Allogene Therapeutics Inc

NASDAQ:ALLO

Earnings Call Analysis

Allogene Therapeutics' Promising CAR-T Advancements

In Allogene Therapeutics' latest earnings call, they spotlight their development of off-the-shelf CAR-T therapies, with a keen focus on novel trials and future patient needs. Notably, the ALPHA3 trial is aiming for a curative first-line treatment for large B-cell lymphoma, with the potential to redefine standard care and generate over $3 billion in U.S. revenue alone. The company also discussed ALLO-329, targeting autoimmune disease with a uniquely designed dual-targeting CAR-T therapy, set for Phase I trials in early 2025. Additionally, the ALPHA2 cohort addresses chronic lymphocytic leukemia, targeting a $3 billion opportunity. The TRAVERSE trial's advances with ALLO-316 in renal cell carcinoma operate under a pioneering approach to solid tumors, expecting a significant update by the end of 2024.

Pivotal Trial and Dual CAR Development Emphasize Innovation

The company is progressing with a clear focus on enhancing its portfolio, especially with developments such as the CD70 dual CAR with ALLO-329. By examining specific T cell subsets, it aims to verify the theory behind the Dagger effect, which is instrumental in the company's strategy of modulating immune responses against malignancies.

Navigating Regulatory Pathways for ALLO-647 Approval

A pivotal trial, the ALPHA3 trial, is underpinning the company's regulatory strategy to garner approval for ALLO-647. Planned interim analysis in mid-2025 will crucially determine its role in treatment. The trial is also designed to test if ALLO-647 is indeed necessary for patients without apparent radiographic disease. Even though the FDA remains stringent on the contribution of effect data, the single trial approach in the frontline consolidation setting could prove advantageous.

Promising T Cell Fitness Advantage in CLL

When discussing the treatment efficacy disparities between alloCAR T and autologous CAR T in CLL, the company is betting on superior T cell fitness originating from healthy donors. This fitness edge could potentially translate into improved clinical responses, notably challenging the 18% CR rate benchmark set by autologous products in CLL.

ALPHA3 Enrolment Optimism Despite MRD Testing Trends

With MRD testing likely to become more prevalent, the company remains confident in ALPHA3 trial enrolment. The standard of care for the proposed control arm is observational, and clinical trials could provide more vigilant patient monitoring. Furthermore, with a one-time administration, the company distinguishes itself by offering rapid and definitive intervention, in contrast to extended treatment regimens, positioning itself ahead of potential competitors.

Community Centers Exhibit High Engagement for ALPHA3 Trial

To facilitate the ALPHA3 trial, the company is including community centers alongside academic institutions. These centers have shown robust interest and eagerness, with a dynamic environment pointing to a blend of site types for the final selection. With community practices expected to contribute significantly, the outreach into non-academic settings is already promising, reflecting a diverse and engaged study milieu.

Renewed Excitement for CAR-T Potentials in Cancer and Autoimmune Disease

In conclusion, the company demonstrates a reinvigorated enthusiasm for its innovative CAR-T applications, extending now to autoimmune diseases with CAR-T 2.0 ALLO-329. The company's commitment to innovation and development in cell therapy is poised to foster a new wave of advances in treatment for patients with diverse medical needs.

Earnings Call Transcript 2023-Q4

[Operator]

Thank you for standing by, and welcome to Allogene Therapeutics' Fourth Quarter and Full Year 2023 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.

[Christine Cassiano, executive]

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 1 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, executive]

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 ] the renewed enthusiasm for biotech and even more so a resurgence in cell therapy. I would argue this is also true for Allogene, our sentiment seemingly shared by many of our investors following the pivot we announced at the beginning of 2020 fall.

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 CAR-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. [indiscernible], which is 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 a 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 minimum 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 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 I trial in early 2025.

Our next 2 core programs also lean into attributes of allogeneic CAR-T. Our new ALPHA2 cohort for cema-cel in chronic lymphocytic leukemia, or CLL, aims to address the growing unmet need among patients whose disease are not controlled by DTK and/or BCL-2 inhibitors. Relapsed/refractory CLL in the 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 any 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 progress.

