Allogene Therapeutics - Q4 2023

Transcript

Operator (participant)

Thank you for standing by, and welcome to Allogene Therapeutics' Fourth Quarter and Full Year 2023 Conference Call. At this time, all participants are in a listen-only mode. After the speaker presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press star one one on your telephone. To remove yourself from the queue, you may press star one one again. Please be aware that today's conference call is being recorded. I would now like to turn the call over to Christine Cassiano, Chief Corporate Affairs and Brand Strategy Officer. Ms. Cassiano, please go ahead.

Christine Cassiano (Chief Corporate Affairs and Brand Strategy Officer)

Thank you, operator, and welcome to all who have joined this call. After the market closed today, Allogene issued a press release that provides a business update and financial results for the fourth quarter and full year 2023. This press release and today's webcast are both available on our website. Following our prepared remarks, we will host a Q&A session. We ask you to limit your questions to one per person, as we will keep this call to an hour and do our best to get to as many questions as possible. Joining me today are Dr. David Chang, President and Chief Executive Officer; Dr. Zachary Roberts, Executive Vice President of Research and Development, and Chief Medical Officer; and 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, and 2024 financial guidance, among other things. These forward-looking statements are based on current information, assumptions, and expectations that are subject to change. A description of potential risks can be found in our press release and latest SEC disclosure documents. You are cautioned not to place undue reliance on these forward-looking statements, and Allogene disclaims any obligation to update these statements. I'll now turn the call over to David.

David Chang (CEO)

Thank you, Christine, and thank you for all who have joined our call today. Rather than looking back, which is the norm for this type of call, I would like to take the opportunity to look ahead. We have recently returned from an investor conference in Boston and were beyond thrilled to feel a renewed enthusiasm for biotech and even more so, a resurgence in cell therapy. I would argue that this is also true for Allogene, a sentiment seemingly shared by many of our investors following the pivot we announced at the beginning of 2024. From our innovative ALPHA3 trial, which is designed to embed cema-cel as part of a curative first-line regimen for patients with large B-cell lymphoma, to specifically creating a CAR T that could meet the unique needs of patients with autoimmune disease and possibly reduce reliance on lymphodepletion.

Our development approach focuses on the distinctive attributes of an off-the-shelf alternative and creates an advantage for our AlloCAR T programs. We are no longer developing CAR T using an outdated playbook. Now that we have established the viability of our allogeneic platform, our products can be developed using a fresh approach, created for what we do, both in design of our trial and design of our constructs to meet the current and future needs of patients and dramatically expand opportunity. ALPHA3, which based on feedback from investors and doctors, is perhaps one of the greatest example of the role an allogeneic CAR T can play in this resurgence for cell therapy. This is the first pivotal trial for frontline consolidation in large B-cell lymphoma with the goal of improving cure rates.

There was significant insight-gathering work and discussion with the FDA in 2023 to inform and finalize ALPHA3. When we revealed the trial in January, there was acknowledgment almost right away that this groundbreaking trial creates the potential to leapfrog all other CAR T and embed cema-cel in first-line treatment. Equally important is the innovative concept of treating minimal residual disease or MRD, together with the benefit of drug-in-a-vial, could open the door to make allogeneic CAR T available in community-based cancer centers, where most earlier-line patients are treated. The more we've talked about ALPHA3, the deeper the understanding, this trial design is something truly unique, a rare opportunity in oncology to do a randomized trial against observation and the prospect of becoming new standard of care in the first-line setting.

Based on the addressable market just in the U.S., the revenue potential could be upwards of $3 billion and could easily double when expanded ex-U.S. This type of opportunity only presents itself when you center on patients and their endeavor to be curative. Our second most asked program by investors after ALPHA3 is ALLO-329 in autoimmune disease or AID. Enthusiasm for CAR T in AID is palpable. However, we have chosen not to rush into the already crowded field with an undifferentiated approach. The future result of that could mean an uphill battle in trial enrollment or worse, at commercialization. Instead, we are applying our deep and hard-earned experience to specifically design our dual targeting CAR T 2.0 for autoimmune disease.

Our design is centered on both scalability and reducing or eliminating lymphodepletion, which we believe is absolutely critical for rapid clinical development and future commercial success. We expect to be in clinic with ALLO-329 in a phase 1 trial in early 2025. Our next two core program also lean into attributes of allogeneic CAR-T. Our new ALPHA2 cohort for cema-cel in chronic lymphocytic leukemia, or CLL, aims to address a growing unmet need among patients whose disease are not controlled by BTK and/or BCL-2 inhibitors. Relapsed refractory CLL in these second and third-line setting represents a commercially attractive opportunity with revenue potential in the $3 billion range in the U.S. We believe an allogeneic CAR-T product is particularly well suited to overcome a limitation of autologous CAR-T, where poor T cell fitness is a known barrier to efficacy.

New approvals could reopen the door of interest in CLL, and we look to charge through it with our program. Our ongoing TRAVERSE trial tackles one of the hardest industry challenges, but one we are willing to undertake, solid tumors. ALLO-316 in renal cell carcinoma leverages our Dagger technology to optimize CAR T cell expansion and persistence to maximize the potential of an AlloCAR T. In the second quarter, we plan to publish what we believe to be fundamental discovery, the algorithm that may mitigate the treatment-associated hyperinflammatory response without compromising the CAR-T function needed to eradicate solid tumor. A more comprehensive update from the TRAVERSE trial is planned for year-end 2024. Now, I'd like to turn the call over to Zach to address some of the more commonly asked questions about our programs.

