement with FDA that this is an appropriate endpoint for the study.

And I think I can be brief similarly about -- my question about outpatient treatment. It's all going to boil down to how the data looks in the final presentation of safety and efficacy, but really safety more than anything else. I think that's where regulatory agencies are going to weigh in on this.

I guess I'd refer back to my original comments about the clinical state in which the patient is treated. So if they have a disease that's out of control and clinically progressing, the likelihood of side effects in that environment just seems to be a lot higher than treating in the sort of low burden MRD positive status.

So we already do a lot of things in the outpatient setting, bispecific antibodies. And CAR T, when we did it on the study, we did it as an outpatient provided patient could stay outpatient. So I don't think it's going to be a huge issue. I think that the bigger challenges will just have to do with maybe some of the way the commercial agreements are set up with practicing sites and how the drug is acquired, making sure that it can be reimbursed. But actually doing the treatment in the outpatient setting doesn't seem terribly concerning.

Our next question comes from [ Kylie Briza ] with Piper Sandler.

This is [ Kylie Briza ] on for Biren. Maybe the first question was, can you just walk us through how many events do you need for the interim and the final EFS analysis and the confidence level on the endpoint for both events?

And then I was wondering if you could also -- given these data, would you expect interest in the trial to increase? And how does that impact your enrollment time lines for the ALPHA3 study?

Let me take the first question, and I'll ask Zach to respond to the second question. In terms of the statistical parameters, I mean, these are information that there are many different dimensions. And generally, we will be sort of keeping the statistical parameters for the study relatively to ourselves, and we will share them at a relevant time point.

Thanks, [ Kylie ]. We -- for the projections that we pointed out, completing enrollment by the end of 2027, we have not baked in any boost to enrollment that might come from these early results. However, we do think that there may be an impact. And certainly, I think that as the first data shown that shows the value of consolidation with an off-the-shelf CAR T, it may generate more interest both by physicians as well as by patients.

Our next question comes from Matthew Phipps with William Blair.

Let me offer my congrats as well on some great initial results here. I was wondering, again, a question on that EFS guidance to event time lines. I was wondering, if that assumption that you all made to get to the interim the next year is based off the 50% risk reduction that you assumed in powering the trial?

And if you think that might need to be adjusted just given the magnitude of separation you're seeing already in clearance rates and how that could impact accrual events?

Matthew, very interesting question. This is a topic that we are constantly sort of discussing internally. Just to be clear, this is a potentially registrational study to preserve the trial integrity, we don't look at the clinical endpoints while the study is ongoing, clinical endpoints, meaning event-free survival or progression-free survival. So that time will come appropriately on the planned analysis.

Our next question comes from Roger Song with Jefferies.

Great. Congrats for the results outstanding. So -- understanding you haven't given us too much the kinetics of the MRD, which is understandable. Just how do you expect the MRD negativity this delta will change over time? And then what do you plan to take another look on the MRD before the EFS with a larger sample size?

Thanks, Roger. Of course, the potential for that MRD clearance rate to change and improve over time exists. As I said, we -- this is just a snapshot of the MRD status at the last check, but there may be additional patients who eventually convert.

However, we -- in terms of checking the MRD status, again, that is not something we intend to do. This was really as the protocol was defined to do this interim futility check. And the next time that we will be looking at data will be at the protocol-specified interim analysis.

Our next question comes from Matthew Biegler with OpCo.

Maybe a follow-up on the kinetics here to the extent you can answer it. But are you seeing any correlation between MRD responses and CAR T expansion in the blood or if you might not even expect to given the lack of CRS and ICANS that we're seeing? Any thoughts there?

Thanks, Matt. I think it's all of the additional correlative data and so forth, we'll have to wait for a future data presentation.

Due to time, we will now conclude the question-and-answer session. I'd like to turn the conference call back over to management for any additional comments.

All right. Thank you. Data shared today from the interim futility analysis increases our conviction that cema-cel has the potential to change perceptions of allogeneic cell therapy, change how CAR T is used and ultimately change the disease trajectory for patients. We look forward to advancing ALPHA3 and delivering on that potential. Thank you.

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

Hello, and thank you for standing by. Welcome to Allogene Therapeutics Fourth Quarter 2025 Conference Call. [Operator Instructions] 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.

Thank you, operator, and welcome, everyone, to Allogene's conference call. After the market closed, Allogene issued a press release that provided a business update and financial results for the fourth quarter and year-end 2025. This press release and today's webcast are available on our website. Following our prepared remarks, we will host a Q&A session, and we will aim to keep the 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 Jeff 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, Christine. As we close 2025 and enter what we expect to be a defining year for Allogene, the environment around us is shifting. Cell therapy has entered a phase defined by evidence, where progress will be measured not by speculation and promises, but by data and disciplined execution. That shift plays to our strength.

Our focus in 2026 is straightforward, delivering meaningful clinical milestones with rigor and speed. This is a year of critical proof points, proof points that could validate our allogeneic platform, not nearly as an alternative, but as the imperative path to making cell therapy scalable, accessible and deliverable at biologic-like scale.

First, with Cema-Cel and ALPHA3, we are asking a bold but important question that could redefine the management of large B-cell lymphoma. Can we intervene earlier, making CAR-T truly accessible in the community setting, meaningfully improve outcomes and alter the course of disease without disrupting the physician's practice. The goals of this study are not about incremental improvement in a late-line setting. It is about shifting the paradigm in the first-line treatment and demonstrating that Cema-Cel can reduce the risk of relapse and improve the cure rate. Importantly, it is about expanding access to community cancer centers that historically have been excluded from offering CAR-T, bringing advanced cell therapy to where most patients are treated off-the-self at biologic-like scale.

Second, with ALLO-329, we are extending the promise of allogeneic cell therapy to autoimmune disease. ALLO-329 is a purpose-built dual CD19/CD70 CAR design specifically for immune-mediated conditions, incorporating our Dagger technology to potentially reduce or maybe eliminate traditional lymphodepletion. We expect to report proof-of-concept data in June 2026 and assuming continued progress, another clinical update by the end of the year. We are entering this execution-focused period from a position of financial strength, having extended our runway into the first quarter of 2028. That gives us the ability to advance ALPHA3 and resolution with focus and discipline.

We have built a broad and innovative clinical pipeline, but we recognize we cannot advance everything at once. Discipline requires prioritization. Today, we are concentrating our resources on the programs where allogeneic CAR T has the greatest potential to demonstrate what this modality can achieve when developed around its inherent advantages, scalability, accessibility and ultimately, the potential for durable cure. At the same time, we believe that as the field recognizes that allogeneic CAR T can deliver at scale with rigor and practicality, it will unlock new opportunities to expand the platform into additional settings and indications.

With that, I will turn it over to Zach to walk through the clinical progress in more detail.

Thanks, David. As David outlined, the second quarter is defined by 2 key programs, Cema-Cel in ALPHA3 and ALLO-329 in resolution. I'll concentrate on the clinical execution behind these studies and what we expect to learn in the months ahead, beginning with ALPHA3.

ALPHA3 is the first randomized study in lymphoma designed to test whether early MRD-guided consolidation with an allogeneic CAR T can prevent relapse. Patients who achieve remission after standard first-line therapy undergo highly sensitive ctDNA testing. Those who are MRD positive and therefore, at high risk of relapse are randomized to observation or treatment with Cema-Cel. In April, we plan to report results from the interim futility analysis evaluating MRD clearance in 24 patients, 12 each in the Cema-Cel-treated arm and the control observation arm, along with early safety data.

We will also outline the anticipated time line and key inflection points as the study progresses. We've anchored expectations around what we and many clinicians believe would be a meaningful threshold, a 25% to 30% absolute delta in MRD clearance between arms. Achieving that outcome would have the potential to alter disease trajectory and meaningfully improve the rate of cure of large B-cell lymphoma in the first-line setting.

At the upcoming analysis, we also intend to provide preliminary safety data and additional perspective on how the use of Cema-Cel is being implemented in community settings. We now have over 60 active sites across the U.S. and Canada with engagement with health authorities and clinical site start-up activities underway in Australia and South Korea. The level of real-world integration of Cema-Cel as consolidation into routine practice across both academic and community centers underscores what we believe is a core advantage of the off-the-shelf model and its potential to expand access beyond traditional CAR T delivery hubs.

I'll now spend a few minutes on ALLO-329, our first-in-class dual CD19/CD70 allogeneic CAR T therapy designed specifically for autoimmune disease. ALLO-329 was engineered for this setting from the outset. It targets CD19-positive B cells and CD70-positive activated T cells, both of which contribute to autoimmune disease. Our Dagger technology is designed to endow the cells with a kind of built-in lymphodepletion to enable optimal cell expansion and persistence while potentially reducing or eliminating the need for conventional cytotoxic lymphodepletion.

The Phase I Resolution trial is a 3+3 dose escalation study enrolling patients across multiple rheumatology indications, including systemic lupus erythematosus, lupus nephritis, scleroderma and inflammatory myositis. The study is evaluating several dose levels beginning at 20 million CAR T cells in 2 parallel dose escalation cohorts, one that includes cyclophosphamide only and one without any traditional lymphodepletion. 20 million cells is a small number, but one that we selected based on our conviction that the Dagger technology in ALLO-329 could drive meaningful in vivo expansion.

For context, competitive programs in autoimmune disease are evaluating doses of autologous CAR T cells that are up to 5 to 10x higher than our starting dose and other allogeneic cell therapy programs are exploring cell doses nearly 50x higher. In June of this year, we expect to report initial proof-of-concept translational data as well as early clinical signals from the first dosing cohort with and without lymphodepletion.

As an off-the-shelf allogeneic CAR T product that does not require any degree of patient HLA matching, ALLO-329 persistence in patients treated with minimal or no lymphodepletion at this low starting cell dose would be a strong validation of the Dagger effect in autoimmune patients. Assuming continued enrollment and follow-up, we anticipate providing an additional clinical update later this year. The opportunity in autoimmune disease could be significant, but success in this space requires tolerability, outpatient feasibility and scalability, particularly as treatment moves into rheumatology practices.

ALLO-329 was engineered with those requirements in mind. Across both programs, our focus remains on disciplined execution with the goal of generating data that clearly define the role of allogeneic CAR T in earlier line oncology and in autoimmune disease.

With that, I'll turn the call over to Geoff.

Thank you, Zach. As we prepare for multiple clinical catalysts in 2026, our financial position is aligned with our strategic priorities. We have been deliberate in concentrating our resources behind ALPHA3 and resolution while maintaining balance sheet strength and operational flexibility.

As of December 31, 2025, we had $258.3 million in cash, cash equivalents and investments. In February of this year, we received an additional $23.7 million previously held in escrow related to Servier's favorable arbitration outcome with Cellectis. We have also made prudent and opportunistic use of our ATM equity facility and have raised an additional $20.7 million year-to-date. As a result of these actions, we have extended our cash runway into the first quarter of 2028, which we believe covers the time frame we currently estimate is needed to complete enrollment in the ALPHA3 trial.

R&D expenses for the fourth quarter were $28.6 million, including $2.5 million of noncash stock-based compensation. For the full year of 2025, research and development expenses were $150.2 million, which includes $12.9 million of noncash stock-based compensation expense.

G&A expenses for Q4 2025 were $13.8 million, including $5.6 million in noncash stock-based compensation. For the full year 2025, G&A expenses were $56.8 million, which includes $24.7 million of noncash stock-based compensation expense.

Net loss for the fourth quarter was $38.8 million or $0.17 per share, including noncash stock-based compensation expense of $8.1 million. For the full year of 2025, net loss was $190.9 million or $0.87 per share, including noncash stock-based compensation expense of $37.6 million and noncash impairment of long-lived asset expense of $2.4 million.

Guidance for operating cash expense in 2026 is expected to be approximately $150 million. GAAP operating expenses are expected to be approximately $210 million, including estimated noncash stock-based compensation expense of approximately $35 million. These estimates exclude any impact from potential business development activities.

With pivotal data from ALPHA3 approaching in April, proof-of-concept data for ALLO-329 expected in June and cash runway now extended into 2028, we believe we are well capitalized to execute through these important inflection points. Our focus remains clear: advance high-impact programs, manage capital responsibly and position Allogene for long-term value creation.

We'll now open the call for questions.

[Operator Instructions] Our first question comes from Tyler Van Buren with TD Cowen.

Looking forward to both data updates next quarter. Can you elaborate on the safety parameters you'll be looking at with the ALPHA3 data update next month? And what the bar is to support broad uptake in the community setting? And perhaps more importantly, how investigators in the community setting have already responded to incorporating Cema-Cel as a seventh cycle of treatment in the front line?

Tyler, thank you very much. I'll ask our CMO, Zach, to elaborate on safety aspect.

Tyler, thanks for the question. So we plan to provide some high-level safety information enough for everybody to understand how well this is being tolerated. Unlikely we'll go into very, very minute detail. But certainly, serious adverse events in both arms, the sorts of adverse events that would lead to hospitalization, those sorts of things, which absolutely kind of feeds into your second and third questions, what is the bar that we need to hit for safety.

We believe that this is best delivered as an outpatient. So therefore, this needs to be a therapy that can be delivered as an outpatient. It does not lead to rehospitalization due to adverse events. And finally, can this be done in the community? And absolutely in the community, it's being done currently, and we look forward to sharing all of the safety aspects that are allowing this to be taken up in the community by physicians.

Our next question comes from Biren Amin with Piper Sandler.

I wanted to focus on the recent ZUMA-7 MRD analysis that were published last month, where exa-cel observed a treatment difference of 20% on MRD negative, which translates to about an EFS benefit of around 27 months versus the control group. given you're expecting a 25% to 30% difference on MRD conversion, what read-throughs do you have from the ZUMA-7 data and your confidence on stopping at your interim EFS analysis? And on that, on the interim EFS analysis, if you could maybe just walk us through how many events do you need and what assumptions on hazard ratio could lead to an early stoppage? And lastly, when can we expect interim EFS data?

Biren, thanks for pointing out on the recent MRD data analysis coming from subgroup of patients who are enrolled in the ZUMA-7 study. We view this study to be very consistent with how we've been looking at the MRD clearance and its correlation to the clinical outcome. Besides the study, earlier study that we have been talking about is IMVigGor-11 study. where MRD clearance difference of 11% led to a very meaningful clinical difference.

So what has been reported with ZUMA-7 is very consistent. And I believe it sort of validates the guidance that we have been providing, which is 25% to 30% MRD clearance difference at the futility interim analysis that we project to share in April. So this is highly consistent, and we do believe that 25% to 30% is going to translate to very meaningful clinical difference in the outcome.

So with respect to your second question, how much can we sort of speculate or model out about how the MRD clearance may translate to the EFS interim analysis. I would say it just involves too many assumptions and speculations, and it's a little bit too early to talk about it. But internally, we are constantly reviewing the data and modifying our assumptions. So stay tuned.