[Zachary Roberts, executive]

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 to 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 onetime dose and simpler administration and logistics. The new Phase I ALPHA2 2 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 a 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 I 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. By 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 2 things to come together, a highly accurate MRD assay and a onetime 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 I ALPHA3 trial and leverages the investigational cutting-edge diagnostic test developed by Foresight diagnostics to identify patients who have minimal residual disease at the completion of frontline chemoimmunotherapy for treatment with cema-cel. Approximately 1/3 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 onetime off-the-shelf treatment that can be administered immediately upon discovery of MRD following 6 cycles of our 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 of administration of CAR T therapies to patients with low disease burden improves both safety and efficacy outcomes. Cema-cel Phase I 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 onetime treatment with cema-cel could happen roughly 2 to 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. Start-up 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 for the current standard of care, which is observation.

The design with the primary endpoint of event-free survival will initially include 2 lymphodepletion arms, one with standard fludarabine and cyclophosphamide plus ALLO-647 and 1 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 or most earlier line patients who seek care. The outcome of this pivotal trial could allow cema-cel to potentially improve curates 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, executive]

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 noncash 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 noncash stock-based compensation.

For the full year 2023, general and administration expenses were $71.7 million, which included $34 million of noncash stock-based compensation expense. For the full year of 2023, our net loss was $327.3 million or $2.09 per share, including noncash stock-based compensation expense of $66 million and $13.2 million in noncash impairment of long-lived asset expense.

With that, we will now open the call for your questions.

[Operator]

[Operator Instructions] Our first question comes from the line of Tyler Van Buren of TD Cowen.

[Tyler Van Buren, analyst]

Congrats on all the progress during the quarter. So I wanted to first ask about your autoimmune approach this time around. I personally have been fascinated by the Dagger technology ever since it was unveiled at the November '22 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 and AID takes 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. And 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, executive]

Tyler, Dave Chang here. Thanks for your questions. And I like how you're sort of squeezing that half question after the first one. On the ALLO-329, I mean, this is a product from the design to how we are manufacturing. It's really built on being able to differentiate ALLO-329 from other CAR T products that's going into the immune indications. And this is already getting pretty in a crowded place. .

I mean the key differentiation as Zack had commented during the prepared remarks is really there are 3 folds. 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, back to the -- in the concept of lymphodepletion. Being able to deplete the activated T cell allows, we believe, ALLO-329 or 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, the starting point for us is lymphodepletion is very much on par with what [indiscernible] CD19 CAR-T players are doing. But we think that we can go even further. What CD70 Dagger can do is through -- going after activated T cells and even the expansion is much greater and also it has potential to start tapering off or eliminating the components of lymphodepletion, either fludarabine a 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 just to conduct the study rapidly in the autoimmune indications but also for the future commercial success.

And that sort of leads to the third point of ALLO-329, which is really the scalability. Not only as an allogeneic, we also believe in the autoimmune indications, the duration of the persistence, I don't think we need a long duration of CAR T persistence. This is really 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, 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, this is one of the top priority programs that we have for 2024.

And our intent is to accelerate the time line as much as we can. Currently, we expect ALLO-329 Phase I/II study to start in 2025, the potential data readout -- Phase I data readout, at least the early portions by the end of 2025. so second question, I'm going to give a very brief response. I mean what's going on with BIOSECURE Bill and WuXi and Allogene, it doesn't impact Allogene at all. And that also leads to something that we have been talking about for some time. We always believe that manufacturing is core to our business. 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. And that's really why we invested in building a fully dedicated allogeneic CAR-T manufacturing facility, which we call CF 1 and that will be a very differentiated and distinctive advantage as we try to expand the use of CAR-T not only in hem/onc but also in AID, where we believe the scalability is the key.

[Operator]

Our next question comes from the line of Salveen Richter of Goldman Sachs.

[Salveen Richter, analyst]

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 the Arbor, CRISPR-based gene editing technology and just how you think about indication, preference starting out? Just maybe help us understand about that profile you're looking for and then how you're going to go after specific diseases within the basket here.

[Zachary Roberts, executive]

Thanks, Salveen. This is Zach. Great question. So what we -- what we wanted to do with the Arbor partnership is really create new opportunities for us that would allow us to internalize that technology sort of independently and move away from the TALEN technology. And so 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 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 eager to share more details. I'm willing to sort of say and speculate at this point that we will be looking carefully over the data that matures in the coming months from the field and 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 will be carefully paying attention to that. The design of the study, again, we'll get into that as we get a little bit closer. But related to Tyler's question before, 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 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]

Our next question comes from the line of Brian Cheng of JPMorgan.

[Lut Ming Cheng, analyst]

We're curious if you can walk through your latest thinking around the Phase I 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.