Zachary Roberts (EVP of Research and Development and CMO)

Thank you, David. As I'm sure you can tell, we are all very excited about our new strategy and thrilled that investors and investigators alike share that enthusiasm. I'll start with CLL because that gets a little less attention than ALPHA3, although it has the potential to pack a powerful punch. It's ironic that complete remissions in relapsed/refractory CLL ignited the CAR-T field many years ago, but that excitement waned for the very limitations we've stated. New approvals could offer a much-needed alternative for these patients, but there remains a growing need for effective treatment post-BTKIs and BCL-2 inhibitor therapies. Recent autologous CD19 CAR-T data has been a positive step for patients with relapsed/refractory CLL, but there is still room for improvement.

Durable responses in relapsed/refractory CLL is likely hindered by an unfortunate reality that T-cell dysfunction and high circulating tumor burden makes manufacturing of highly active T-cells difficult. There is strong scientific rationale to believe that an AlloCAR T product derived from healthy donor cells could create a clinically meaningful advance for these late-stage patients, with a one-time dose and simpler administration and logistics. The new Phase 1 ALPHA2 cohort will include 12 patients treated with cema-cel. This study, driven by investigator enthusiasm, is now enrolling patients, and we plan to have initial data at the end of this year. I'll now talk about ALLO-329 in autoimmune disease, our next intended advance. We believe the approach we are taking to reduce or even eliminate the need for standard lymphodepletion will be critical to meet the unique requirements for these patients.

The risk tolerance of these patients is very different than those with cancer, in large part because of patient demographics, wide availability of effective therapies, and rheumatologists' general lack of experience with chemotherapy, leukapheresis procedures, and cell therapies. Our wholly owned, next-generation, site-specific integration-based, dual targeting CD19, CD70 AlloCAR T is designed to reduce or eliminate the need for standard chemotherapy while targeting CD19-positive B cells and CD70 positive activated T cells, both of which play a role in autoimmune disorders. We have invested in this highly differentiated dual targeting approach to set us apart from the pack and position us for long-term success. All current CAR-T programs in AID are targeting CD19, and therefore solely addressing the B-cell component.

We believe that introducing CD70 will allow the elimination of both pathogenic B and T cells that underlie autoimmunity, thereby potentially increasing effectiveness in diseases with direct or indirect T-cell involvement, possibly allowing us to extend beyond indications in which strict CD19 targeting has demonstrated clinical benefit. Of course, the ability to manufacture hundreds of off-the-shelf CAR-T doses from a single healthy donor leukapheresis could provide an additional competitive advantage during clinical trial execution and would much more readily meet the potentially enormous commercial demand. Initiation of this Phase 1 trial with ALLO-329 is expected in early 2025. We are very excited to have partnered with Arbor Biotechnologies for use of their proprietary CRISPR gene editing technology to support our overarching next-generation AlloCAR T platform in autoimmune disease. Finally, I am particularly proud of and excited by ALPHA3.

Make no mistake, this was a year of hard work, but bringing this novel trial to life with the broader Allogene team, our advisory boards and potential investigators, both comprised of academic KOLs and community oncologists alike and securing the support of the FDA is already one of the highlights of my career. The elegant design of this innovative trial and the aha that comes with it is likely why we get asked, "Why hasn't anyone tried this before?" It simply wasn't possible until now. To run a study like ALPHA3, we needed two things to come together: a highly accurate MRD assay and a one-time powerful treatment that could be administered immediately. We believe we now have the right combination.

The design of the ALPHA3 first-line consolidation trial builds upon the results demonstrated in the phase 1 ALPHA2 trial, and leverages an investigational cutting-edge diagnostic test developed by Foresight Diagnostics, to identify patients who have minimal residual disease at the completion of frontline chemo immunotherapy for treatment with cema-cel. Approximately one-third of LBCL patients who initially respond to R-CHOP will relapse. Unfortunately, until recently, there has been no way to know which patients would go on to never experience a disease recurrence and which would have their cancer relapse. The standard of care after frontline treatment has, for decades, been to simply watch and wait for this disease to relapse.

ALPHA3 takes advantage of cema-cel as a one-time, off-the-shelf treatment that can be administered immediately upon discovery of MRD, following 6 cycles of R-CHOP, positioning it to become the standard seventh cycle of frontline treatment available to all eligible patients with MRD. ALPHA3 builds on the growing understanding that administration of CAR T therapies to patients with low disease burden improves both safety and efficacy outcomes. Cema-cel's phase 1 safety profile, with low rates of CRS and ICANS, already permits its use in the outpatient setting in relapsed/refractory patients, and may further improve in patients with no radiological evidence of disease. What's incredibly exciting is that the outcome of this pivotal trial could allow cema-cel to be embedded in the frontline setting, where autologous therapies are far less feasible. Why? Consolidating response with an MRD positive result post R-CHOP requires immediate and definitive action to prevent an impending relapse.