Our next question comes from Michael Yee with UBS.

We had 2 questions. One was your thinking -- the first question is your thinking around the interim analysis and what was defined whether you took that interim analysis on EFS. In other words, if the MRD conversion is super high, is that what would drive your thinking to take the EFS? So that is the question number one. And then question number two is on autoimmune, and we wanted to understand the target product when you get your data coming up. Is this to be a low lymphodepletion, a no lymphodepletion type program? What are you trying to envision with the profile of that product?

Yes. So 2 great questions. In terms of -- this is somewhat similar to what Biren was trying to get. I mean, one thing is that there isn't enough data out there to see how MRD clearance, the relationship between that and clinical outcomes such as event-free survival. Whether this is a linear relationship, meaning that if there is a greater difference in the MRD clearance, there will be greater difference in the clinical outcome. That kind of data, while plausible, there is such paucity of the data, so we can't really establish the relationship other than saying, well, it is possible that if we see greater MRD clearance difference, that may translate to greater clinical benefit.

And I get to the point about how that may sort of put us in the time of intermediate analysis. I mean, interim EF analysis is alpha spending analysis. It is the primary endpoint analysis at a smaller event rate. And there is always a possibility that interim analysis may cross the statistical boundary. I mean that's why part of the reason that we do the interim analysis, not just us, everybody who does the interim analysis. But let's stay tuned.

I mean our focus right now is the MRD clearance that we promised to communicate in April of this year. And with the second question on the target product profile with the autoimmune program, our CD19/CD70, as Zach has covered in his prepared statement, this is highly differentiated program. that is endowed with the Dagger technology's that may enable ALLO-329 to work at low or no lymphodepletion. So in the ongoing study, the baseline case that we are testing is low lymphodepletion, which is essentially using cyclophosphamide only.

So standard lymphodepletion involves both cyclophosphamide and fludarabine. We took out the fludarabine altogether, and we lowered the cyclophosphamide dose to only 1 day infusion. So that is the baseline case that we are testing. And also, we are testing as part of the study, no lymphodepletion. So target product profile, we are trying to get to is providing a meaningful B-cell depletion that's leading to reset of the immune system. as cyclophosphamide along, I think that will be the base case.

And obviously, if we can get to that without any lymphodepletion, there will be a great win, not just for the field, but the patients and everything that people are trying to do with B-cell depletion in the autoimmune space.

Our next question comes from Salveen Richter with Goldman Sachs.

On the overall Cema-Cel market opportunity and commercial positioning as CD3 bispecifics move to the front line, this could influence MRD positivity rates or directly exclude patients from Cema-Cel eligibility. Just curious to get your thoughts on the evolving LBCL landscape and how you see Cema-Cel positioned long term?

Salveen, this is Zach. Great question. So it's been an interesting few years as these bispecifics have been approved in late lines and now are moving into front line. I think if the early Phase I data in untreated patients is consistent with the overall Phase III readouts, there is a likely outcome that a certain percentage of patients may be cured with these very intense upfront regimens. So there is a possibility that there will be fewer MRD-positive patients.

However, I think we very much need to wait for those final data before we begin to consider how the market opportunity may evolve and not just efficacy but also safety and the pace at which these complex and expensive regimens are taken up in the community. Our initial feedback is that not everybody is going to be lining up to be giving these very, very complex regimens that often require hospitalization for step-up dosing and so forth. So we're watching this space very carefully, but we believe that the MRD positivity rate is largely going to be unchanged for the next many years.

Our next question comes from Matt Phipps with William Blair.

The update on time line staying on track. When you look at that foresight CLARITY data that looks at rates of MRD positivity post R-CHOP, are there any patterns around higher-risk baseline characteristics such as double-hit, triple-hit genetics or is in the 4s or something that you see in those patients that don't reach MRD clearance? And maybe you can remind us how Cema-Cel performed in those types of subgroups in your previous relapsed/refractory trial?

Great question. This is Zach again. So absolutely, there does appear to be differential MRD positivity rates according to the baseline risk of patients, which is, of course, no surprise. The MRD positivity at the end of treatment is an extremely high risk for disease progression, and it is precisely disease progression that was used to generate those risk stratification tools. So it's very consistent that if you've got a high-risk disease at the time of diagnosis, you are more likely to be MRD positive at the end of frontline treatment. And of course, then you're more likely to experience a relapse.

So the beauty of ALPHA3, however, though, is that there are lots of examples out there where patients who even have low-risk disease turn up to be MRD positive at the end of treatment. And these are the patients that oncologists sort of -- it keeps oncologists up at night because you think that the patients are going to do very well and then they end up experience a relapse. So one of the things that we find so exciting about ALPHA3 is that everybody gets a shot at upfront cure, and we do the risk stratification at the end of treatment and then escalate care accordingly with the consolidation dose of Cema-Cel.

Looking back at our Phase I experience, we definitely saw good activity across the risk spectrum. So we do not anticipate there being gross disparities in the risk profile of these patients in the context of ALPHA3.

Our next question comes from Samantha Semenkow with Citi.

This is [ Ben ] on for Sam. Can you talk about expectations for the observation arm in the ALPHA3 study? What is the expected rate of spontaneous MRD conversion? And if there's any data you could help us to triangulate this?

Ben, this is Zach again. Great question. We get asked this one quite a lot. So we have long assumed that the number of patients who are clearing MRD without further treatment will be a non-zero number. We've modeled it about 20%. So in the 12-patient arm that we'll be revealing next month, we're talking about 2 to 3 patients that we expect to potentially have an MRD conversion from positive to negative. This comes back to the fact that no test in medicine is perfect. There are false positives and false negatives with every single test that you can perform, including PET scan.

In fact, one of the reasons that MRD is so exciting, and we believe will transform the care of these patients is because the false positive and false negative rates of the MRD test are significantly better than they are for PET scan. So this is why we are -- when we're talking about the efficacy that we hope to see in April next month is relative to the spontaneous clearance rates. So when we talk about 25% to 30% we expect that improvement over the baseline clearance rate because patients, of course, are eligible to spontaneously clear in both arms. So we should expect that 20% distributed in both arms.

As far as the data that we've used to model this goes, if you look at the publications around the test, the Foresight test, there is a group of about 20 patients, 20% of patients or so who are MRD positive at the end of frontline treatment who never go on to experience disease progression. So we've used that number to model the spontaneous clearance rate.

Our next question comes from Matthew Biegler with OpCo.

Wondering how you're thinking about label expansions here or if you'll need one to include other MRD assays. I know Adaptive has a test out there that's similar. And if so, kind of what kind of validation work would that entail?

Matt, Zach again here. So it's a really, really good question, and it's actually a very germane one because it's -- you're absolutely right. Adaptive has a test that's been on the market now for a few years. They're seeing rapid uptake across both academic and community centers. So we see this as strongly validating that MRD as a concept is going to become part of the standard of care. But they're not the only ones. Of course, Natera, who recently acquired Foresight also has a test called Signatera that is used for lymphoma.

So coming to your question, do we think that we will be restricted to use with Foresight, I think time will tell. I will say that in other areas of oncology where a diagnostic test has been required to determine eligibility for treatment. very rapidly, there is a proliferation of people using different tests to determine eligibility for targeted therapy, for example, without necessarily requiring a specific regulatory approval. So we are, of course, watching this very carefully, but we believe that there will be some ability to mix and match in a commercial context.

Our next question comes from Asthika Goonewardene with Truist.

Just a quick one for me. What proportion of the community centers that were treating patients on the ALPHA3 study had previously had auto CAR T and/or transplant capabilities? I'm just trying to tease out like as you roll this out into trial sites in the community where you had a substantial number of centers that is the first put in the CAR T rodeo with an allogeneic product.

As Zach again. So I want to make sure I understand the question. Are you asking how many patients in the ALPHA3 study have previously been treated with transplant or auto CAR?

Yes, looking specifically at the sites. I'm just wondering about your site adaptation and how -- if they didn't have any auto CAR T capabilities or transplant capabilities, if you were able to successfully bring them on board and have them set up for alloCAR T?

Got it. Yes. Okay. Great question. So the study is open in about 60 sites now in North America. We've said it's roughly 50-50 community and academic. Of the community practices, a subset of those are CAR T naive, so to speak. They've never given CAR T. They don't have a transplant program. And those centers are actively enrolling and treating patients in ALPHA3 using Cema-Cel as their very first CAR T that they've ever given to their patient.

And I can say that it has gone very smoothly at those centers, and we are seeing very good uptake, very good tolerability with the product. And because this is -- can be done bought at the bedside, administered in an infusion clinic, there isn't the need for the infrastructure or the dedicated team to manage autologous CAR T transplant. So we've been able to kind of slot right into how these clinics run their day-to-day infusions.

I'm just wondering, are you able to comment on maybe what proportion of the community setting community centers are these auto CAR T naive sites?

So I would say that I'm not going to be able to do that off the top of my head here. The sites that are listed on our clinicaltrials.gov, they're all listed out there by sites. We'll provide a little bit more information on this, Asthika, at the time of the data update next month.

Our next question comes from John Newman with Canaccord Genuity.

Just had a question on ALLO-329 in the Resolution 1 trial. Just curious when you present top line data, if you plan to present any data on not just depletion of CD19 positive B cells, but depletion of the CD70 positive T cells. And also curious as to roughly what type of a time point after treatment you're looking at presenting data.

John, let me give Zach a break and respond to your question. So ALLO-329, the resolution study in autoimmune indication, that study is progressing well. It is a dose escalation study. And as Zach had covered in the prepared remarks, we are starting at very conservative dose of 20 million cells just to safeguard the patients with a product that has never been tested in humans. So the study is ongoing. And at the time of the data analysis, many of the things and more, a lot of translational data, we have plans -- we are collecting the samples, and we have plans to analyze.

Probably at this point, it's too premature to go into details of time points of sample collection. But the data communication, which will be primarily focused on dose level 1, I mean, we believe that's about the time that we may come to treat all the dose level 1 patients and translational aspect of what we are seeing in the -- with the 20 million dose will be the focus of the data communication.

Our next question comes from Jack Allen with Baird.

This is [ Chris ] on for Jack. Just going back to ALPHA3, I was just curious if you can provide some more color on just the overall pace of enrollment for the study? And then just a follow-up to that. I know you're limited on how much you can share on an ongoing trial. But can you share whether the percentage of patients showing MRD positivity following R-CHOP is similar to your expectations heading into it?

Chris, Zach again. So we don't give kind of month-to-month updates on the pace of enrollment. We have said that we expect to complete enrollment in the trial by the end of 2027. So that is very much on track. And with respect to your second question, is the rate of MRD positivity consistent with our assumptions, the answer is yes.

Our next question comes from Brian Cheng with JPMorgan.

Just first, can you talk a little bit about the expectation for the top line? Will there be data to understand the trend of MRD clearance at several time points? Or will we only get MRD rate at one defined time point? And if that is the case, can you remind me what time point would that be?

Brian, Zach here. So as we've been saying for a few months now, we've kind of outlined how frequently we're monitoring these patients for MRD. So we start checking at 45 days post randomization, then again at 90 days and then every 3 months thereafter. As far as the data that we will share next month, we will not be giving kind of longitudinal MRD status patient by patient. So we will be giving really top line information how many patients cleared in the observation arm, how many patients cleared in the treatment arm.

Okay. And then just a follow-up. Can you talk about the variability then of MRD clearance that you expect across a longitudinal period when you look at this interim first cut of 24 patients?

Do you mean how many patients may fluctuate around? Is that what you mean?

Yes. Yes, just the variability based on the different time points. So let's say, if you take a look at the MRD rate at 25 days post randomization versus, let's say, 6 months down the line, do you expect some spontaneous positive to negative or vice versa between those time period? How do you think about the variability across these 24 patients?

Got it. Okay. So the first thing that you need to keep in mind is that when patients have relapsed with large B-cell lymphoma, it tends to happen pretty fast. The median time to disease progression from last dose of treatment is 6 months or less. And so MRD is highly predictive of relapse, highly prognostic test, very accurate. So we do not expect patients to spend a whole lot of time with very little MRD or MRD positive month after month after month. That's just generally not what happens in the majority of patients.

Of course, coming back to a previous question, this idea of false positivity, there are going to be a few patients who have this low level of MRD positivity that never spontaneously clears and who can go for a long time before they relapse. So I think we're going to get a bit of a mixed bag. But for the most part, these patients have very, very high-risk disease, and we expect them to be MRD positive and likely to have disease progression relatively quickly after their last dose of treatment.

And Brian, let me just sort of comment in additional comment. Our guidance on what would be a meaningful MRD clearance differential, 25% to 30% also factors in if there was some kind of variability due to assay, sample collection. So as I've said in the prepared remarks, we believe that the guidance that we have provided 25% to 30% is very conservative and factors in many different elements in situations like this.

And frankly, to Biren's question, the recent publication that again highlights a small difference in MRD clearance can translate to a very meaningful difference in the clinical outcome. I think that is very reassuring to us and really validates one of the key assumptions that went into providing that 25% to 30% guidance.

Our next question comes from Luca Issi with RBC.

This is [ Katy ] on for Luca, and congrats on all the progress and looking forward to data soon. We have a question on the statistical assumptions for Cema-Cel. Can you talk about for the fatality analysis in a scenario where the delta versus observation is 10% to 15% versus the 20% to 25% that you're hoping to see, which is closer to IMvigor011 versus LMA-7, would that prompt you to stop the trial? Again, I appreciate you're taking some of these details close to your vest. -- but any color on that is much appreciated. And maybe related to it, I think the trial is 220 patients, but you're looking at futility with just 24 patients. So what gives you the confidence that 24 patients is a large enough sample size?

Yes. So there are many layers of questions. Let me give Zach a break. This is Dave Chang. In terms of the futility aspect, I mean, usually, futility analysis gets done early on to see whether no hypothesis is in question, in which case study may be stopped for the lack of futility. I think we are a little bit past that point because earlier last year, because of unrelated event, we had to do an unplanned analysis of MRD clearance with a very few patients.

And from that data, which we have communicated where majority of the patients were converting into MRD negativity, we essentially have cleared the futility bar. So we have made some remarks about, in some ways, this interim futility analysis is a misnomer because it's really trying to get early signs of what's going on with MRD clearance. So that will be communicated.

With respect to the statistical aspect of the study powering and all that, those are the details that we haven't shared. And frankly, those are information that's better suited for when the study is complete and published providing all the details. So we will continue to be a little bit coy about not providing any statistical powering and assumptions behind the study.

But with respect to what the control arm versus the treatment arm, we may see, when we say 25% to 30% is absolute delta we are talking about. So if the control arm has baseline MRD clearance or MRD-positive patients going to MRD negativity for any reason at 15% to 20%, what we expect to see is in the treatment arm, that's 25% to 30% in addition to that 45% to 50%. So that's more or less what we have been sort of setting the bar for the futility analysis.