[David Chang, executive]

Brian, DAVE Chang, I'll take that question. Great question. What I can say is stay tuned. In terms of steps of dose escalation and lymphodepletion, I believe those are details that given our team's history and conducting the clinical studies, they can execute those pretty well. I more like to think about the objective of the Phase I study with 329. I mean there are 3 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 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 questions that we want to answer is whether we can administer ALLO-329 will reduce or with no lymphodepletion and have the same type of immune resetting phenomenon. I think that will be really the focus of how we design the Phase I study. And of course, trying to get that answer as quickly as possible. I mean that led to -- that leads to a couple of different study designs, but all these things are being discussed right now.

[Operator]

our next question comes from the line of Michael Yee of jefferies.

[Unknown Analyst]

This is [ Mac ] on for Michael. I was wondering, switching away from the autoimmune focus, thinking about the first-line study for ALPHA3. How do you ensure that 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. I guess, as a corollary, when would we be able to expect some initial data from these patients

[Zachary Roberts, executive]

Matt, this is Zach. Thanks for the question. So as far as the first part of your question, 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 academic KOLs who have been part of the CAR T story for 10, 15 years, all the way to community oncology practices that 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.

And 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 innovative approach to studies in LBCL and people are really excited to be part of that. As far as data goes, we -- as we get a little bit closer to the start of the study in midyear 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 -- we -- 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. And so all of these patients starting again, middle of this year will count towards the overall end that's required for the pivotal study. So unless we jeopardize trial integrity by sharing those results, we will not be sharing a data update at the middle of next year.

[David Chang, executive]

And [ Brian ], I would add, I like the question about your focus on enrolling the patient, execution of the study, which I think is the key. 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 from the technical perspective, we believe that this highly derisked. I mean, after all, this is comparing against observation, watch and wait. So we feel pretty good about that.

Execution is the key. And frankly, I think study start and enrollment, I think that is a pretty significant derisking information about the ALPHA3 studies. So stay tuned. I mean our team is working really hard to make sure that we execute this study as quickly as possible.

[Operator]

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

[Jack Allen, analyst]

Congratulations on the progress. In 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?

[Zachary Roberts, executive]

Jack, thanks for the question. So we haven't gone into detail about how many patients are going to be included in that analysis. I'll say that it's sort of 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, how are we going -- is there an internal bar that we're going to be looking for.

So there's really 2 parts to this, right? We want to make sure that we are improving upon the standard of care, which is watch and wait. And we think, as David pointed out, that we've largely derisked that question through our experience in Phase I. We know that cema-cel is an active therapy. So we think that we will be able to clear that ball. 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 this is a very well thought out prospectively designed analysis that we think is going to lead us to the right answer.

[Operator]

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

[John Newman, analyst]

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 for autoimmune disease, namely lupus. Can you say which targets could be better? And why? Obviously, different targets sort of crept up at different times during the life cycle of B cells. But just curious as to your thinking on that.

[David Chang, executive]

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

The other question around the indications that we are interested in. we can sort of think about this from 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 the CD19 CAR T would be very good. And also lupus/nephritis is commercially 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 if we can differentiate from others, I think we have a good -- we will have a good traction even in the crowded field. but also being able to go after the activated T cells potentially opens the door to other autoimmune diseases, where going up to CD19 may not be sufficient and multiple sclerosis as a class of disease is one. Autoimmune diseases that affect the nervous system, I think that also falls in. So frankly, yes, we have to be focused and we have to go after certain indications. But right now, I don't think we have to decide and we have enough time to finalize that decision in the next 3 to 4 months. So stay tuned. .

[Operator]

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

[Unknown Analyst]

This is [indiscernible] for Sami Corwin. 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 the U.S. or ex U.S. or a combination of both?

[David Chang, executive]

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

So our view is 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 opportunities to do a quick development program that just becomes a more real and something that we can easily do very quickly.

[Operator]

Our next question comes from the line of Kelsey Goodwin of Guggenheim.

[Kelsey Goodwin, analyst]

Mine 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 BCL2 inhibitors? .

[Zachary Roberts, executive]

The question was around the durability that we can expect?.

[Kelsey Goodwin, analyst]

More so than a positioning and 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, executive]

Yes. Okay. Thank you. So well, as a reminder, that study will enroll patients that have [ BTK ] Inhibitors and BCL2. Now there is a noncovalent BCL BTKinhibitor, pertibrutinib 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 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. Number one, I think that the modality is promising in this patient population. Number two, I'll point out that 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 while we are 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 being able to meet or even exceed the bar that has been established by the autologous players.

[Operator]

Our next question comes from the line of Reni Benjamin of JMP Securities.