A one-time treatment with cema-cel could happen roughly 2-3 days post MRD positive test results. As we have seen, autologous CAR-Ts have had difficulty penetrating community cancer centers and accessing earlier line patients. Use of cema-cel won't rely on the same complex logistics that have hindered CAR-T adoption, nor will there be a reliance on referrals, as the intent is for CAR-T to be available in these community cancer centers. An allogeneic like cema-cel is what these doctors have been waiting for as entry to the modality in their centers. We believe these differentiated attributes of cema-cel cannot be reproduced by autologous CAR-T, bispecifics, or any other treatment modality. Startup activities for ALPHA3 have been initiated.

The study will randomize approximately 230 patients who are MRD positive at the end of frontline therapy, to either consolidation with cema-cel or the current standard of care, which is observation. The design, with the primary endpoint of event-free survival, will initially include two lymphodepletion arms, one with standard fludarabine and cyclophosphamide plus ALLO-647, and one without ALLO-647. The trial start is planned for mid-2024 and will be conducted in a wide array of cancer treatment centers, including community cancer centers, where most earlier line patients seek care. The outcome of this pivotal trial could allow cema-cel to potentially improve cure rates and become the only treatment approved for frontline consolidation, with the potential to significantly reduce the need for CAR-T in later lines. We look forward to answering any additional questions you have on our pipeline during the Q&A.

I'll now hand the call over to Jeff.

Geoffrey Parker (CFO)

Thank you, Zach. I'd like to echo David's comments made at the beginning of this call. It's been a very exciting few months speaking with current and prospective investors. The enthusiasm expressed for our strategy has been greatly appreciated and inspirational for our team. Such broad and unanimous enthusiasm is something that is unique in my career. We look forward to having ample opportunity to continue to share our vision and program updates throughout the year, especially on ALPHA3, TRAVERSE, our CLL trial, and ALLO-329, our CAR T 2.0 for autoimmune disease. Our vision is bold, and we recognize that cash runway is critical. We are pleased that the changes we've made following our announcement in early January have focused the strategy and extended our runway into 2026, but acknowledge that extending that runway must remain a focus.

Rest assured that while we actively manage costs, we will also be actively pursuing opportunities to build our cash reserves. We do, however, have a strong cash balance, ending 2023 with $448.7 million in cash, cash equivalents, and investments, and we have no debt. As we look ahead to a full year 2024, we expect a cash burn of approximately $190 million. We expect our full year 2024 GAAP operating expenses to be approximately $280 million, which includes estimated non-cash stock-based compensation expense of approximately $60 million. From a longer-term perspective, we continue to forecast that our cash runway will support our operations into 2026. This guidance excludes any impact from potential business development activities.

Full year 2023 research and development expenses were $242.9 million, which included $31.9 million in expenses associated with non-cash stock-based compensation. For the full year 2023, general and administration expenses were $71.7 million, which included $34 million of non-cash stock-based compensation expense. For the full year of 2023, our net loss was $327.3 million, or $2.09 per share, including non-cash stock-based compensation expense of $66 million and $13.2 million in non-cash impairment of long-lived asset expense. With that, we will now open the call for your questions.

Operator (participant)

Thank you. As a reminder, to ask a question, you will need to press star one one on your telephone. To remove yourself from the question queue, please press star one one again. You will be limited to one question before returning to the queue. Please stand by while we compile the Q&A roster. Our first question comes from the line of Tyler Van Buren of TD Cowen. Your question, please, Tyler.

Tyler Van Buren (Analyst)

Great. Hey, guys. Congrats on all the progress during the quarter. So I want to first ask about your autoimmune approach this time around. You know, I personally have been fascinated by the Dagger technology ever since it was unveiled at the November 2022 R&D day, when we saw a response in renal cell without ALLO-647 or the full FCA regimen. So I'm glad to see that technology being deployed to ALLO-329 for autoimmune disease. However, removing lymphodepletion altogether in AID takes it another big step further. So why do you think this is feasible in autoimmune, and how would you intend to test that in the early innings of clinical trials?

Maybe for a second question or half a question, forgive me, can you just briefly talk about the potential impact from the Biosecure Bill and WuXi to Allogene's business?

David Chang (CEO)

Hi, Tyler, Dave Chang here. Thanks for your questions, and I like how you sort of squeeze in that half question after the first one. You know, on the ALLO-329, I mean, this is a product, you know, from the design to how we are, you know, manufacturing. It's really built on, you know, being able to differentiate ALLO-329 from, you know, from other CAR T products that's going into the autoimmune indications. And, you know, this is already getting pretty in a crowded place. I mean, the key differentiation, as Zach had commented during the, you know, during the prepared remarks, is really there are three roles.

You know, one, this is a dual CD19, CD70 CAR, and what that allows the ALLO-329 to do is not just depleting the pathogenic B cells. It can also deplete CD70-positive activated T cells, which we believe play a pretty significant role in the autoimmune disease itself. The other part is, you know, you know, back to this, you know, concept of lymphodepletion. Being able to deplete the activated T cell allows, we believe, ALLO-329 or a CD70 Dagger-containing products to work well even as an allogeneic CAR T product without being dependent on having to use a CD52 antibody. So one, you know, the starting point for us is lymphodepletion is very much on par with what our colleagues, CD19 CAR T players are doing.