And I'm not showing any further questions at this time. I'd like to turn the call back over to management for any further remarks.

Well, thank you very much, and thank you for very pertinent and engaging questions. We said at the onset that cell therapy has entered a phase defined by evidence. That is where we intend to compete through data and disciplined execution and proof.

The questions facing the field is no longer theoretical. I would say they are practical questions. Can these therapies be delivered broadly? Can they move earlier in the disease course? Can they extend beyond highly specialized cell therapy centers? And can they do so in a way that is sustainable?

At Allogene, those are the questions we have been building towards from the beginning. With Cema-Cel, we are testing whether intervening at the point of molecular relapse can change the trajectory of disease. With ALLO-329, we are evaluating whether a purpose-built dual-targeted allogeneic CAR T can open a new chapter in autoimmune disease, one defined by scalability and accessibility. The coming year will not be about projections. It will be about proof. And with runway into the first quarter of 2028, we are positioned to execute with discipline and let the data guide what comes next. Thank you for your continued support.

Operator, you may now disconnect.

Thank you. Ladies and gentlemen, this does conclude today's presentation. You may now disconnect, and have a wonderful day.

Good afternoon, and thank you for joining our session of Citi's Virtual Oncology Leadership Summit. I'm Sam Semenkow, one of the senior biotech analysts here at Citi, and it's my pleasure to be hosting Allogene's CMO, Zach Roberts. Zach, welcome, and thank you so much for joining us today.

Thanks, Sam. Good to be here.

And if those listening live, if you have any questions during the session, please feel free to e-mail them to me at [email protected]. I'll be happy to ask them on your behalf or send them through the portal if you're watching through Velocity.

Okay. So Zach, it's great to have you here. We are rapidly nearing the first data for the ALPHA3 study. This is a major milestone for Allogene. Maybe just to set the stage, could you just share a bit about cema-cel, give a little background there, the design of the ALPHA3 study and a little bit about what data we're expecting in early 2Q?

Sure. So cema-cel is an off-the-shelf allogeneic CAR T cell targeting CD19. It has been in the clinic for a number of years now. The first Phase I study was run in the relapsed/refractory large B-cell lymphoma setting. So these are patients who are third line. And we saw very good results in that Phase I. We published in the Journal of Clinical Oncology last year, showing comparable efficacy to approved autologous products as well as similar, if not numerically improved safety, including CRS and ICANS.

In 2024, early 2024, we pivoted away from developing cema-cel in the third-line relapsed/refractory lymphoma setting and moved it into this novel frontline consolidation trial that we call ALPHA3. ALPHA3 is the first of its kind in lymphoma, and it's unique for a number of reasons, but it's extremely well tailored for an off-the-shelf onetime treatment like cema-cel. So the gist of the trial is patients, who are newly diagnosed with large B-cell lymphoma undergo standard frontline treatment. It's not part of the trial. This is just regular care that they receive with their oncologists, wherever that is, whether it's in the community or at an academic center or what have you.

And the patients who achieve a remission to that frontline regimen, which is about 90% or so, will undergo -- and this is part of the trial, will undergo an ultrasensitive minimal residual disease test that is based on a circulating tumor DNA. So it's a PCR-based test on blood. And this test is far more sensitive than the CAT scan that the patient has received to demonstrate their remission. And so if we find that these patients who are in remission have MRD in their blood, minimal residual disease, it means that there is residual tumor in these patients' bodies and that you just can't see on scan.

So what ALPHA3 is doing is this taking those patients who are MRD positive and therefore, at a very high likelihood of having a relapse and randomizing them to the current standard of care, which is just close observation, watching and waiting, which is what you would do for these patients normally, waiting for their disease to come back or whether you treat at that moment with cema-cel. So if you give a dose of cema-cel to those patients, while they're in remission, but remain MRD positive, can you improve their long-term outcomes. So that is the core premise of ALPHA3.

And we -- as I said, we think it's extremely well suited to this platform because it's like a seventh cycle of treatment. You just give the patients an additional round of therapy if they need it. And we -- as you pointed out, we're very excited because just around the corner in April, we're expecting our first look at data from this trial. And the specific data set that we will be examining and discussing publicly is whether or not we can eradicate or clear the minimal residual disease in these patients who receive cema-cel. So we'll be looking at the rate of clearance from MRD positive to negative in both the observation arm as well as in the cema-cel arm, and that data will be shared publicly.

Got it. Well, we're looking forward to that. So can you share a little bit about how you're thinking about the bar for success in the futility analysis? I'm wondering what comps did you use to help frame this bar? And any context into how you're thinking about how that should translate for the rest of the study?

Yes. So I mean, the first thing to consider is that MRD status is highly prognostic. So if you're MRD positive, chances are your disease is going to come back. If you're MRD negative, chances are very good that your disease is never going to come back. So except that sort of as why this futility analysis looking at MRD is being conducted in the first place because we do believe that if you clear your MRD, that means good things are ahead.

As far as what percentage of patients do we expect to clear their MRD in this upcoming analysis, we've settled on a 25% to 30% absolute difference between the 2 arms. And I call out the absolute difference intentionally because we do expect the MRD clearance in the observation arm to be nonzero. Historical data suggests that it's going to be around 20%. The number of patients in this analysis is 12 in each arm, 12 patients in the observation and 12 in the treatment arm. So 1 or 2 patients might clear their MRD spontaneously. That is fully expected. It doesn't mean that there's something wrong.

But we expect those same 10% to 12% -- sorry, 20%, 1 or 2 patients to clear in both arms. So we want to see a delta on top of that when we add the cema-cel. So that is what gives us this 25% to 30% improvement in MRD clearance. And why is that number important? First of all, you have to appreciate that if you look at this as a frontline study, which I think reasonably you can because these patients have not experienced a relapse.

Outcomes there have been remarkably stable since rituximab was added to CHOP in the early 2000s. And only very recently did we see somebody actually beating R-CHOP, and that was the POLIVY R-CHP regimen from the POLARIX trial. And when you actually dig into the details of that approved regimen, there was really only a modest improvement in outcomes, about a 6.5% absolute improvement in PFS at 2 years over R-CHOP.

What that translates to in sort of clinical practices is that you needed to treat 17 patients with Pola-R-CHP to prevent PFS event that you would have seen with R-CHOP alone. If you look at the second-line outcome, so -- and specifically looking at auto CAR trials, Yescarta versus transplant, Breyanzi versus transplant in the ZUMA-7 and TRANSFORM studies.

In those cases, about 30% delta -- there was about a 30% delta in the 2 arms, and those were both very, very positive trials. So -- and when I say delta, I mean, in response rates and complete remission rates and MRD is sort of a proxy for response rates. However, neither of those 2 examples incorporated MRD. So MRD use as an eligibility criteria for determining whether somebody should get treatment or not, this is a pretty new concept. ALPHA3 is actually one of the very first trials to be doing it.

However, we weren't the first. And there was actually a very interesting study that was just published a few months ago in the New England Journal, highly analogous study design, but in muscle invasive bladder cancer. So very, very high-risk bladder cancer patients. Like in ALPHA3, they underwent definitive frontline treatment, were in remission after, in this case, surgery, but they underwent an MRD test, very similar to the test that we're using in ALPHA3 and patients who are MRD positive were randomized to placebo versus additional treatment in this case with a checkpoint blocker.

And even though that was a very, very positive trial with respect to the primary endpoint, disease-free survival as well as overall survival, so likely a practice-changing finding here. In a post-hoc analysis, they went back and looked at the MRD clearance rate in these patients. And in that context, they only found an 11% delta. So 14% of patients in the placebo arm cleared their MRD as again, we expect some of our observation patients to clear MRD and 25% of the patients in the treatment arm cleared their MRD.

Even with that modest difference in MRD status, they saw a very, very positive trial outcome. So for all 3 of these data points, we think that 25% to 30% would be a very, very solid outcome for us at this upcoming analysis.

Great. Okay. That makes a lot of sense. And you talked a little bit about the observation arm and the rate of spontaneous clearance. Do you know what drives that? Is it a false positive on the test and those patients were never positive to begin with?

So there's probably a few reasons, Sam, that, that can happen, one of which is they are -- the test is correctly identifying mutant DNA, which is what we're looking for in tumor-specific DNA in circulation. However, that residual disease was left over from a tumor that was already cleared, right? Because this is cell-free DNA. These are not viable tumor cells that we're finding. We're just finding DNA fragments.

So there could be a real detection of mutant DNA, but that tumor is all dead. So there's -- that's a false positive. rarely, but it's nonzero. You can also be amplifying tumor that looks -- amplifying DNA that looks like tumor DNA, but it isn't. That is very, very uncommon, but it does happen with all tests. So there's a few reasons why you can end up with a false positive rate, which we have to account for.

Got it. Okay. And then what time points are you measuring MRD? I'm wondering if everyone will be from the same time point when you say they have or haven't cleared? Or are we going to see a little bit of trajectory of multiple time points? And I guess, is it the most recent test that you're evaluating them on? So how should we think about that going into the data?

Yes. So in order to avoid introducing a lot of bias because obviously, these patients are being enrolled kind of continuously, we're looking at everybody at the same time. And we picked a day that is -- we feel is a good time to look because there is some dynamism in the early days after cema-cel, but the day 45 is when we're looking at the first time post randomization, and it will be that data is that we share.

Got it. Okay. That's helpful and clear. And then to your point about the bladder cancer study that had a very modest delta for the MRD clearance rate, it being around 11%. I guess I'm wondering how do you think about what a true no-go scenario looks like, if you were to get something that is below 25% given the context that we have from that study and how it might transfer to the LBCL study.

So how -- what would a no-go scenario look like versus some intermediate study where you don't make that 25% bar, but it's less?

Yes, Sam, it's kind of tough to pin that down because I think it's going to come a little bit of the eye of the beholder here. And I mean the beholder can be Allogene, and we can look at this 11% from the IMvigor trial and say, oh, an 11% in ALPHA3 may still yield a very positive outcome. But we're not the only stakeholders here, right? And investigators are going to be looking at this data and trying to determine whether that is something that they want to put their patients on or whether they're going to take their chances and potentially just give them salvage therapy.

So I can't give you a number right now. It's probably something lower than 25% to 30%, but it would be surprising if we and the investigating community would tolerate 11%. But you never know. And so I think we're really anchoring to this 25% to 30%. We think it's achievable, and we think it would be -- if that translated to a 25% to 30% difference in EFS that, that would be a practice-changing finding that would really revolutionize lymphoma care.

Right. Okay. That makes sense. And to your point, I think at the beginning, cema-cel has been shown to have a higher response rate in patients that had lower tumor burden, which is exactly the type of patient, maybe even more so of what you're seeing in the ALPHA3. Is that accurate?

That is. So in that Phase I publication that we put out last year, we did a subgroup analysis and found that patients with low disease burden in that context. So these are not MRD patients, they're relapsed/refractory patients, but you obviously get a spectrum of disease burdens in a trial like that. You've got some patients with very, very bulky disease and then you've got some with just a little bit. And when we went back and looked at outcomes based on the disease burden by 2 different measures, sort of how much we can measure by scan as well as a blood marker that correlates with the disease burden, which is lactate dehydrogenase or LDH.

In both cases, we saw significantly better efficacy than in patients who had very bulky tumors. And we -- of course, we weren't the first to find this. This has been shown now repeatedly in autologous CAR T as well. And in fact, that -- those observations have already begun to change practice with people doing things like trying to actively debulk tumors, while the CAR T cells are being manufactured so that by the time you give your Yescarta or Breyanzi or Kymriah, the patient is starting with far less tumor than they would have been had you not done that because both safety and efficacy outcomes tend to be better in those patients. So that -- we've taken that obviously, to the logical extreme with the ALPHA3 trial and are treating patients with the minimal detectable disease that we can -- that you can imagine.

Right, right. Exactly. So we did have an investor question come through. They're asking, will you be providing any guidance on the safety profile during the futility analysis?

We do expect to provide some safety. It's likely not going to be exhaustive, but in order to kind of be balanced about efficacy and safety. And we know -- I mean, we've said for a long time that in this particular context, safety is a very important thing because these patients are in remission. So you don't want to be hospitalizing the patients for toxicity. You want this to be convenient. So if you can manage this being done as an outpatient as we're doing in ALPHA3, that's even better. So we'll share some additional color on safety as well as likely, where the patients in the trial are coming from. Are they coming from academic centers, they're coming from community centers, et cetera.

Got it. Okay. This investor is also asking about how you're thinking about the penetration of MRD testing in this setting? Are the majority of patients being treated in the community? And any commentary on community doc experiences that you're able to share now or if you'll be able to share it at the time of the readout?

Yes, we'll share some detail there. I can speak at a high level now, though. I mean, we've got about 50% or so of our clinical trial sites that are on ct.gov could be characterized as community practices. Some of those have never given CAR-T before. So they've opted out of autologous CAR-T products. They just don't offer them to their patients. These are patients who would otherwise need to be referred. So we do have several sites, large network practices who are treating patients with CAR-T for the first time. So in terms of the patient distributions and testing, it's about even. And then -- sorry, remind me the other 2 questions, Sam?

Yes. He was saying -- any experiences that you could share and do you have penetration of MRD testing?

Yes. So we're at the cutting edge here of MRD. I will say that the field is moving very quickly. And so we picked a diagnostic partner at the start of ALPHA3 based on the strength of their data. That was a private company, Foresight Diagnostics that had spun out of Stanford, and that was their data that really sort of sparked the ALPHA3 design. That company has since been acquired by Natera as of December of last year. And so there is an aggressive sort of push to get MRD testing into the lymphoma space.

I think it's beyond question at this point that the momentum is building extremely quickly, and we see established MRD tests like clonoSEQ by Adaptive Biotechnologies being undergoing rapid growth in the lymphoma practices across the country.

The reality is that this test is just a better test than PET/CT, which is what we've been using for decades. It gives better information to the patients and the doctors about what to expect from their disease. It's easier to do, right? You're not exposing the patient to radiation and booking scanner time. And so we think that this is going to revolutionize disease assessment. So penetration admittedly is on the low side now, but it's going to be growing very, very quickly just because it's an easier, better tool to provide information on prognosis.

Got it. That's super helpful. And then maybe just let's take a step back, sort of building on this. And can you just walk us through the patient journey from diagnosis to dosing with cema-cel? And I guess, how you think about that translating into real-world utilization as well?

Yes. So one of the beauties of ALPHA3 is that we are silent on those upfront decisions that are made by the clinician that are targeted to that individual patient in front of them. So patients who are diagnosed with large B-cell lymphoma come in all shapes and sizes from very, very sick patients who end up in an emergency room somewhere and are diagnosed and treated with their first cycle in the hospital because they're so sick versus patients, who are diagnosed with relatively slow-growing disease, low burden in the outpatient context.