[Reni Benjamin, analyst]

Congrats 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 results that you would like to see by the end of this year? I know there's only going to be about 12 patients worth of data. Just how do you plan on kind of dissecting that. And I guess, just as a second part of that, 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 treatment in combination with drugs that are already out there. I remember way back when Kite, Juno were thinking about combination studies in a frontline setting. And just wanted to know how you guys were thinking about this?

[Zachary Roberts, executive]

Yes. So as far as the bar for 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 why we believe that moving into CLL is exactly the right thing that we should be doing with cema-cel because the data that's before the FDA right now suggests that an improvement of 50% ORR and a sub-20% CR rate is something that is 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 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 is an attractive avenue to pursue. And in fact, our focus in consolidation in 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 that are relative nadir is a very interesting proposition and can be applied to other indications as well. Combination is 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 looking at that carefully as the program matures as well.

[Operator]

Our next question comes from the line of Kalpit Patel of B. Riley Securities.

[Kalpit Patel, analyst]

Yes. 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 have targeting a CD70? And how might these effects influence outcomes for autoimmune disease patients?

[Zachary Roberts, executive]

Thanks, Kalpit. Good question. So that is the detailed work on sort of the subsets of T cells is ongoing in the context of our 316 program. And so really trying to understand are there certain compartments within that T-cell lymphocyte population that are more differentially affected by CD70 targeting therapy. So we're doing that work in the context of our ongoing 316. And in fact, 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 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 the conventional or regulatory or are involved in autoimmune pathogenesis. And there's literature that supports the role of CD70 in certain autoimmune disorders like lupus. And so 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 subpopulations as we execute the 316 study. And of course, we'll be paying close attention to that within 329.

[Operator]

Our next question comes from the line of Luca Issi of RBC Capital.

[Luca Issi, analyst]

Congrats on 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 setting, the FDA basically asked you to show PFS superiority when you actually [indiscernible] in a dedicated randomized trial. However, it looks like the FDA is not okay. We're 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, but feels to me that the FDA has kind of lowered the bar here despite your action moving in earlier settings. One, would that be fair? And two, if so, what drove that change in posture from the regulators? Any thoughts there much appreciate it

[Zachary Roberts, executive]

So I don't -- 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 condensed was 2 trials in the third-line setting into a single trial in the frontline consolidation setting. So we've really got, 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, the reason that we're running this part of the study, the way we're running it in a randomized fashion, is because we want to 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 even -- that does not contain ALLO-647. 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 COE for 647. So I would not say that there has been a change in regulatory stance there .

[Operator]

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

[Karina Rabayeva, analyst]

This is Karina for Asthika. Following up on CLL, [ [indiscernible] has generated an 18% CR rate. How might the efficacy of alternate CAR T compared to autologous in CLL and particularly considering the centrally superior T cell fitness. And also what data would you like to see in validating the efficacy of AlloCAR T in this context?

[Zachary Roberts, executive]

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 CLLs are 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 dodged 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 I've sort of addressed what we think the target is here, of course, the 18% CR rate. That's been established as potentially registerable. We'll see what happens with the decision by the FDA there. But 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]

Our next question comes from the line of Laura Prendergast of Raymond James.

[Laura Prendergast, analyst]

I'm just curious, is MRD testing as expected becomes more broadly used, do you expect having any issues in enrolling ALPHA3, especially since some patients will be randomized to a control arm with no therapy? How do you think about this? And if you expect in the future competition in this setting, given the broad use of MRD testing?

[Zachary Roberts, executive]

Thanks, Laura. So we don't -- we are not worried in the least about the patients who are going to 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 in -- during the study start-up that there that there is a 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, then they would be [indiscernible] 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. And 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 onetime administration, so there's no need for a long period of treatment or maintenance therapy. This is, as we said, kind of a seventh 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 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 launched this study before any of our competitors

[Operator]

Our next question comes from the line of William Pickering of Bernstein.

[William Pickering, analyst]

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 a small percent of total sites. And do these centers need to already be [indiscernible] to participate?

[Zachary Roberts, executive]

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 there's even a little bit of friendly competition among some of them to really be the first to open. So we've been very encouraged by the reception that we have gotten

As far as the percentage goes, it's going to be -- we're going to -- we're definitely going to have some academic centers because they are as excited about this concept as the community oncologist. So there's going to be a continuum 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

[Operator]

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

[David Chang, executive]

Right. Thank you for joining on our call today and your continued support. We are more excited than ever about the potential for Allogene and the opportunity to fulfill the promise of allogeneic CAR-T for patients with cancer and now extending the 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]

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