But we think that we can go even further. What CD70 Dagger can do is, you know, through going after activated T cells, and even if the expansion is much greater and also it has potential to start, you know, tapering off or eliminating the components of, lymphodepletion, either fludarabine or cyclophosphamide. And it's not just a laboratory concept. We actually have clinical data coming from our CD70 or ALLO-316 program from the TRAVERSE study. So I think this is going to be a very interesting proposition that we believe is critical, not, you know, just to conduct the study rapidly in the autoimmune indications, but also for the future commercial success.

And that sort of leads to, you know, the third point of, you know, ALLO-329, which is really the scalability, not only as an allogeneic, we also believe in the autoimmune indications, you know, the, the, the duration of the persistence. I don't think we need a long duration of CAR T persistence. This is really, you know, depleting the pathogenic lymphocytes deep enough so it can reset the immune system. So when we think about this, for the indication that we're going, you know, we believe that the construct ALLO-329 can be effective at very low cell dose. So we are very excited, and as we have said, you know, this is one of the top priority programs that we have for 2024, and our intent is to accelerate the timeline, as much as we can.

Currently, you know, we expect ALLO-329 phase 1 study to start in 2025, and the potential data readout, phase 1 data readout, at least the early portions, by the end of 2025. So second question, I'm gonna give a very brief response. I mean, you know, what's going on with Biosecure Bill and WuXi and Allogene? It doesn't impact Allogene at all. And, you know, that also leads to, you know, something that we have been talking about for some time. We always have believed and that manufacturing is core to our business. You know, for that reason, from early days, we built fully integrated CMC manufacturing team that covers not just process and analytic assay development, but the supply chain and manufacturing.

you know, that's really, you know, why we, you know, invested in building a fully dedicated allogeneic CAR T manufacturing facility, which we call CF1. That will be a very differentiated and distinctive advantage as we try to expand the use of CAR T, not only in heme, but also in AID, where we believe that scalability is the key.

Operator (participant)

Thank you. Our next question comes from the line of Salveen Richter of Goldman Sachs. Your question please, Salveen.

Salveen Richter (Analyst)

Good afternoon. Thanks for taking my question. With regard to your autoimmune disease program, apart from the Dagger technology here, could you speak to the strategy here with regard to bringing in, you know, the Arbor CRISPR-based gene editing technology and just how you think about, you know, indication, preference, starting out? Just maybe help us understand about that profile you're looking for, and then how you're gonna go after specific diseases within, the basket here.

Zachary Roberts (EVP of Research and Development and CMO)

Yeah, thanks, Salveen. This is Zach. Great question. So, you know, what we wanted to do with the Arbor partnership is really, you know, create new opportunities for us that, you know, would allow us to internalize that technology sort of independently and move away from the TALEN technology. And so, you know, the CRISPR-based platform that Arbor brings will allow us to have some flexibility in introducing site-specific integration, which we also believe will improve the overall product profile and safety profile of this for this unique patient population. So really it is a tool to allow us to go, you know, fast and in new directions with product design.

As far as the clinical trial goes, as we get a little bit closer to the launch of that program, we'll be, you know, eager to share more details. I, you know, I'm willing to sort of say and speculate at this point that, you know, we will be looking carefully over the data that matures in the coming months, from the field and, you know, learning what we can learn about inroads being made into other indications. Of course, lupus is the indication in which the clearest clinical proof of concept exists, and so we'll be, you know, carefully paying attention to that.

The design of the study, again, we'll, you know, we'll get into that as we get a little bit closer, but, you know, related to Tyler's question before, you know, we are very much looking at how far we can push this lymphodepletion reduction, as we can, including potentially testing, no lymphodepletion at all. So, you know, stay tuned for, more details on the clinical development plan as we get a little bit closer to the launch of the program in early 2025.

Operator (participant)

Thank you. Our next question comes from the line of Brian Cheng of J.P. Morgan. Your line is open, Brian.

Brian Cheng (Analyst)

Hey, guys. Thanks for taking my questions today. We're curious if you can walk through your latest thinking around the phase 1 for ALLO-329. Specifically, how many doses do you plan to execute? Are you doing dose escalation in autoimmune patients? And if so, which indications should we expect, since there are quite a few players now already in indications like lupus and myasthenia gravis? Thank you.

David Chang (CEO)

Hey, Brian, David Chang, I'll take that question. You know, great question. You know, what I can say is stay tuned. In terms of, you know, steps of dose escalation and lymphodepletion, I believe those are details that, given our team's track history in conducting the clinical studies, they can execute those pretty well. I more like, you know, to think about the objectives of the phase 1 study with 329. I mean, the three things that we have called out, the differentiation coming from being able to go after B cells and T cells, that's more of a biologic, clinical, you know, question that needs to be addressed through the conduct of studies and going after different indications.

But also, as we have called out, one of the important question that we wanna answer is whether we can administer, you know, ALLO-329 with reduced or with no lymphodepletion and have the same type of immune resetting phenomena. I think that will be really the focus of how we design the phase one study. And of course, you know, the, you know, trying to get that answer as quickly as possible, I mean, that leads to- that, that leads to, you know, a couple different study designs, but, you know, all these things are being discussed right now.