Those clinicians and patients can make decisions to treat those patients completely without thinking about ALPHA3 or MRD testing, you pick a regimen that suits the patient in that moment. About 2/3 of these patients, generally speaking, across the board, will be cured with that frontline therapy. And one of the reasons why MRD testing is going to grow rapidly in this space is if you're MRD negative at the end of treatment, you are about 90% sure that you're never going to experience a relapse. So this is highly valuable information for these patients.

And indeed, in the context of ALPHA3, about 4 out of 5 patients that we test are MRD negative. And that's great news. It's great news for the doctor. It's great news for the patients. About 1 in 5 that we're testing are coming back positive. So in this context then, if you complete frontline treatment, you get your MRD test and you're found to be positive, then you are screened for ALPHA3, very straightforward eligibility criteria. And then if you test in and agree to participate, then you are randomized to either close observation, which is what you would currently get.

There's no treatment decision right now that's approved that's based on MRD status alone or you are randomized to the cema-cel treatment. The cema-cel treatment is -- comes with a standard lymphodepletion or conditioning regimen that's comprised of fludarabine and cytoxan, the standard regimen that is given for CAR T cells in other contexts and then a single infusion of cema-cel.

It is entirely up to the patient and the doctor to do this inpatient or outpatient. Majority of patients are being managed fully as outpatients. Both the lymphodepletion as well as the cema-cel infusion can be done in infusion clinics and the patient is sent home. And then in both cases, observation or cema-cel treatment, then you enter routine follow-up to assess for safety outcomes as well as disease recurrence.

Got it. Okay. And then how has enrollment been progressing? I think maybe this time last year, you had implemented a few changes in how you went about screening. I'm wondering, are you seeing any remaining bottlenecks across your sites? Or have you largely worked through those challenges that you previously identified?

We've largely worked through them. And just to kind of provide a little bit more background on that, you're absolutely correct. It was just about a year ago now that we made an adjustment to the expected completion of enrollment time line based on a slower-than-expected start to enrollment.

And there's quite a few reasons, and I won't belabor them all here, but they can all be summarized in a nutshell, which is the patients that are being screened for MRD and consented for the MRD test itself, which is the first step to get into ALPHA3. These patients are just generally not thought of to be clinical trial patients in the first place, right?

They're getting a standard regimen. They're doing well, right? By definition, they're in remission at the end. And so it was sort of an additional piece of the workflow for -- to get the clinicians to think, oh, I should address this very healthy patient in remission with a potential clinical trial option. It just -- it took a little bit of training and muscle memory to be built up to do that. But once that was established and we sort of crafted materials to help train doctors to inform patients on the value of the MRD testing. Once that kind of took hold, it really changed the game, and now it's being done quite routinely for all potentially eligible patients in these practices. And again, we're agnostic on frontline regimen.

As long as they're not on a clinical trial or receiving some experimental regimen, any regimen is potentially eligible for ALPHA3. So these patients are being approached now routinely.

And so we've taken these best practices and now are applying them to all the new sites that are onboarding. So we really have, as I said, largely solved some of those initial challenges that were just due to the fact that this is a very novel study design.

Got it. That's great to hear. And do you think that given that, that you'll have a bit of a better sense of when you might have some of that final EFS readout timing? And is that something we could hear about during the futility analysis readout?

Yes. So we do expect to provide a little more detail on the time line for the upcoming efficacy analyses. And it's not just the primary. We actually have an interim EFS analysis as well. That's not the futility analysis that we're talking about for this coming April, but it will occur later. And we'll provide more detail on that when we share the interim futility data. We are saying, however, that we are on track to complete enrollment by the end of next year.

But because these patients with MRD-positive disease tend to progress very quickly, we expect that -- those events to come in fairly rapidly. So we expect relative near-term EFS data in both the interim analysis as well as the primary, but more details to come.

Got it. That was going to be my next question. How long does it generally take for an MRD-positive patient to relapse in this setting?

Yes. So it can be very, very fast. And there's obviously a Kaplan-Meier curve associated with this and about 1/3 of the patients are going to progress within 3 months or so. Median time is about 6 months or less from their last dose of chemo. So this really is kind of an emergency, if you think of it that way and trying to prevent the relapses which comes back to, again, what makes cema-cel such a uniquely well-positioned product to treat MRD disease because there's no waiting. You don't need to apheres a patient and wait for manufacturing. Many of those patients, if you were to try to do this with an autologous product, would end up progressing during manufacturing, which, of course, is the whole premise of ALPHA3 is to prevent that relapse.

Similarly, if you try to do it with a bispecific or something else, you end up putting patients on more chronic therapy, which from the day of their diagnosis, they've been told by probably multiple people that they have a curable malignancy. And if they achieve remission at the end of 6 cycles, they're good to go. And then you do this blood test and then you say, okay, well, I've got another 6 or 12 months of treatment to give you. A lot of patients aren't going to be okay with that. Whereas with cema-cel, you just -- it's an off-the-shelf product, you give it to them, it's one and done and you move on. So it's a lot more attractive.

Right. No, definitely. And then in the prior question and response, you mentioned the interim EFS analysis. Remind me, is that something you plan to share with the Street? Or would that be more of an internal check?

So I think stand by for more detail on that one, Sam. Obviously, I think as we get closer to that and a lot can change between now and then. So I think probably better for me to defer answering that question directly until we've got the interim futility analysis in just a few weeks.

Got it. Okay. TBD. And then just sticking with the EFS theme, can you just speak to, I guess, how predictive MRD negative is to maintaining EFS? And just share a little bit more about how you're thinking about that 25% to 30% will actually -- or MRD clearance rate will actually translate into that stat. I mean, based on the Kaplan-Meier curves we've seen based on MRD status, it seems pretty clear. Is that what we should be looking at and how we're thinking about probability of success if you achieve this?

I think that's very fair, Sam. The whole value proposition of this MRD test is that it gives you good prognostic information. And that -- the frontline MRD test is highly prognostic. That's in our corporate deck. But it's also been looked at in the second line post CAR-T. It's been looked at the third line post CAR-T.

And no matter where you look, if you clear MRD from positive to negative, it tends to mean that you are cured. Now it's not 100%, of course, right? And some patients who do clear MRD end up having a relapse at some point in the future. I mean no test is perfect. But by and large, it correlates highly with long-term disease outcomes.

Yes. No. Okay. That makes a lot of sense. And so then one of the questions I've gotten a few times actually over the last couple of weeks is why wouldn't the MRD clearance rate for cema-cel be higher than that 25% to 30% delta? If you're expecting 20% in the observation arm, give or take, why wouldn't it be more than that 45% to 50% in the cema-cel arm?

Yes. Look, to be very clear, we would love it to be more. Obviously, we would love it to be everybody, right? The whole point is we're trying to cure patients with ALPHA3. And the more patients that we can cure the better. However, cancer is a formidable enemy, right? And these patients -- some of these patients, unfortunately, are destined to die of lymphoma no matter what we, Allogene, their doctor, anybody else does about it, right?

I mean even if you look at autologous CAR T in the second line, it's still better than even odds that if you get Yescarta, Breyanzi, that you will have a disease progression and will die of lymphoma. I mean the long-term disease control in those trials was 40% or so. So some of these patients just have bad disease biology, and we have to account for that. Do we think that we have stacked the deck in favor of this intervention to eradicate that minimal disease?

Of course, that's why we designed the study the way we did because the tumor is almost gone. It's just not quite. So we think that we put these patients and cema-cel in a good position here. But we have to wait for the data and to come back and think, all right, what does good look like here?

It's not -- it shouldn't be based on some hypothetical around, well, cema-cel should do better than this. We should really anchor to the clinical outcomes that are already there. And 25% to 30% improvement in cure in frontline would be transformational. That would be something that has not happened since rituximab was added to CHOP. So that's something that we are anchoring to, we think, would be really great. If it's 50%, you'll hear me shouting from the rooftops.

Yes, absolutely. And that's a good comp, I guess, to the rituximab piece. It's a good way to think about it.

Okay. So let's say that it is a positive study. And I mean that like on the EFS primary endpoint. So down the road, how do you envision the commercial launch looking? Do you have some strategies in place for increasing MRD testing? I feel like you've already kind of done that from your trial sites. Is that something you can extrapolate out to a more broad setting and how you're educating the sites? And how do you think about administering or convincing physicians to administer cema-cel to their patients?

Yes. So I mean the short answer, Sam, is it's all going to depend on the data. And the premise of your question is that we have a positive study, so let's work with that. The big question is how plentiful will these MRD-positive patients be? Now the answer to that question is we expect about 30% of patients, who achieve a remission to be MRD positive. Maybe not all of them will be positive on the first test. So as I mentioned earlier, we're seeing about 20% MRD positivity. That is because there are some patients who actually are below the limited detection on that first test at day 45. But at some point down the road, they end up above the limit of detection and are MRD positive, but have not yet relapsed.

We envision as is already being done with the approved MRD test for lymphoma, that these patients will be tested serially after they complete frontline. In fact, some of these patients have been tested over the course of frontline as well because that has been shown to be prognostic too. If you have a big reduction in your MRD level during treatment, that tends to mean that you're on a better trajectory than if you don't.

So these patients are going to be monitored serially. So we will be able to catch these patients at the MRD positive yet still in remission stage across the board. So that will get us to that 30%. The launch of the various MRD tests is going to be important here. And we often -- we originally did get some questions around, well, you've picked this test that is being developed by a small private biotech that is just sort of finding its footing.

Was that -- is that the best thing to think about commercialization? At Allogene, we like to think of ourselves as very science-focused and we follow the data where it is, and they had the best data as we were designing the ALPHA3 study. I think that commercial overhang for the launch has largely been taken off the table since Natera acquired Foresight in December. And obviously, Natera is a huge player, probably the world's dominant player in minimal residual disease testing. And we expect them to be quite aggressive in promoting MRD testing.

And we think the data absolutely supports it. So by the time ALPHA3 is read out and is positive and is FDA approved, of course, lots of wood to chop between here and then. But the premise of your question is that's where we'll be. We expect MRD testing to be done pretty much for every patient. And as of now, we are still the only trial that is pegging a clinical decision on the result of the MRD test.

So we may be the only therapy that's available to patients who are MRD positive, not yet experiencing clinical relapse. So we kind of have a wide open path for a commercial launch here. At least that's how we see it at this time.

Got it. Okay. And I have another investor question here. They're asking about a doctor's willingness to use cema-cel ahead of autologous CAR T or bispecifics. And let me expand the question even further. How do you think about competition from CAR-Ts that are in trials now for first-line large B-cell lymphoma 2-parter?

Yes. So I'll take the second one first. So there are -- there's really only one trial that's open currently for patients who are newly diagnosed. That is a study that is focused on the highest-risk lymphoma patients and these -- when I say highest risk, I mean, when a patient is newly diagnosed with DLBCL or other large B-cell lymphomas, there is a set of tools that we can use to risk stratify your likelihood of having bad disease versus curable disease.

And the frontline studies in -- with CAR T cells or even other highly intense regimens like bispecifics are only focusing on the subgroup of patients, who at diagnosis look to be high risk. Some of the issues with that concept is these -- while validated, these upfront risk stratification tools are notoriously imperfect.

And a patient who looks to be very high risk on day 1 actually does extremely well with R-CHOP and is cured. And then the other end of the spectrum is also true that you have a patient who by these risk stratification tools looks to be low risk, and they're the ones who have primary refractory disease and end up having a horrible outcome. So one of the great things about ALPHA3 is that we don't really pay attention to those upfront risk stratification tools.

We let everybody get their risk stratification at the end using an actual test that is binary. If you're positive, you're high risk, if you're negative, you're low risk. So we think that in terms of attractiveness to an everyday clinician, an ALPHA3 type approach is going to be more attractive than that sort of upfront giving somebody CAR T that may actually do just fine with a standard regimen.

Of course, we are also being able to do this in the community, whereas in the context of autologous CAR T that just isn't happening at any appreciable level. So 80% of patients with newly diagnosed lymphoma are treated in the community. And we -- by our product design and attributes, we're able to target those patients, whereas that's not the case for autologous. And then remind me the other part of the question, Sam, sorry.

Just the willingness to use cema-cel ahead of autologous CAR T and I assume in the relapse setting or bispecifics.

Yes. So I think if I'm being totally honest, I think every clinician is going to have to make that determination on their own. I think if you are practicing at a major academic institution and you've got ready access to autologous products and you're reasonably confident that if a patient progresses, you can rapidly administer safely with good efficacy outcomes, autologous CAR T, maybe you'll wait. I do think that, that's an awful lot to ask of the patient. If you have conducted this MRD test, as I expect everyone will have an MRD test done eventually.

And then it comes back positive and you tell the patient, okay, well, we're just going to sit on this and wait for your disease to come back and hope it doesn't come back in your brain or some other horrible situation that is going to make autologous CAR T a little tricky versus giving you something that we can do right now as an outpatient and hopefully, that does the trick.

So ultimately, it's going to come down to the data. And if that 25% to 30% holds and we have a positive EFS outcome in the end, I think it's going to be hard-pressed for clinicians to say, I'm just going to wait to give Yescarta if the cema-cel data looks positive. It just -- it's going to be an easier product to give and right in line with the frontline treatment. It's just -- it's more amenable to sort of everyday practice and better for the patients in my view.

Got it. Yes, that makes a lot of sense. Okay. So then we only have a couple of minutes left. Maybe Zach, you could just recap expectations for everyone ahead of the futility readout and any other closing remarks that you wanted to share?

Yes. I mean I think all eyes are on this upcoming futility analysis. It's expected in April. And we -- for all the reasons that we've discussed, Sam, we think it's going to be a really meaningful update. And even though we refer to it as a futility analysis, we actually think that this is going to be a highly derisking data set for the overall study. And the other thing that I just want to leave everybody with is Allogene set out 7 or 8 years ago with a vision to revolutionize the way CAR-T is given. And originally, that was focused on the fact that this was off-the-shelf and allogeneic.

And of course, that still applies. But what ALPHA3 really represents is an evolution in that in our belief and how we can change practice. And being able to treat patients before they relapse to drive up that cure rate is really something that cema-cel, we believe, is very uniquely set up to do.

And so we're terribly excited about this upcoming futility analysis to see whether we're on the right track here and hopefully, one step closer to making a big difference for patients across the treatment spectrum, not just in academic centers or ATCs, but right where they're diagnosed with their local oncologists, this really will be a revolution for patients.

Got it. Absolutely. And I share your excitement looking forward to the data. Well, thank you so much, Zach. This has been wonderful, incredibly informative, and I really thank you for your time here today. Operator, with that, we can go ahead and close the call.

Hello, and thank you for standing by. Welcome to Allogene Therapeutics Third Quarter 2025 Conference Call. [Operator Instructions] 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.