Operator (participant)

Thank you. All right, please stand by. Our next question comes from the line of Michael Yee of Jefferies. Your question, please, Michael.

Speaker 18

Hi, this is Mack on from Michael. Was wondering, you know, switching away from the autoimmune focus, thinking about the first line study for ALPHA3, how do you ensure that, this, you'll be able to enroll this study? And I guess, what gives you confidence in, your ability to enroll the study in a timely fashion? And I guess, as a corollary, when would we be able to expect some initial data from these patients? Thank you.

Zachary Roberts (EVP of Research and Development and CMO)

Hey, Matt, this is Zach. Thanks for the question. So, as far as the first part of your question, you know, why are we confident that this study will be able to be enrolled quickly? In a word, enthusiasm. I think, what we have seen so far as we have reached out to investigators across the treatment spectrum from, you know, academic KOLs, who have been part of the CAR T story for 10, 15 years, all the way to community oncology practices that have a large volume of patients, but have not yet made the jump into CAR T. The response to the study has been uniform, and it's been extremely positive. We are seeing levels of engagement from investigators, clearing obstacles to open the program as quickly as they can.

We've seen that left and right. So there is a palpable level of enthusiasm around this concept, really driven by the possibility of curing patients after frontline and preventing a relapse from ever occurring. This is a very novel and innovative approach to studies in LBCL, and people are really excited to be part of that. As far as data goes, you know, as we get a little bit closer to the start of the study in mid-year of this year, I think we'll be in a position to provide a little more clarity on when enrollment is going to complete and when data will be available.

What we have said, and I'll reiterate here, is that, you know, the study is designed to have an interim analysis that is currently slated for middle of next year, when we will examine MRD conversion from positive to negative. Everybody that comes into the study will be MRD positive, so we're looking for evidence of clearance of MRD, as well as safety and translational outcomes. And we will use that interim analysis to select the lymphodepletion arm that will be carried forward for the rest of the accrual period. So as we pass through that gate, we will make a modification to the study design, and that will be plainly visible to all who are paying attention.

We will not, however, be able to share granular detail from that analysis because this study is pivotal from the very first patient that's enrolled. So all of these patients, starting again, middle of this year, will count towards the overall N that's required for the pivotal study. So, lest we jeopardize trial and data integrity by sharing those results, we will not be sharing a data update at the middle of next year.

David Chang (CEO)

And Brian, you know, I would add, you know, I like the question about your focus on enrolling the patient and execution of the study, which I think is the key. When, you know, when you look at what we are doing in ALPHA3, I mean, that's built on all the data that we have generated from the ALPHA2 in relapsed/refractory large B-cell lymphoma setting. I mean, we shared that data before with all of you, and this is really on par with autologous CAR T therapy, which I don't think any of the other allogeneic CAR T companies can say that yet. And, you know, from the technical perspective, we believe that this is highly de-risked. I mean, after all, this is comparing against observation, you know, watch and wait. So we feel pretty good about that.

Execution is the key, and frankly, I think, you know, study start and enrollment, I think that is a pretty significant de-risking information about the ALPHA3 study. So stay tuned. I mean, our team's working, you know, really hard to make sure that we execute this study as quickly as possible.

Operator (participant)

Thank you. Our next question comes from the line of Jack Allen of Baird. Please go ahead, Jack.

Jack Allen (Analyst)

Great, thanks for taking the question, and congratulations on the progress. I'm kind of same vein as the last question. I wanted to ask about that interim analysis in the middle of 2025. I understand that it sounds like you may not be planning to outwardly share the results, but any context you can provide around the number of patients you're looking to have for that data set? And is there an internal bar you're thinking about that you're looking to reach as it relates to pushing the study forward past that interim analysis? Thanks so much.

Zachary Roberts (EVP of Research and Development and CMO)

Hey, Jack, thanks for the question. So we haven’t gone into detail about how many patients are gonna be included in that analysis. I’ll say that it’s sort of, you know, maybe unhelpfully, not too many, not too few. We want to have enough statistical power to make a good call. And with respect to the second part of your question, you know, how are we going—is there an internal bar that we’re gonna be looking for? So there’s really two parts to this, right? We wanna make sure that we are improving upon the standard of care, which is watch and wait. And we think, as David pointed out, that, you know, we’ve largely de-risked that question through our experience in phase 1. We know that cema-cel is an active therapy.

So we think that we will be able to clear that bar, but of course, we'll be paying attention to it. And then, of course, we have an additional set of criteria that we'll be using to make the selection of FCA versus FC. So, you know, this is a very well thought out, prospectively designed analysis, that we think is gonna lead us to the right answer.

Operator (participant)

Thank you. Our next question comes from the line of John Newman of Canaccord Genuity. Your line is open, John.

John Newman (Analyst)

Hi, guys. Thanks a lot for taking the question, and thanks for all the updates. Just curious if you could comment a little bit more regarding the potential targets in autoimmune disease. So obviously, your approach, is dual targeting. Other companies out there are also looking at CD19, but some are looking at CD20, and we have additional companies with BCMA CAR Ts that are sort of considering treatment of autoimmune disease, namely lupus. Can you say which targets could be better, and why? Obviously, different targets sort of crop up at different times during the life cycle of B cells, but just curious as to your thinking on that. Thank you.

David Chang (CEO)

Yeah. So in terms of, John, you know, great question, and, you know, frankly, I think, you know, this is a topic that, you know, we are sort of looking into. But, you know, ultimately, I believe that when you look at the ontogeny of these cells, the targets that you have mentioned, you know, CD19, CD20, and BCMA. If you look at the, you know, the coverage of CD19 expression, that's probably, you know, most broad and probably is better suited than other targets. But, you know, this is, you know, something that we also have to find out from, you know, the clinical data as different players test these different targets. You know, the other question around the indications that, you know, we are interested in.

You know, we can sort of think about this from, you know, generating early proof of concept of not requiring a lymphodepletion, if that is the primary objective, and actually that is. Indications where the proof of concept has been established with a CD19 autologous CAR T would be very good. Also lupus nephritis is, you know, commercially, a very attractive indication as well. So lupus is definitely in the play. I know it's getting crowded, but remember, our ALLO-329 has a very distinct and differentiated approach. So you know, if we can differentiate from others, I think we will have a good traction even in the crowded field.

Also being able to go after, you know, the activated T cells, potentially opens the door to other autoimmune diseases, where going after CD19 alone may not be sufficient. You know, multiple sclerosis as a class of disease is one, autoimmune diseases that affect the nervous system, I think that also falls in. Frankly, yes, you know, we have to be focused, and we have to go after certain indications. You know, right now, I don't think we have to decide, and we have enough time to finalize that decision in the next, 3-4 months, so stay tuned.

Operator (participant)

Thank you. Our next question comes from the line of Sami Corwin of William Blair. Your question, please, Sami.

Caleb Wong (Analyst)

Hi, this is Caleb Wong for Sami Corwin. Thanks for taking the question. So given the number of CAR T cell companies pursuing autoimmune disease indications, how are you guys thinking about competing for patients in future trials? Would you be more focused on enrolling patients in U.S. or ex-U.S., or a combination of both?

David Chang (CEO)

You know, I think, you know, that's a relatively, you know, you know, you know, simple to me. I mean, when you think about, you know, there are, you know, multiple different companies, taking different assets into the autoimmune indication, yes, it is true. But when you think about in a number of potential patients that are out there, you know, what, you know, the current clinical studies are covering is, you know, not even a tip of an iceberg. I mean, you are probably talking about, you know, fewer than 100 patients out of, you know, 20, 30, 100,000 potential patient population that we can go after. So our view is, you know, we are less concerned about that as long as, we maintain the differentiation.

And frankly, if you can get rid of the lymphodepletion, I think the opportunity to do a quick clinical, you know, you know, development program, that just becomes a more real and, you know, something that we can easily do, you know, very quickly.

Operator (participant)

Thank you. Our next question comes from the line of Kelsey Goodwin of Guggenheim. Please go ahead, Kelsey.

Kelsey Goodwin (Analyst)

Oh, hey, good afternoon, and thanks for taking my question. Mine is on CLL. How do you think about the ideal placement for CAR T, given kind of the age of this patient population and the durability that we see with BTKs and BCL-2 inhibitors? Thank you.

Zachary Roberts (EVP of Research and Development and CMO)

The question was around the durability that we can expect?

Kelsey Goodwin (Analyst)

More so the positioning and, you know, what kind of patients would you want to get on this, given kind of the age at diagnosis and how durable the responses are with the inhibitors that are already approved?

Zachary Roberts (EVP of Research and Development and CMO)

Yes. Okay. Thank you. So well, as a reminder, the study will enroll patients that have BTK inhibitors and BCL-2. Now, there is a non-covalent BCL BTK inhibitor, pirtobrutinib, that's been approved. That has shown that in a similar patient population, there is some benefit to that drug. However, similar to the established modalities, this is non-curative. And so what we have seen from the autologous experience in CD19 for CLL is that, you know, some patients, a significant fraction of these patients can actually have very meaningful, durable, complete remissions that go on for months or even years, and so, and in a patient population that has failed these prior therapies. So-...

You know, number one, I think that the modality is promising in this patient population. Number two, I'll point out that, you know, just looking at our experience from LBCL, is that our toxicity profile is wholly consistent with a somewhat more frail population, with very low rates of high-grade CRS and ICANS, and consistent with outpatient dosing, which we do have experience with. So, you know, while we are, you know, getting our feet wet with this phase I study and getting ready to share data later on this year, we will be paying very close attention to how that toxicity profile plays out in this patient population, as well as, you know, being able to meet or even exceed the bar that has been established by the autologous players.

Operator (participant)

Thank you. Our next question comes from the line of Reni Benjamin of JMP Securities. Please go ahead, Reni.

Reni Benjamin (Analyst)

Thanks, guys. Thanks for taking the questions, and congrats on the, on the progress. Maybe just, continuing with the, thought of questions around CLL. What would you consider to be kind of the go, no-go, you know, results that you would like to see by the end of this year? You know, I, I know there's only gonna be about 12 patients worth of data. Just, you know, how do you, how do you plan on kind of dissecting that? And, and I guess just as a second part of that, you know, just given your experience with LBCL, do you think there might be an opportunity to move cema-cel to some type of a consolidation or more of a frontline, you know, treatment, in combination with drugs that are already out there?