Thank you, operator, and welcome, everyone, to Allogene's Third Quarter 2025 Conference Call. After the market closed, Allogene issued a press release that provided a business update and financial results for the third quarter of 2025. 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 the 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, Christine. This quarter has been about conviction, conviction in our science in the path we have chosen and in the future we are building for patients. We are aware of the shifting conversation in the field. Every new modality brings excitement and speculation about what the future might hold. But true innovation isn't about chasing what's next. It is about delivering what patients need now. And if a platform can safely, effectively and at scale deliver curative therapies, it doesn't just shape the future. It redefines it.

At Allogene, our focus has never wavered. We are advancing the platform we believe is not only essential to making cell therapies accessible and scalable, but one that could fundamentally and the current paradigm and even the one others are still imagining by making the promise of curative onetime off-the-shelf cell therapy a reality today. And that's exactly what allogeneic cell therapy represents. It's not a breach to something else. It is the foundation. Allogeneic technology delivers the scalable backbone needed to democratize access, reduce the overall cost of care and bring transformative and potentially curative treatment to far more patients than ever before.

We expect allogeneic therapy to be central across oncology and autoimmune disease because it combines the precision and power of autologous with a flexible, efficient and commercially viable model, no other approach can. Its capacity for multiplex gene engineering allows the creation of future platform products within a single cell, an advance that we believe will be critical for addressing complex cancers, including solid tumors. This is an incremental progress. It's a leap forward that reshapes what's possible. We have done the hard work to make the future real.

Our leadership in manufacturing, translational science and clinical development positions Allogene to endure and lead, setting the standard for how cell therapy can be delivered at scale and with impact. Each of our programs, cema-cel, ALLO-329 and ALLO-316 reflects that strategy to make cell therapy scalable, practical, successful and in some cases, curative. At Allogene, we are not waiting for the future of cell therapy. We are creating it with conviction, with data and with a platform built for lasting impact.

As we move into next year, we are preparing for what we expect to be a defining moment with pivotal interim data from cema-cel in the ALPHA3 trial in first-line consolidation and proof of concept from ALLO-329 in autoimmune disease, both milestones that we believe will shape the next era of cell therapy. With that, I'll now turn it to Zach to share updates on our R&D progress.

Thanks, David. Our programs this quarter continue to demonstrate the conviction David spoke of, conviction in our science and our execution and the discipline required to advance truly innovative medicines. Across ALPHA3, Resolution and Traverse, we're driving forward a portfolio that spans earlier line lymphoma, autoimmune disease and solid tumors. Each is a distinct challenge, but together a unified demonstration of the strength and versatility of our allogeneic platform.

In ALPHA3, our pivotal trial of cema-cel has now been streamlined into a 2-arm randomized study comparing treatment after standard Fc lymphodepletion versus observation. This structure balances efficacy, safety and scalability, which are critical for translating CAR-T therapy into earlier lines of treatment. We are now at more than 50 active sites across the U.S. and Canada with expansion into Australia and South Korea expected early next year. The planned futility analysis focused on MRD conversion remains on track for the first half of 2026. A positive outcome would not only demonstrate disease modification in earlier line lymphoma, it would also mark a key step toward a potential BLA submission.

As we look ahead to the upcoming futility analysis and the questions we often get about what success looks like at this stage, there are 2 key benchmarks worth keeping in mind. The first is the pivotal POLARIX study, and the second is the recent IMvigGor-11 trial in bladder cancer, which is highly analogous to what we're doing with ALPHA3. The POLARIX study, which evaluated polatuzumab plus chemoimmunotherapy in frontline DLBCL demonstrated a modest 7% improvement in progression-free survival over standard treatment. That result alone underscores how much opportunity remains for meaningful progress and the transformative potential of ALPHA3. While ALPHA3 is the first study of its kind in LBCL, the concept of consolidating remission in patients at high risk of relapse has guided adjuvant trials in solid tumors for decades. Highly sensitive MRD tests are emerging as powerful tools to identify patients at greatest risk of progression.

The recent data from the IMvigor 11 trial in bladder cancer is a powerful illustration of this approach. Patients with no evidence of disease after definitive frontline treatment, in this case, surgery, underwent a ctDNA-based MRD test. Those who are ctDNA positive while in remission were randomized to immunotherapy or placebo. Notably, ctDNA clearance differed by only 11% between arms at cycles 3 or 5, yet both the primary endpoint of disease-free survival and the key secondary endpoint of overall survival were statistically significant, representing a potentially practice-changing advance. While every study is different, the new IMvigor 11 data provides a valuable analog for illustrating the potential impact of this kind of approach. Achieving an approximately 30% delta between cema-cel and observation would represent the largest improvement in lymphoma outcomes since the approval of rituximab. Given these reference points, we believe our study is well positioned to deliver a highly meaningful difference and the potential for a successful trial outcome. Together, these insights reinforce our confidence in the strength of the ALPHA3 program and its potential to meaningfully advance lymphoma treatment.

As we look beyond cema-cel, our Dagger technology continues to demonstrate its value across indications. In the TRAVERSE trial, the Dagger technology enabled ALLO-316 produced durable responses in nearly 1/3 of patients with metastatic kidney cancer and high CD70 expression. These responses following standard Flu/Cy and a single infusion of ALLO-316 highlight the built-in lymphodepletion advantage of the Dagger technology, enabling best-in-class CAR T cell expansion in solid tumors.

The TRAVERSE trial provided important insights that helped shape the design of our dual CD19/CD70 construct in autoimmune disease. Rather than repurposing a construct from another indication, we set out to create something truly fit for purpose designed from the start with a long-term application in mind for autoimmune disease and the patients who would be treated. We were the first to engineer CAR specifically for this setting, pairing dual targeting with our Dagger technology to achieve intrinsic built-in lymphodepletion through selective immune modulation. ALLO-329 is a first-in-class allogeneic CD19, CD70 dual CAR T product designed to target both CD19-positive B cells and CD70-positive activated T cells, which are key drivers of autoimmune disease. This approach is intended to simplify administration, improve tolerability and extend the reach of CAR-T therapy to a much broader patient population. If successful, it could represent a step change in the treatment of immune-mediated diseases.

That is what we aim to achieve in the resolution study, our Phase I basket trial in autoimmune disease, which is now enrolling for lupus, myositis and scleroderma. We expect to report translationally important biomarker and early proof-of-concept data in the first half of 2026. Dave and I spend a great deal of time in the field of investigators. Their enthusiasm remains strong because they see how these studies could fundamentally change the accessibility of cell therapy. By enabling treatment delivery within community networks where most patients receive care, we are aligning with how these institutions operate clinically and economically. This model reduces referral barriers, simplifies logistics and supports sustainable integration of advanced therapies into routine practice.

Clinical development is complex. We compete for patients, particularly in autoimmune indications and face both scientific and operational challenges. But each challenge strengthens our understanding and sharpens our execution. That is the nature of innovation, iterative, demanding and grounded in data. Collectively, our programs underscore that allogeneic CAR T is not an iteration. We believe it is the foundation upon which the next generation of cell therapy will be built. The science continues to advance. The early signals remain strong, and our focus is on turning that progress into real-world impact for patients. With that, I'll hand the call over to Geoff.

Thank you, Zach. The operational and scientific progress that David and Zach described is backed by a strong financial foundation and disciplined capital management. Our focus remains on advancing our clinical priorities while maintaining flexibility to capture long-term value for shareholders.

As of September 30, 2025, we had $277.1 million in cash, cash equivalents and investments. Our disciplined approach to resource management continues to support a cash runway that extends into the second half of 2027. R&D expenses for the third quarter were $31.2 million, including $2.8 million of noncash stock-based compensation. G&A expenses for Q3 2025 were $13.7 million, including $5.9 million in noncash stock-based compensation. Net loss for third quarter was $41.4 million or $0.19 per share, including noncash stock-based compensation expense of $8.7 million. We continue to expect 2025 cash burn of approximately $150 million and full year GAAP operating expenses of approximately $230 million, which includes an estimated noncash stock-based compensation expense of approximately $45 million.

This guidance excludes any impact from potential business development activities. The impact of our allogeneic platform extends well beyond our disciplined cost structure. By manufacturing product in advance and at scale, we lay the groundwork for a more efficient and sustainable model for the broader health care system. Allogeneic therapies have the potential to meaningfully lower the overall cost of care for cell therapy, expand access beyond specialized centers and make transformative cell therapies available to patients in a way that is both clinically practical and economically viable. With important clinical catalysts on the horizon and a solid financial foundation, we remain confident in our ability to execute and deliver on the opportunities ahead. We will now open the call for questions.

[Operator Instructions] Our first question comes from the line of Salveen Richter with Goldman Sachs.

For the futility analysis in the first half of next year, could you see any data beyond MRD conversion? And can you just expand on the 30% bar that you commented on? And then just remind us how enrollment is progressing for ALPHA3 and whether you've seen any changes post discontinuation of the FCA LD arm earlier in the year?

Salveen, this is Zach. I'll go ahead and answer that one. So for the first part of your question, will we be sharing anything additional besides the MRD conversion. At this time, we plan to really focus on the MRD conversion. This is not an interim analysis in which we intend to allocate alpha. So we really are looking at this MRD conversion and not any of the primary endpoints for efficacy. As far as the 30% bar that we mentioned in the prepared remarks, I think we went into some detail as to why we think that, that would be a pretty significant win for cema-cel in that trial with the benchmarks of the POLARIX data showing a 7% improvement in PFS in frontline lymphoma and then sort of looping in some recent data that was published from an analogous trial in bladder cancer, showing an 11% MRD clearance in that clinical context, yet still having a significant primary endpoint win on disease-free survival as well as an overall survival win there. So we think that 30% would be a pretty strong showing for cema-cel as it pertains to the MRD clearance rate.

And then I think the third part of your question, Salveen, was around enrollment. And we'll say -- I'll reiterate here that we're on track for our -- the interim analysis, the futility analysis in the first half of next year. As far as impact of the study conduct change when we had the grade 5 event over the summer and went to a 2 arm as instead of a 3 arm, I think the general view of the investigators is that they are pleased to be working with a regimen that they consider a standard in CAR-T and not having to use an additional component with the CD52 antibody. So it appears as though that has had a slight uptick in terms of the patient screening for this trial.

Our next question comes from the line of Tyler Van Buren with TD Cowen.

This is Sam on for Tyler. Just for the over 50 U.S. and Canada active sites, what percent of these have made it through that initial internal setup period and are now able to start actively enrolling patients?

Sam, this is Zach again. We have gotten a lot better at forecasting how long that internal setup takes as well as sort of incorporating that into our time lines. So I would say that of the over 50 that are active, it's going to be close to all of them that are open to enrollment. Only the most recently activated sites might still have a few remaining things that they need to do before they switch on. But for the most part, all 50 of those 50-plus are actively screening and enrolling patients.

Our next question comes from the line of Jack Allen with Baird.

Congrats to the team on the progress made over the course of the quarter. I guess I'll ask one on the autoimmune program with 329. It seems like that's starting to get off the ground here, and you're going to have an update in the first half of next year. I just wanted to hear any updated thoughts you have around the size and breadth of the data set we should expect next year from that program.

Chad, this is David Chang. Let me take that question, giving Zach a little bit of break. In terms of the scope of that data communication, as we have previously said, there will be a handful of patients where we can show biomarker as well as the early clinical responses. So that's the extent of it. And frankly, what we have seen with autologous programs is a handful of patients are sufficient to really understand what's going on with the CAR-T therapy. So we are hoping that the initial communication early first half of next year will be a very meaningful communication.

Our next question comes from the line of Sami Corin with William Blair.

On the progress I'm curious how many patients have consented for MRD testing now in ALPHA3 and if you're seeing the expected rate of MRD positivity that you initially theorized you'd see?

Sami, it's Zach. So I don't think we have -- since we made that update earlier this year around the number of patients who had consented, we haven't really been providing kind of regular updates on that. I can say, generally speaking, that the pace of consenting has at least held steady since that early part of the year. So we're really growing numbers. And as far as the MRD positive rate goes, it is holding steady to our assumptions.

Our next question comes from the line of with Asthika from Truist.

This is Karina. So Caribou recently reported that their allogeneic CAR T product derived from younger donors demonstrated improved durability. Have you observed similar associations in your experience?

Carina, let me take that question. Yes, we follow Caribou and in terms of their recent announcement of the result looks pretty encouraging. But in terms of the material, I mean this is something that we have been following pretty closely, and we have a good way to identify the exciting materials that will result in very potent and consistent products.

Our next question comes from the line of Samantha Semenkow from Citi.

Another one on the autoimmune program. I'm wondering, there's some recent data in the autologous space in pemphigus where there was no lymphodepletion in that trial that showed some pretty encouraging results. I'm wondering if there's any read-through that you can take into your program. Obviously, you have the CD70 CAR as well. But I'm curious if this increases your optimism on showing pretty robust efficacy without lymphodepletion.

Samantha, Dave here. Thanks for that great question. I have to say that what we are seeing in both autologous CAR-T therapy, so obviously, autologous and allogeneic, there are different issues. But what we have seen just gives us even higher confidence that ALLO-329. This is CD19 dual CAR that has built-in lymphodepleting capability that ALLO-329 in the low-volume setting, such as in the autoimmune disease setting where it targets essentially the resident B cells and activated T cells, it will work well without the lymphodepletion. Obviously, we have to show that. And just as a reminder, in the ongoing study, we will be testing 2 different cohorts, one with a reduced lymphodepletion. So this is just with the cyclophosphamide alone. And the second cohort will be without any lymphodepletion.

Our next question comes from the line of John Newman with Canaccord.

So David, given that 329 is pretty unique in that it targets both B cells and activated T cells, I'm wondering, in the initial data readout, will you be able to get a look at the phenotype of the remaining T cells, just to see if perhaps there's anything left after you hopefully wipe out all the CD70-positive T cells.

John, I think that's definitely something that we are looking -- we will be looking at, but I think it will be -- now that's also going into very nuanced questions about how the CD70 is working. I mean we certainly have looked at the fraction of CD70 positive versus CD70 negative T cells. And keep in mind, most plascent T cells are CD70 negative and are not affected by ALLO-329. And there's a real benefit of just eliminating activated T cells and activated T cells here potentially those that are contributing to the autoimmune disease itself as well as our reactive T cells. So in terms of how much data we will be sharing when we announce the proof-of-concept data in the first half of 2026, -- let me not go too much into that, but the question is really very relevant, and we will certainly be looking at CD70 positive and CD70 negative fractures.

Our next question comes from the line of Clara Dong with Jefferies -- our next question comes from the line of Reni Benjamin with Citizens Bank.

Also for ALLO-329, -- when you talk about the biomarker data, David, are there any in particular that would alert you to achieving a B-cell reset? And when we get those results, will the results be robust enough that it can help you, help us as an analyst and decide which indications you might move forward with?