I remember way back when, you know, Kite, Juno, were thinking about combination studies in a frontline setting, and just wanted to know how you guys were thinking about this. Thanks.

Zachary Roberts (EVP of Research and Development and CMO)

Yeah. So as far as the bar for, you know, internal decision-making, of course, we'll watch the data as it rolls in. But I'll again point out that the bar is not all that high here. And actually, that's one of the things that, you know, why we believe that moving into CLL is exactly the right thing that we should be doing with cema-cel. Because, you know, the data that's before the FDA right now suggests that, you know, an improvement of, you know, 50% ORR and a, you know, sub 20% CR rate, is something that is, you know, probably, well, not probably, is attractive to the treating physicians and patients who are in this predicament of having failed the approved therapies.

So we'll be watching, you know, the FDA's response to that data set very carefully, and as our data matures, being able to make a decision about whether to move that into a phase II registrational study. As far as the other question goes with respect to consolidation and/or combinations, I do think that that that is an attractive avenue to pursue, and in fact, you know, our focus in consolidation and large B-cell with ALPHA3 is a testament to our belief that a consolidation strategy or treatment with CAR T-cells when the disease is at a relative nadir is a very interesting proposition and can be applied to other indications as well.

Combination's a little bit more of a challenging idea, but it certainly has been floating around, and I think there's a strong biological rationale to do that. And so we'll be, you know, looking at that carefully as the program matures as well.

Operator (participant)

Thank you. Our next question comes from the line of Kalpit Patel of B. Riley Securities. Please go ahead, Kalpit.

Kalpit Patel (Analyst)

Yeah, hey, thanks for taking the question. Maybe just one on ALLO-329. Can you discuss any thoughts on broader immunomodulatory effects beyond direct cytotoxicity, such as any impact on regulatory T cells, since you know you have targeting of CD70? And how might these effects influence outcomes for autoimmune disease patients?

Zachary Roberts (EVP of Research and Development and CMO)

Thanks, Kalpit. Good question. So you know, that is the detailed work on sort of the subsets of T-cells is ongoing in the context of our three-one-six program, and so really trying to understand, you know, are there certain compartments within that T-cell, you know, lymphocyte population that are more differentially affected by, by, CD70 targeting therapy. So, you know, we're doing that work in the context of our ongoing three-one-six, and in fact, you know, a good strong support for this idea of being able to target activated T-cells has now been demonstrated, as David mentioned, from the translational results from the TRAVERSE trial.

So, you know, I think what we can take away, knowing what we know from our in vitro work and the clinical trial with CD70 CAR, is that we do see differential suppression of activated T-cells. And we know that those activated T-cells, be they conventional or regulatory, are involved in autoimmune pathogenesis. And so, there's, you know, literature that supports the role of CD70 in certain autoimmune disorders, like lupus. And so, you know, we think that in addition to the Dagger effect, which is one of the key reasons that we're pursuing CD70 as a dual CAR with ALLO-329, we do think we'll be able to modulate the specific activated subset of those T-cells.

And so we'll look at the careful, you know, subpopulations as we execute the ALLO-316 study, and of course, we'll be paying a close attention to that within ALLO-329.

Operator (participant)

Thank you. Our next question comes from the line of Luca Issi of RBC Capital. Please go ahead, Luca.

Luca Issi (Analyst)

Oh, great. Thanks so much for taking my question, and congrats on all the progress. Maybe, Zach, can you just expand a little bit more on the interim look in mid-2025? I think when you were running the trial in the third line settings, the FDA basically asked you to show PFS superiority when you actually add anti-CD52 versus no anti-CD52 in a dedicated randomized trial. However, it looks like the FDA is not okay with just showing patients converting from MRD positive to MRD negative within the context of the same pivotal trial and actually not a separate trial, which is not randomized. Like, it feels to me that the FDA has kind of lowered the bar here despite your actually moving in earlier settings. 1, would that be fair? And 2, if so, what drove that change in posture from the regulators?

Any thoughts there? Much appreciated.

Zachary Roberts (EVP of Research and Development and CMO)

So I don't, I don't think. Thanks, Luca, for the question. I don't think that there's been a change in the FDA's opinion on what would constitute a contribution of effect data package. I think what we have done in the design of ALPHA3 is condense the what was two trials in the third line setting into a single trial in the frontline consolidation setting. So we've really got a, in a way of speaking, a trial within a trial. And the first part of the study that will culminate with the interim analysis next year is designed to generate the contribution of effect that will support the registration of ALLO-647.

Now, that said, you know, the reason that we're running this part of the study, the way we're running it in a randomized fashion, is because, you know, we wanna actually address the scientific question of whether ALLO-647 is truly required in these patients with no radiographic evidence of disease. And so there is still a chance, I would say a good chance, that we select the arm that does not contain ALLO-647. So, but be that as it may, the reason that we have designed it, how we have done it, is to specifically address the FDA's requirement for ALLO-647. So I would not say that there has been a change in regulatory stance there.

Operator (participant)

Thank you. Our next question comes from the line of Asthika Goonewardene of Truist. Please go ahead, Asthika.