Yes. Great question. I mean there are 2 parts to your question. One is whether the biomarker data will give us a lot of insight about how AL-329 is working. Having seen most of the data that's coming out in this space from a CAR T, I do believe that the biomarker data will be very meaningful. But also, we intend to show some early clinical responses depending on how long the patient has been followed up. So when we communicate the proof-of-concept data in the first half of 2026, it will be more than just a biomarker. There will be early sort of clinical responses that may corroborate with what we see in the biomarker data.

The second question to me is probably the most fascinating one. And if anything, I believe that we have probably very broad indications that we can potentially consider. The fact that 329 targets both CD19 and CD70 really allows us to not just think about those autoimmune disorders that are heavily B cell driven, but also autoimmune diseases that are very T cell dependent or has a big T cell component. So essentially from the rheumatology indications to neurology indications such as multiple sclerosis or even metabolic indications such as type 1 diabetes, and it could be considered. So stay tuned.

Our next question comes from the line of Brian Chen with JP Morgan.

This is Ron on for Brian. Can you talk about your level of confidence in the MRD conversion to event-free survival? And then when you said around 30% MRD conversion as the bar, can you clarify a bit on the time point that is going to be meaningful for LBCL? And then how soon dosing do you think we can reach that level of conversion? Zach, do you want to take that question?

Yes, I can take that question. So Ron, I may need to have you repeat 1 or 2 of them. But I think the first question was how confident are we in the prognostic value of MRD conversion as it relates to the study endpoints, I would say we're pretty confident, high confidence actually, given everything that we know about the performance of this assay after frontline, which was recently published in JCO as well as after CAR-T has been shown at ASH a couple of years in a row. The test seems to be pretty good and actually correlating with long-term outcomes. Can you repeat the next 2 questions? I heard the second one, but I didn't hear the third one.

Yes, of course. Sorry. When you said the bar you said of 30% MRD conversion, can you clarify a bit on the time point that's going to be meaningful for LBCL? And then how soon after dosing do you think we can reach that level?

I see. Okay. So yes, the 30% that we've been talking about, I think we've provided some context already on this call why we picked that number. I mean another way to look at that is that's equivalent or maybe even slightly better than what rituximab brought when it was added to CHOP. So if the MRD conversion is roughly predictive of clinical endpoints, as I just described, I think it is, that would be a pretty significant win. Some might even call a home run. As far as the time point goes, we haven't gone into detail around what exactly -- what time we're drawing these MRD results. But what I can say is that is a pretty dynamic test, meaning that it goes up fast and it goes down fast. And so we are able to assess MRD relatively soon after the CAR-T is infused. Again, we haven't specified exactly what that time point is. But we are pretty confident that the time point that we selected is going to be predictive for the clinical outcomes.

Our next question comes from the line of Luca Issin with RBC Capital Markets.

This is Catia on for Luca. Congrats on the progress this quarter. And if I can push on the last question on the timing of analysis for MRD. Is the futility study for stopping the trial as MRD is below your bar of 30%. And I think you mentioned the last time the 30% MRD bar is partially based on other autologous CAR-Ts objective response rate. And correct me here, if I'm not understanding this correctly, but that is from a potentially much longer follow-up. So is there a chance that you see insufficient MRD at your futility analysis first half next year, but we'll probably just have to give it more time. Any color there much appreciated.

Yes. Let me take that question. I think there are some questions still around what would look good for the study. And in terms of the MRD conversion, which is the primary -- the reference point that we will be looking at the futility analysis, I think we are very well grounded with the assumptions that we are making, and that assumption is supported from many different angles, the data that's coming from the autologous CAR T therapy as well as more new data coming from other MRD-based studies. So we feel very comfortable about how we will be conducting the futility analysis in the first half of next year.

Our next question comes from the line of Robert Burns with H.C. Wainwright.

This is Katie on for Rob. My question is more about your -- if you have any more recent interactions with the FDA and if you feel like the kind of move towards greater flexibility in CAR-T oversight might give you some accelerated pathways or reduce some friction for you guys to get to market.

Yes. We have a lot of ongoing communications with FDA. And so far, it has been very timely and very productive. And the question that you are raising, it is a very interesting one. I mean, I think we will have to see when the time comes, but all the indications that we can make from what FDA has said is that a single-arm approach with CAR-T therapy, that path is still wide open. And FDA is carefully reviewing the other side of the BLA requirement, what is needed on the CMC side. So we view this to be very positive for what we are doing.

Our next question comes from the line of Clara Dong with Jefferies.

[Technical Difficulty] I apologize for technical issues. And just one question from me. How are you controlling for variability in the MRD assay sensitivity, if any, across different sites? And what steps are you taking to ensure consistency in MRD conversion assessment for the futility analysis?

Claire, that's an easy one. The MRD test is all being done centrally by Foresight Diagnostics. So all the sites are doing is collecting the samples and then sending them into the central lab. So we don't expect there to be any kind of technical variability in the test performance.

Ladies and gentlemen, that concludes our question-and-answer session. I would now like to turn the conference back over to David for any additional comments.

Thank you, operator. Let me close out by saying that everything we have built over the past 7.5 years has led to what's ahead in 2026. There are many ideas about where cell therapy is headed, but progress depends on staying focused on what is real and achievable. At Allogene, we kept our focus on building therapies that are scalable, reproducible and ready for patients.

In the first half of 2026, we expect 2 major milestones, interim futility data from ALPHA3 with stem-cell in first-line consolidation and proof-of-concept results from ALLO-329 in autoimmune disease. These will not be theoretical advances. If successful, they will mark true clinical validation of the allogeneic platform, shaping our company's trajectory and building broader confidence in the potential of allogeneic CAR T therapy. The opportunity ahead is significant. We are entering 2026 with conviction, clarity and momentum and are excited for what the coming months may hold. Operator, you may now disconnect.

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

Good afternoon, and thank you for joining. I'm Sam Semenkow, one of the senior biotech analysts here at Citi, and it's my pleasure to be hosting Allogene's Executive Vice President and CMO, Zach Roberts, as a part of Citi's SMID Biotech C-suite virtual fireside chat series. Zach, welcome, and thank you so much for joining us today.

Thanks so much for having me, Sam.

If anyone live on the call has any questions during the session, please go ahead and e-mail them to me directly at [email protected], and I'd be happy to ask them on your behalf.

So Zach, why don't we sort of jump right in? Maybe at a high level, let's just talk about Allogene's pipeline and where you are today as a company.

Sure. So Allogene was founded in 2018. We have been, since the beginning, a company focused on allogeneic cell therapies, initially for oncology indications, and now we've recently expanded into autoimmune indications as well. We currently have 3 clinical programs that are ongoing. We've got our lead pivotal program with its CD19 off-the-shelf allogeneic CAR T product called cema-cel. And this is being developed in a very unique indication in what we call frontline consolidation for large B-cell lymphoma. And we'll have plenty of time, I think, during the call to talk more about this ALPHA3 trial. So I'll save that for later.

The second program, another oncology program is a solid tumor program in advanced and metastatic renal cell carcinoma. This product is called ALLO-316, and it's targeted to CD70. And we recently showed the culmination of a Phase I program at ASCO just earlier this summer. And very exciting data in that program. We saw a 31% overall response rate in patients with multiply relapsed/refractory metastatic RCC. And these responses were quite durable, really a first for the field, especially as it pertains to allogeneic cell therapies, again, another off-the-shelf product.

And then the third and final clinical program is our autoimmune program, as I alluded to previously. This product is new and novel in a few ways, also healthy donor-derived off the shelf, but it's the first dual targeting CAR that targets both CD19 and CD70. And this was really designed to enable targeting both pathogenic B cells, but also pathogenic T cells. And these are T cells that specifically upregulate CD70 on their surface. CD70 is a marker of T cell activation. And there's another unique feature of the CD70 molecule, CAR molecule and that it incorporates what we call the Dagger technology. And a way of shorthand in thinking about what Dagger is it's essentially built in lymphodepletion. And so these cells, once we infuse these allogeneic CAR T cells, resist the patient's immune system from rejecting them. And by doing that, they actually garner a proliferative burst. So they begin to expand on their own. And we were actually able to show in that kidney cancer program that we can do this with markedly less lymphodepletion than is generally required for allogeneic cell therapies.

So I share this to illustrate one of the defining features of this 329 program is that we are bringing this to autoimmune patients with less or even no lymphodepletion at all and relying entirely on this built-in lymphodepletion that we call the Dagger effect. So that's a very high-level summary, Sam, of Allogene's history as well as our current pipeline.

Yes. Thank you for that. You gave us a lot to work with there, and you're correct. So let's start with the cema-cel ALPHA3 trial. You mentioned this is a unique indication. It absolutely is. But let's talk a little bit about that opportunity of that unique indication. What's the size of the market? And where do you think that cema-cel could really deliver in that space?

Yes. So one of the exciting things about this trial is that it incorporates a new disease assessment tool that is rapidly becoming standard in diffuse large B-cell lymphoma, which is called the minimal residual disease or MRD. And what MRD is -- enables a clinician and a patient to do is even in patients who appear to be in remission, they can get this additional very sensitive, very specific blood test. So it's not a scan, it's a blood test that measures circulating tumor DNA. And if circulating tumor DNA is found in the blood, that is a very strong indicator that these patients will have their cancer come back.

And so -- and sometimes it's very quickly and sometimes it actually can be many months, but it gives both doctor and patient a better understanding of what to expect from their cancer. So with that kind of foundation, we looked at the market opportunity here and even incorporating what we believe will be the uptake of MRD in the coming years, we assess this to be approximately a $5 billion global opportunity because it essentially will capture most of the patients, if not all of the patients who eventually go on to relapse with their DLBCL and are currently being treated with salvage regimens like autologous CAR T. So we really have kind of in a manner speaking, sort of leapfrogged the second and third lines and found ourselves right between front line and second line. So it's a fairly large market opportunity globally.

Okay. And there are no other cell therapies or any other drugs targeting this population currently, correct?

Currently, no.

Okay. Do we have any indication that there may be others entering the space or that just hasn't happened yet?

So we spend an awful lot of time talking to lymphoma physicians, both global KOLs, but also community doctors. And what we find is nearly universally, people think that this is a very forward-looking study design and one that stands probably the best chance at improving frontline outcomes in large B-cell lymphoma for the last 25 years. So we believe this is a good idea. We think it's a solid study design. And we expect there will be competition. We hear rumors from time to time that there may be something in the works. But so far, we haven't had anything concrete come to our awareness.

Got it. Okay. So then maybe let's talk a little bit about the study design and maybe it could be helpful to walk through the patient flow and of the study design and how they get from screening to enrollment and into the study.

Sure. So before I get there, it probably makes sense to just level set on what a typical patient journey is today in the current standard of care with a new diagnosis of large B-cell lymphoma. So patients notice symptoms, a lump, night sweats, what have you. They come to their doctor, they get a biopsy, they're found to have diffuse large B-cell lymphoma. And then almost everybody, certainly in the United States, at least 2/3 of patients, maybe a little bit more, will get started on a very standard, very old regimen called R-CHOP. And that's actually 5 different drugs. Each drug has a letter in R-CHOP that stands for the drug. And that's given for 6 cycles every 3 weeks, 1 cycle every 3 weeks. And most patients, about 90% of patients who are treated with this or similar regimens will achieve a remission, meaning that their cancer is in better shape at the end of this than it was when they started. And most of those patients will be in what we call a complete remission, meaning that their scans are completely clear. There's no evidence of residual tumor.

About -- the remaining 10% will have what's called primary refractory disease. Those patients are, frankly, in rough -- they've got a sort of a tough road ahead, they will go directly to a second-line salvage regimen like autologous CAR T or bone marrow transplant or increasingly a bispecific-based regimen. But for the patients who are in remission, about 2/3 of those patients will actually be cured. They will never hear from their cancer again and 1/3 will actually have their cancer come back.

So it's really at that end of therapy at the end of the 6 months that when you have a clean PET scan or a scan that suggests that you're in remission, that PET scan actually is not a very good disease assessment tool. There's false positives, there's false negatives. We've known about these for decades, but it's the best tool that we currently have that is widely used. Where the MRD tests are beginning to make major changes is if you layer on top of that PET scan an MRD test of these very specific performance characteristics, it will significantly improve your ability to prognosticate or see the future of what's going to happen. So let's say a patient has a complete remission by PET scan. If they get an MRD test and it's positive, we are almost -- we're about 90% sure that, that patient's tumor is going to come back. They are going to relapse.

So even though a PET/CT is showing that these patients are clear to their disease, we know that their trouble is ahead. And conversely, if you have a PET scan that remains positive on some small amount, but their MRD test is negative, we actually are very confident, again, about 90% or so that these patients will actually never relapse. And so those patients are very good to observe. So that's the frontline care. We won't talk too much about the second and third line, but just to round out this conversation, patients, even if they achieve a remission who are destined to relapse will go for some number of months and then their disease will come back, and that is when they're eligible for a second-line regimen. And when I say come back, I mean they have a PET scan and/or symptoms that illustrate that their tumor has come roaring back. And that is actually a clinical emergency and those patients need to be treated right away, which is one of the challenges that faces the autologous CAR T in that setting, which is currently the best we have to offer, but trying to get all that set up in the context of a rapidly progressing tumor can sometimes be a bit of a challenge.

So that's really the focus of ALPHA3 is if we treat those patients at the time of their MRD positivity, we are able to prevent that relapse from ever occurring.

Before I go into the design of the study, I do have a client question that came in. They're asking what percentage of patients will remain MRD positive after R-CHOP? A limited number of studies show 20% to 25% MRD positive. So they're looking -- curious how you're thinking about that percentage.

Yes. So that's about right. If you take a single MRD draw at the end of frontline treatment, that's a reasonable number to guess that somebody is about 20% likely to be MRD positive, even though they're in remission. What we do know is that pretty much everybody, of course, nothing is 100%, but pretty much everybody who eventually relapses will turn MRD positive before that clinical relapse. It's a question of whether we're actually measuring that MRD positive, that MRD status at that time. But as these tests begin to gain support and backing and are increasingly being paid for by insurance, it's likely that MRD will become part of the longitudinal assessment that's performed on these patients, not just PET/CT.

So these patients will -- even if they're MRD negative at the end of frontline treatment, they will, at some point, turn MRD positive prior to a relapse. So even though it's 20%, which is not exactly the total number of patients that we do expect to have their tumors come back, it's quite likely that, that remainder will actually turn MRD positive prior to that relapse.

Got it. So it's a sensitivity of the test or just a marker of when you have enough of that tumor that MRD positivity can then be detected. Right now, for ALPHA3, you're getting them right after they're cleared in remission of some sort, then they get the MRD test right after that. Is that correct?

That's correct. I'm just noticing my camera is getting a little bit blurry, and my apologies for that. Let me just turn it off and turn it right back on. That seems to fix the problem. I don't know what's going on with it on this Thursday morning.

You're clear.