Karina Rabayeva (Analyst)

Hi, this is Karina for Asthika. Thanks for taking the question. Following up on CLL, liso-cel has generated an 18% CR rate. How might the efficacy of Allogene CAR T compare to autologous in CLL, and particularly considering the potentially superior T cell fitness? And also, what data would you like to see in evaluating the efficacy of Allogene CAR T in this context?

Zachary Roberts (EVP of Research and Development and CMO)

Thanks, Karina. So I think I like the way you asked that question because I think it really speaks to a primary motivator for us opening this trial, and that is that we believe that the underlying T cell fitness coming from a healthy donor-derived product is going to be superior to the T cell fitness that is derived from a patient leukapheresis, because CLL is a notoriously immunosuppressive malignancy, number one. Number two, often those T cells are surrounded by a very high circulating leukemic burden, which makes isolation of those cells for manufacturing all the more difficult. We, you know, we dodge both of those problems, starting with healthy donor material.

So we think that there is a chance that we will actually have a meaningful improvement over what has been shown by autologous, but of course, that's why we're running the experiment. And, you know, I've sort of addressed what we think the target is here. Of course, the 18% CR rate that's been established as, you know, potentially registerable. We'll see what happens with the decision by the FDA there. But, you know, we think that given the comparability that we believe we've shown in large B-cell against autologous products, that we should at least be able to meet that.

Operator (participant)

Thank you. Our next question comes from the line of Laura Prendergast of Raymond James. Your question, please, Laura.

Laura Prendergast (Analyst)

Hey, guys. Thanks for taking the question. So I'm just curious, you know, as MRD testing, you know, as expected, becomes more broadly used, do you expect it having any issues enrolling ALPHA3, especially since, you know, some patients will be randomized to a control arm with no therapy? You know, how do you think about this, and if you expect, you know, in the future, competition in this setting, given the broad use of MRD testing?

Zachary Roberts (EVP of Research and Development and CMO)

Thanks, Laura. So we are not worried in the least about the patients who are gonna be randomized to observation. That is the current standard of care, and that means that these patients, there is no data anywhere, let alone an approved agent, to direct the physicians to offer another line of therapy to patients who are in the observation arm. So we don't think that there... In fact, we know for a fact, based on the work that we've done already during the study startup, that there is wide agreement that this is the most appropriate management for these patients, which is the current standard of care observation.

These patients will be monitored very closely in the context of a clinical trial, probably as closely, if not more so, than they would be were they not participating in a clinical trial. That's the nature of clinical investigation, and this is going to be part of why we think patients will be willing to sign up for this study. As far as competition goes, there is a good chance that at some point we will see some company in the development of agents for patients with MRD only disease. We do think that we have a unique product profile with you know, one-time administration, so there's no need for a long period of treatment or maintenance therapy.

This is, as we said, kind of a 7th cycle of treatment these patients can get and just go home and move on. And number two, there's these patients can progress very quickly after they complete frontline therapy, and they have MRD disease. So being able to act definitively and very rapidly, and I'll remind you that we initiated treatment within 2 to 3 days after patients are enrolled in our third-line study. So we know that we can we can affect this treatment extremely quickly. So we think we have a built-in advantage with our modality, and that's on top of the strong lead advantage that we have, having you know, launched this study before any of our competitors.

Operator (participant)

Thank you. Our next question comes from the line of William Pickering of Bernstein. Please go ahead, William.

William Pickering (Analyst)

Hi, thank you for taking my question. In your ALPHA3 trial, you've talked about including community centers. Could you speak to the level of interest that you're getting from these centers? Do you expect it to be a large or small percent of total sites? And do these centers need to already be FACT accredited to participate? Thank you.

Zachary Roberts (EVP of Research and Development and CMO)

So, I will say that the reception that we have gotten from these community practices has been very, very positive and very. There's a high level of engagement and enthusiasm. Many of them are moving extremely quickly to be ready to open the study. You know, there's even a little bit of friendly competition among some of them to really be the first to open. So, you know, we've been very encouraged by the reception that we have gotten. As far as the percentage goes, it's gonna be... We're definitely gonna have some academic centers because they are as excited about this concept as the community oncologist. So there's gonna be, you know, a continuum. You know, we don't exactly know yet.

We haven't completed the full selection of the entire panel of programs. But I will say that there will be a substantial percentage of patients coming from these community practices in the overall study.

William Pickering (Analyst)

Thank you.

Operator (participant)

Thank you. I would now like to turn the conference back to David Chang for closing remarks. Sir?

David Chang (CEO)

All right, thank you for joining on our call today and your continued support. We are more excited about than ever about the potential for Allogene and the opportunity to fulfill the promise of Allogene CAR T for patients with cancer, and now extending that promise to patients with autoimmune disease with our CAR T 2.0, ALLO-329. As someone who has been involved in developing cell therapies, I'm particularly excited about what's happening in the field today, thinking differently and putting innovation at the forefront. That is exactly what is needed to fuel this new resurgence in cell therapy. I look forward to providing updates to our exciting programs throughout the year. With that, goodbye.

Operator (participant)

This concludes today's conference call. Thank you for participating. You may now disconnect.