Thank you, Sam. That's absolutely correct. So we are performing the MRD test just a short number of weeks after the final cycle of that R-CHOP regimen or a similar regimen like Pola-R-CHP is completed. So we are at about the time that, that end of therapy PET/CT, which is currently standard, that's when we do this MRD test.

Got it. So if that 20% to 25% ends up being accurate, that's about the patient population that you could pull from to potentially enroll into ALPHA3?

Correct. But we actually believe that the commercial opportunity is more likely going to be reflected by any MRD-positive patient regardless of the timing of their last line of therapy.

No, that makes sense. Okay. So then maybe let's just talk about the journey into ALPHA3. So they have been tested or they finished their R-CHOP, they're in the sites being tested for MRD. They come back MRD positive. How do you get these patients enrolled effectively into the study?

Yes. So once they're MRD positive, their prognosis is communicated to them by their physician and say, okay, this is not good news, frankly, means your tumor is very likely to come back. At that point, they will sign informed consent for the trial, and we'll undergo a few sort of screening assessments to ensure that they're appropriate for clinical trial enrollment. And then once those are complete and the patient is eligible, they are randomized into the study. And then the study design currently is a 1:1 randomization either into the current standard of care for MRD-positive patients who are in remission, and this will be my opportunity to say that currently, MRD is an experimental diagnostic tool. It is not baked into any recommendations for treatment decisions.

So the current standard of care in a patient who is in remission is to observe regardless of their MRD status. So that is the control arm in ALPHA3 is a watch and wait or a very close observation or they get randomized into the other arm, which is treatment with fludarabine Cytoxan-based lymphodepletion and a single infusion of our off-the-shelf CD19 CAR T cell cema-cel.

Got it. Okay. And I think one of the biggest questions I get from investors is how are they going to enroll this study, given it is a very novel indication. You've just said that the standard of care is to not treat. I know you have a number of sites, both community and academic. I'm curious what are the challenges that you've seen in enrollment? And what have you done for mitigating? And I guess if there's an update you could provide today of how that enrollment is going at a high level that I think would be quite helpful.

Sure. So I would say that every study has its challenge. Every single clinical trial, there are growing pains when you first launch and ALPHA3 is, of course, no different. We are doing a lot with ALPHA3. We are testing a novel modality for CAR T cell, but it's off-the-shelf CAR T cells. We are also implementing as part of eligibility determination, this MRD test, which is currently not standard. I will say that it is rapidly becoming more widely used.

When we first started talking about ALPHA3, maybe 2, 2.5 years ago with doctors, we found that very few of them were using any MRD assessment as part of their standard patient management. And we see that anecdotally, but also in sales information from MRD developers that this is becoming more widespread. But in the early days of ALPHA3, we had to really educate about the utility of MRD and why a doctor who has been giving R-CHOP and assessing disease with PET/CT for decades why they suddenly would layer on this additional test. So we had to build support around the MRD. Many, many doctors are early adopters, and they're super enthusiastic about MRD. And so they loved ALPHA3 right out of the gate as soon as we started talking about it.

But then also educating the patients that it's not just about your PET scan. There is an additional piece of information that we need to collect and changing that mindset with both doctors and patients that a PET/CT is not telling you the whole story. So that was part of the early challenge that we faced in just really implementing this study.

There are some other operational issues like in the United States, CAR T cells are generally given by transplant doctors and R-CHOP is generally given by lymphoma doctors. And in many academic centers, those 2 groups are separate. Oftentimes, they don't even sit in the same team rooms. So the study might sit in CAR-T in the transplant group, but we needed to facilitate daily communication between the lymphoma doctors and the CAR-T group so that we could get the MRD screening rates up to where we needed them to be.

So it took us a few months to figure all that out and then deploy -- sorry about my camera again, Sam. Let me just do this again. And then deploy mitigation strategies. And so that really was sort of end of 2024, early 2025. We -- since those mitigation strategies have been implemented, we not only have improved performance of the existing early sites that came online that were so eager. But also as new sites have come online, we have brought to them kind of a best -- a package of best practices on how to implement this study effectively. So those new sites are coming on sort of hitting the ground running. And so what we really have seen over the course of 2025 is markedly improved patient identification, markedly improved MRD screening rates, and that has translated into a study enrollment.

Okay. And so that feeds into your expectation for the futility analysis in the first half of '26. That -- remind me if I'm correct here, I believe it's up to 12 or about 12 patients in each arm will be included in that futility analysis?

That's correct.

Okay. And what are the expectations there? Like what would be good for you to pass that futility and to move and continue the study?

Sure. Before I answer the question, let me just put a little bit of context out there. So I briefly mentioned another frontline regimen that's often used in the United States, especially for patients with newly diagnosed DLBCL, and that's a regimen called Pola-R-CHP. And it's based on a drug called polatuzumab vedotin or Polivy. And the R-CHP is kind of a modified R-CHOP. So it's essentially R-CHOP plus. That regimen was the first new regimen to be approved in DLBCL in 25 years, about 20 years or so, since R was added to CHOP. And that study had about a 7% improvement in PFS, and that led to approval of Pola-R-CHP. I think that illustrates very clearly that R-CHOP is a very effective regimen, and it's been really surprisingly difficult to beat it.

So with that kind of a backdrop, how we think about this futility analysis coming up that you just mentioned is if we can see a 30% improvement in the efficacy assessment that we're doing at that futility analysis, that would be a major advance in the frontline outcomes for these patients with newly diagnosed disease. I will point out that the efficacy assessment that we're using at that futility analysis is not the primary endpoint of the study, which is event-free survival, but rather looking at the MRD conversion. So everybody that comes into ALPHA3 comes in MRD positive, as I pointed out earlier. And what we're looking to see is whether that MRD positive becomes an MRD negative after they're enrolled in the study. And so what we're looking for is a roughly 30% or better delta between the MRD conversion in the 2 arms, observation versus cema-cel. We would consider that a pretty substantive improvement, especially given what historical improvements have been even with approved regimens like Pola-R-CHP.

Got it. Okay. And so for that readout, 30% right? And that is based off the second line Yescarta and Breyanzi sort of complete response rate. Is that correct?

Yes. So that's another...

Sort of a proxy.

That's another way to look at it. So if these patients do progress, as we expect almost all of them will, the MRD positives, what is their likely outcome in the second line? And even though we have kind of anchored to ZUMA-7 and TRANSFORM, those are the large randomized trials examining Yescarta and Breyanzi versus autologous transplants in the second-line salvage regimen. The sad truth of the current status of relapsed DLBCL in the United States and globally is that the vast majority of patients don't actually even get those therapies. They don't even get CAR T. They get something else that doesn't work as well as CAR T or they get nothing at all. And we actually see about 1/3 of patients in the U.S. based on recent claims data shown at ASH last year, about 1/3 of patients don't even get second line at all. So there really is quite an opportunity to improve upon the outcomes in relapsed disease. And MRD positivity is absolutely a proxy for impending relapse.

Do we have any data that says people on this test that you're using can come in and out of MRD positivity. I'm wondering if there's any sort of, I guess, base level of potential false negative that we should expect in the futility analysis?

Yes. So that's uncommon. No test is perfect, but we do -- we expect that at a very low rate to occur. So typically, what happens if you're MRD positive, you stay MRD positive. Now we know from existing retrospective data that it's not 100%. And there are some patients who stay MRD positive for a long time, but it takes a while for their disease to recur. And in a very small number of patients, maybe 20%, even out 3, 4 years, those patients have yet to recur even though they've stayed MRD positive. And in the case of toggling back and forth, that is an extraordinarily uncommon event.

Okay. Great. Good to know. And then for -- going back to patient enrollment, I forget the phrase you used, maybe it was markedly improved in the cadence or success rate that you're seeing. I mean, does that give you confidence that you're going to meet the first half '26 guidance for that futility analysis? Like based on what you know right now, how confident are you?

We are confident, and we are seeing good performance in enrollment. We're bringing on more sites every month. So yes, that is a solid guidance. I'm going to switch my cameras here, hopefully get rid of it. I don't know what's going on with this blurriness here. But let me just switch to my laptop, which might be a little bit better.

You flipped. You did one of those flips. That's fun.

Yes, I did a flip.

Okay. We'll see if that works better for you. Okay. So then let's say you do pass this, let's say, at least 30% MRD conversion rate, you continue the study, you have a planned interim EFS analysis and then a final EFS analysis. And correct me if I'm wrong, but I'm not sure if you've been able to give guidance for the timing of that. Do you know when you might feel comfortable providing guidance on timing for those readouts?

Yes. So you're absolutely correct. We have not provided detailed guidance on the timing of the EFS analysis. There is an alpha-spending interim analysis, and then there's the primary analysis. And we are deferring providing guidance until we do the update with the futility results in the first half of next year.

Got it. So we'll know more then. And I assume that factors in the enrollment rates that you're having now and that you're seeing and you'll be able to guide towards that. Okay. Just thinking about how long it might take for the study to reach the number of events needed for both the interim, but more importantly, I think, the final EFS analysis. How long does it take for a patient that comes back MRD positive to generally progress in the watch and wait arm for -- towards a second line or recurrence of their disease where they would need second-line therapy?

Yes. So it's variable, as you would expect. The best data that we have to look at on this comes from the recently published JCO manuscript from our partners, Foresight Diagnostics, who is the group that is developing the test that we are using for this purpose, it's called PhasE-Seq and in that group of patients, overall, the median time to progression for an MRD-positive patient at the end of treatment was less than 3 months. So it tends to be a fairly rapid event, but there -- of course, it's a Kaplan-Meier and you do have some patients that take longer and so forth.

So in any case, it happens quickly. And already on the study, we've had patients who have come back MRD positive and then for this or that reason, didn't qualify for enrollment and randomization in ALPHA3. And we're already hearing back that some of these patients are progressing very quickly within a few short months. So the experience in ALPHA3 seems to bearing out with that recently published data set from the Foresight group. I'll also add, this is another reason why we think an off-the-shelf cell therapy is really the best tool in this context because you have to act very quickly, arguably much more quickly than you can act with an autologous product.

The other limitation to an autologous product is that there may not be very many T cells that have recovered from the 6 cycles of R-CHOP. And that also brings into question whether even a bispecific would work very well because there's just not that many T cells to engage with your T cell engagers. So really bringing in a product that is built from fresh T cells derived from healthy donor in an off-the-shelf rapid way is probably the best modality to consolidate an MRD-positive patient who, in many cases, may only have a few weeks before a clinical relapse.

Got it. Okay. And maybe let's just talk about that. We talked a lot about the study design and the patient dynamics, but we haven't really talked about cema-cel and the data you have supporting the efficacy here. Can you just walk through -- I know it's in the later stages, but one of the things that I found interesting is that the patients with lower tumor burden seem to have better outcomes, and that seems to work really well or correlate quite nicely with what you likely would see in an MRD-positive patient. Can you just give a high level of that background for everyone?

Sure. So cema-cel got its start as cell therapies often do in patients with relapsed/refractory disease. And in this case, of course, it was large B-cell lymphoma. And we recently also published the results of that Phase I in the Journal of Clinical Oncology. And the highlights are that the efficacy seemed on par with what the autologous products were delivering in a similar line of therapy. And we saw about a 58% complete response rate in the Phase II regimen that we studied in that Phase I. And as you point out, the less disease burden that you had at the time of your cema-cel and all these patients -- these were not MRD-positive patients. These are patients with full-on relapse. But there's patients who have very bulky and aggressive relapses and then there are patients who have slow growing and small relapses.

And so in any given population, you're going to have a spectrum. And so what we wanted to learn was whether we saw what was emerging in the autologous field that patients who have low disease burden when they receive their CAR T cell infusion, what are their efficacy outcomes. And this has now been shown in several different settings in the autologous setting -- several different therapies in the autologous setting that treating patients with low disease burden means that they have better outcomes, both safety and efficacy. So we looked at this, and we looked at patients who had low disease burden and we sort of arbitrarily cut a line at 1,000 millimeters squared of the sum of product diameters and -- which is relatively small, but not very small, still visible on scan. And 100% of those patients achieved a complete remission to cema-cel.

We also looked at another serological marker of disease aggressiveness and burden, which is lactate dehydrogenase, it's a blood test. And in the patients with low or normal lactate dehydrogenase, which is a marker of low disease burden and low disease aggressiveness, over 80% of those patients achieved a CR. So this really does, number one, replicate the findings in autologous, but number two, and very significantly, strongly indicates that if we take that even further into a patient whose only evidence of disease is this ultrasensitive blood-based molecular ctDNA test that we will be able to induce durable complete remissions in those patients even more effectively than patients with relapsed/refractory disease.

I have a question from another investor coming in. Did you ever check MRD status in patients from the Phase I study after cema-cel treatment?

So the short answer is we had a few samples that were appropriate. You kind of have to plan for MRD testing. There's like a special tube that you have to draw. So we did go back as we were talking about ALPHA3, and we looked at these results and for a reasonable number of patients, not all, we did have some samples, and we're able to show that we were able to clear MRD in some of those cases.

Okay. In some of the cases. And was it -- did it correlate with a lower tumor burden cases?

It was a mix. So we had some patients who had high disease burden who did very, very well in that study. And you can go back and look at the swim lane plot from the JCO. We've got patients that are out past 4 years. Several of those patients did have the low disease burden, but there are also some patients with sort of more measurable disease.

Okay. Interesting. And then going back to the patient enrollment piece, I'm wondering if you could -- if there's any framework you could share, I doubt you could give specifics about the rate of the number of patients that are going into screening and the ones that make it through screening and then the ones that actually go into enrollment and remain in the study. Is there any framework on how you could talk about what that funnel looks like?

Yes. So I think the biggest piece of that funnel that we talked about came up a bit earlier, which is what the MRD-positive rate is that sort of 20%-ish range. So without getting into all the nitty-gritty details here, one of the other things that we learned about this study and its execution is that getting to patients early in their treatment course actually is much better for their kind of likelihood of actually conducting MRD test and then coming into ALPHA3 than waiting until the very last minute because often what patients will do when they've been given a diagnosis of LBCL, they've immediately been told by their doctor that they have a very good chance of being cured of this cancer, which is true. That is what sort of clicks with folks and then they go through their 6 cycles of R-CHOP. They expect to be cured at the end because that's what they've been told. They have a clean PET scan and they're like, okay, it's time for me to take that cruise that I've booked to reward myself for getting through this successfully.

To then come back and say, well, we also have this other test, which will tell you -- tell us more accurately whether your disease is ready to come back. Patients with -- in the early days like, what are you talking about doc? This feels like a bait and switch. So we now talk to these patients quite a bit earlier, and that comes with both pluses and minuses. On one hand, we find these patients early, they get put into a log book, we follow them through, we get the MRD test. But what also happens is we don't really know what's going to happen with those patients when we talk to them after their first cycle or their second cycle. Some of those patients, about 10% will have primary refractory disease and will blow through the R-CHOP and need to go on to second-line autoCAR. That patient obviously is not going to go on to get MRD tested. Some patients will have toxicity to R-CHOP and they'll decide they don't want to any more therapy or they'll develop a new comorbidity.

So we do see a sort of narrowing of that funnel even before we do get to MRD testing, and then we see about 1/5 of those patients coming back as MRD test positive. Once we clear that MRD positivity, we're dealing with a smaller pool of patients, but they tend to actually end up in the trial because the opportunity is so compelling. Even for patients who are randomized ultimately to the observation arm, they are getting something more than they would be getting if they were just being cared for outside of a clinical trial, namely more frequent clinical visits, more frequent scans critically, right? We're scanning these patients more often because we really want to see that disease come back sooner or if it does, we want to act on it quickly. So we're able to offer something comforting to these patients who are MRD positive are now expecting their disease come back any day if they come into ALPHA3.

Got it. Okay. That's really helpful. And then so for the final EFS analysis, I'm going to skip ahead all the way to that. Can you -- any framework you can say on the number of events that you're expecting? And what, I guess, is the powering for a successful study on that readout?

Yes. So we haven't provided a lot of the details on the statistical design of the trial, and I won't do so today. But suffice it to say that the bar is pretty low here. The study is designed treatment against observation. There is a huge opportunity to improve upon outcomes, specifically in this ultra-high-risk patient population who is MRD positive. And you can see that manifested in the overall study size, which is only 220 patients that need to be randomized.

Got it. And so that's a good segue because now I want to talk about the commercial market. So let's say -- I mean, well, for one, this is novel. It will take education and physician engagement in a commercial launch. But I'm curious, these sites that you have right now, they're the ones that are going to have experience with cema-cel right out the bat. So perhaps they are early adopters. When you look at the population of patients, total patients in the U.S., let's just say, that are being treated at these sites, do you have a sense for what the opportunity is for the early adoption just solely in those sites? And then maybe you could talk about how it expands out to other sites that obviously will have interest in this, if approved?

Yes. So that's a great question, Sam, and it gives me a chance to kind of talk about our commercial strategy in kind of a big picture sense. So I worked at Kite as did Allogene's CEO, and I was involved in the ZUMA studies and led to the approval of Yescarta. And one thing as exciting and as transformative experience for me as that was one of the things that was sort of plainly obvious along the way was not very many patients are going to be able to get this treatment for any number of reasons, insurance, but primarily, it's who your doctor is. And 80% of patients in the United States don't get treated at places like MD Anderson and Dana-Farber and Moffitt Cancer Center and Fred Hutch, right? They get treated at their local community oncology practice.

And so if we were going to bring the promise of CAR T, the modality to everybody who could benefit from it, we really needed to break the mold about how and where this therapy was given. And so that was baked into our clinical strategy. We wanted to bring this trial not just to the MD Anderson and the Dana-Farber and the Mass General. We wanted to bring it to community practices. And so if you look at our site activation list currently on ct.gov, you see about 50% of the currently open sites are community practices. Some of those, a nontrivial number of them, have no CAR T experience. These are local community practices that have, for many reasons, decided not to invest in the infrastructure needed to deliver a cellular therapy like autologous CAR T or bone marrow transplant. They are some of the largest proponents of ALPHA3 because it's for the first time, giving them access to this curative modality for their patients, and they're able to hang on to their patients. They don't need to refer them out to a big academic center.

So right out of the gate at the time of approval, you're absolutely right. The centers that were part of the clinical trial will have a head start. But this is a very different launch strategy than any autologous therapy ever was or will be because it's off the shelf. We shipped it overnight. It's ready to thaw up the bedside and infuse. Most of our patients in the trial and actually a significant number of patients even in the Phase I relapsed/refractory are being fully treated as outpatients. So we call this therapy in ALPHA3, the seventh cycle of treatment for patients at high risk. And that really is resonating with a large fraction of the community oncologists out there. So this is a little bit of a hint of how we think our commercial strategy and commercial launch is going to go. It's going to be a lot less complicated or costly as launching Yescarta was.

Got it. Okay. And not to push, but do you have a sense for what that percentage of patient coverage is within your sites?

It's really hard to guess. I mean, even with a fairly sizable number of U.S.-based sites, somewhere around 50 currently, that's probably not capturing a huge coverage of patients. Just it's not -- it's really hard to achieve that with any clinical trial. You would need hundreds, if not thousands of sites open to really come close to capturing a large percentage of patients. But what matters is that this is a therapy that is easily transferable to new sites.

Got it. Okay. And is there a difference in how you need to educate the community physicians versus the academic physicians that presumably have a lot of experience with the autologous CAR Ts?

Yes. So 100%, right? I mean, again, drawing on my own experience of the early days of autologous CAR, that was -- those therapies were brand new. There was CRS, there was neurotoxicity, all that stuff needed to be studied and learned and mitigated kind of as we were going through the trial. Our product tends to be pretty well tolerated, and it's very, very outpatient friendly. That said, we don't want to just sort of drop it off at the front door of these community practices and say, go ahead and give this to your patients. So there's a lot of training that goes in, not just how to handle the product itself, but what to expect after the drug is infused and what CRS looks like, what neurotoxicity looks like, even though with a low disease burden, we don't expect much of that in the trial. we do want to make sure that patients are safe.

One benefit that we've been able to draft on is that many of these practices are using bispecifics, which are approved in later lines. And they come with CRS, they come with neurotoxicity. So they've become a little bit more comfortable dealing with drugs like tocilizumab and steroids and managing these patients. So the time was really right for us to bring this to those practices because they already had a functional knowledge of what a T cell toxicity looked like. So some of our work is done, but we're obviously being very careful, and we want to make sure that everything is being done safely.

Yes. That's a good point. Okay. So we spent a good amount of our time on ALPHA3. I just want to give an opportunity what haven't we touched on that you think is really important for everyone to understand.

I think this came through during our conversation, and I'll try to keep it brief. But I mean what we're really doing here is transforming care. And that's hard, but it's always hard when you're transforming care. And we really are looking ahead to what DLBCL management is going to look like in the very near future with MRD, and we expect that there will be additional trials that like ALPHA3 is such a compelling thought to be able to consolidate a low disease burden. So I would look at this opportunity as truly transformative, and that comes not just for the care of patients, but also for Allogene and the market opportunity that we talked about at the beginning. This is really a fairly sizable and exciting opportunity for us as a company to really put an impact here in this field.

Got it. Okay. Great to hear. So -- and we'll look forward to that futility analysis in the first half. But let's talk about your autoimmune asset, ALLO-329, which also has data expected in the first half. So your intro talked about it, dual CD19, CD70. I guess just walk us through the Phase I basket study that you've initiated and the study design and how you're handling lymphodepletion in this trial.

Yes. So as I mentioned, this therapy has through this Dagger technology built-in lymphodepletion, and that was very well documented in our kidney cancer program, which also has the CD70 CAR. So for interested listeners, that presentation is available on our website. You can see some data around this Dagger effect and why we think it's so important. So when we were designing ALLO-329, we really did it from the ground up for patients with autoimmune disease. And we knew that one of the biggest barriers to widespread uptake of cell therapies for autoimmune patients is they don't want chemo, and I don't blame them and their doctors don't want to give chemo. So we had to have a plan for that. And it just didn't feel right to us to take an asset that was designed for oncology and just bring it into autoimmune and hope we can do it without LD, lymphodepletion.

So that's where the CD19, CD70 idea was born. So as I mentioned, we baked it into the study design. We actually have 2 parallel cell dose escalation arms as you do typically in a Phase I, you dose escalate a number of cells that you give. One with Cytoxan alone. So some lymphodepletion, but as I said, a dose that is commonly used in rheumatology patients. So it doesn't include fludarabine. It's not a super high dose of Cytoxan. It's something that they might be offered in their usual clinic. And then there's a parallel arm with no lymphodepletion at all, no chemotherapy, nothing else.

So we're really excited about this. Doctors are really excited about it. It is truly differentiated. We are starting to see now some other sponsors starting to play with no lymphodepletion. They don't have the benefit of the Dagger that we do, though. And you mentioned the basket design. This is a true basket study. We've got 4 indications, lupus, lupus nephritis, if you count that as a second, inflammatory myositis and systemic sclerosis or scleroderma. And what makes this a very flexible design is we don't have targets for individual indications. So our first dose cohort could be 1 of each or 2 of 1 and one of the other. And it gives a lot of flexibility to sites, some of which have more myositis patients, some of which have more lupus patients. So there was a lot of flexibility baked in that the investigators have really liked. So we think that this will help us with enrollments in this competitive environment.

And how do you handle which arm patients get enrolled into? Is it just random or based on the site? And is that how it's handled? And you said they are enrolling in parallel, correct?

Yes, they're enrolling in parallel. I mean they're -- without getting into a lot of specifics, it's likely going to be roughly one here, one there. We're not going to be looking at an individual patient and making a decision based on their characteristics or their diagnosis, are they appropriate for this or that arm. We really are going to try to enroll them in parallel, more or less alternating. It's not -- there's not a formal randomization or anything like that.

Got it. Okay. And then so for the initial readout, what data should we expect? Should we get data from both of these lymphodepletion cohorts?

That is the goal. We expect in the first half of next year to have data from both of these arms, certainly in the early dose cohorts. This is a dose escalation study. And we're expecting some biomarker data looking at the change in the number of B cells and T cells in the periphery, maybe their surface phenotype as has been reported by other CAR T data sets and then some early safety and efficacy as well.

Okay. Excellent. And I guess once we see that, we'll have a better feel for this, but you sort of alluded to some other companies taking away lymphodepletion or reducing it. And obviously, you have the Dagger technology. But is there any difference in how you handle the reduced lymphodepletion versus some of the others that are trying it in the field? Or like is your Cytoxan level less or the same? I'm just curious any other differentiating aspects in the design.

Yes. So I mean, again, I'll say that we're -- to be perfectly blunt, I mean, we came to this a little bit later than some of the other sponsors. And we had to be quite disciplined internally to not just rush into it with, say, cema-cel or whatever, right? And we really wanted to be focused and goal directed, but really be quite systematic about what does the right product design look like. So we spent a little bit of time with that. We brought this product forward. And then with the study design, the same exact thing, like let's design something that is fit for purpose.

So I'll give you one example. I mean the Cytoxan dose that we're using, it is the standard dose that is given to rheumatology patients of a drug that is given to rheumatology patients. It's not kind of like it or like a CAR-T dose, but we're giving rheumatology, it is the dose that these patients get. So -- and we started with that in mind. So again, this isn't let's iterate, let's hope for the best and work our way into something that suits rheumatology. Let's start with something that really will resonate with that population and that group of doctors.

Got it. And is there your expectation that the CD70 piece of the equation, how necessary is that for when you remove lymphodepletion? I'm asking this because you mentioned there are a couple of other sort of endeavors out there for other assets. what are your expectations for how differentiated your data could be with CD70 and reduced or no lymphodepletion versus other assets that don't have CD70 and reduced and no lymphodepletion?

Yes. So I mean, I want to make sure that I put this -- we're speculating here, right, because ultimately, we have to run the study. And even once you have data, cross-trial comparisons are always tricky. So -- but knowing what we know about the Dagger, we think we have a very good shot at getting robust cell expansion with low to no lymphodepletion. And I'll even say, without giving away too many details that as we've been preparing a publication for the CD70 kidney cancer program on the heels of the ASCO presentation that I mentioned earlier, we performed some additional translational analysis, which is further built our confidence that this Dagger will propel the cells in the autoimmune patients to divide even in the absence of significant lymphodepletion.

So based on those actual translational results as well as developing preclinical results, we think we have a really good chance of doing this. And I don't also want to give short shrift to the fact that CD70 is likely an important molecule in autoimmunity by itself to say nothing of the Dagger effect in cell expansion. We know that patients with treatment refractory and severe lupus and other inflammatory disorders have higher frequencies of CD70 expressing T cells in their bloodstream. We know that CD70 is important on B cells in these patients. So having the dual targeting of a relevant molecule on activated lymphocytes will give us additional benefit on the efficacy side, we expect. And while some may say that, hey, look, CD19 looks like it might be enough, I'm not sure we know that yet. I mean we have heard that some patients are progressing and certainly, we're seeing in vivo patients not having as deep a response as patients with autologous CAR.

So it's quite likely that you might need to tackle the T cells on some level as well even within the rheumatology disorders. That is probably going to be more significant as we expand into other diseases, neurology, endocrinology, gastroenterology, where classically there is a larger role for the T cells in those -- in that pathology. So a CD19 targeting B cell may not have much to offer in that case, whereas we expect to expand very aggressively outside of rheumatology once we've established proof of concept there.

Yes. No, when you start to add in other therapeutic areas outside of rheumatology, it gets quite a large, well, you multiply the TAM quite a lot Okay. So that's very helpful. So I guess, I want to just -- one of my last questions is how Allogene is thinking about the capital allocation. You have two really interesting assets, one late stage, one much earlier stage. I think 316 is on pause for future clinical development. But how are you thinking about it going forward? And just remind us on your cash runway?

Yes. So we have cash runway into the second half of 2027. And from a company prioritization perspective, our sort of highest probability of technical success, I think, currently sits with ALPHA3, the design of that study, randomized FDA discussed and agreed design as a pivotal design. Randomizing against observation is not something that comes around all that often in oncology. We know it's an active therapy. We have a very sound clinical and commercial strategy there.

So accordingly, the most of our resources, time and dollars are being spent on ALPHA3. That said, we are very excited about 329 and are looking for ways to move very aggressively with the expansion of that program upon achievement of proof of concept that we expect to share in the first half. And then 316, like this data is potentially transformative. I mean we've never seen -- and when I say we, I mean, as a field, we have never seen solid tumor data like what we presented in the kidney cancer trial at ASCO as an oral presentation in the main GU session, that has never been shown with an off-the-shelf CAR T therapy. We think that data is tremendously exciting. We are eager to move that program forward. As you point out, we're not internally doing that right now, but we are having partnership conversations on this program, and we're hoping to find a way to move that forward in the future.

Got it. Thank you, Zach, for that. I guess that's the end of my list of questions. I just want to turn it back to you for general closing remarks you might have.

Sure. Sam, thank you so much for this opportunity. It's really wonderful for us to be able to talk with your investors here. We think Allogene is a great opportunity. We've got a lot of very exciting programs, including a pivotal program up and running. It's a very, very exciting time in the field of cell therapy. I know it's been kind of a tough few years for the sector, but with companies like ours, new technologies like MRD and other things coming to the fore, I really feel like we've got a rowing renaissance here. And we just -- the next few months are going to be very telling for the field and for Allogene. So it's wonderful to be able to share that with your listeners.

Yes. Well, I'm looking forward to all of the data in the first half. And thank you, Zach, for being here today. It's been a wonderful conversation. Very much enjoyed it.

Thanks, Sam.

Okay. All right. With that, operator, we can go ahead and close the call.